JP2010053079A - 5-aminolevulinic acid derivative and its salt - Google Patents
5-aminolevulinic acid derivative and its salt Download PDFInfo
- Publication number
- JP2010053079A JP2010053079A JP2008220006A JP2008220006A JP2010053079A JP 2010053079 A JP2010053079 A JP 2010053079A JP 2008220006 A JP2008220006 A JP 2008220006A JP 2008220006 A JP2008220006 A JP 2008220006A JP 2010053079 A JP2010053079 A JP 2010053079A
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- Prior art keywords
- salt
- formula
- group
- compound
- monosaccharide
- Prior art date
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- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical class NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 150000003839 salts Chemical class 0.000 title claims abstract description 52
- 229960002749 aminolevulinic acid Drugs 0.000 claims abstract description 44
- 150000002482 oligosaccharides Chemical group 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 51
- 150000002772 monosaccharides Chemical group 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 32
- 229920001542 oligosaccharide Polymers 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 150000001414 amino alcohols Chemical class 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 claims description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Chemical group CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical group C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 claims description 4
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Chemical group CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 4
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Chemical group CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 claims description 4
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims description 4
- 229950006780 n-acetylglucosamine Drugs 0.000 claims description 4
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical group OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 3
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Chemical group C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 125000002353 D-glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
- OVRNDRQMDRJTHS-ZTVVOAFPSA-N N-acetyl-D-mannosamine Chemical group CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-ZTVVOAFPSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 19
- 201000011510 cancer Diseases 0.000 abstract description 19
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 abstract description 18
- 229950003776 protoporphyrin Drugs 0.000 abstract description 18
- 238000002428 photodynamic therapy Methods 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 235000000346 sugar Nutrition 0.000 abstract description 6
- AVIUPIMDGOIUCT-UHFFFAOYSA-N 5-amino-4-oxopentanamide Chemical compound NCC(=O)CCC(N)=O AVIUPIMDGOIUCT-UHFFFAOYSA-N 0.000 abstract description 5
- 125000002947 alkylene group Chemical group 0.000 abstract description 5
- 230000003834 intracellular effect Effects 0.000 abstract description 4
- 125000006850 spacer group Chemical group 0.000 abstract description 2
- 125000001483 monosaccharide substituent group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- -1 ALA ester Chemical class 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000035508 accumulation Effects 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical group ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical group CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 238000002271 resection Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Chemical group CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 230000000886 photobiology Effects 0.000 description 3
- 239000003504 photosensitizing agent Substances 0.000 description 3
- 239000003223 protective agent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- QIGJYVCQYDKYDW-UHFFFAOYSA-N 3-O-alpha-D-mannopyranosyl-D-mannopyranose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(CO)OC(O)C1O QIGJYVCQYDKYDW-UHFFFAOYSA-N 0.000 description 2
- 229950010481 5-aminolevulinic acid hydrochloride Drugs 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
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Abstract
Description
本発明は、５−アミノレブリン酸（ＡＬＡ）の誘導体であって、悪性腫瘍治療剤などとして有用であり、生体に投与後に悪性腫瘍組織への集積性が高く、細胞内で速やかに５−アミノレブリン酸を生成することができる５−アミノレブリン酸誘導体又はその塩に関する。 The present invention is a derivative of 5-aminolevulinic acid (ALA), which is useful as a therapeutic agent for malignant tumors, has high accumulation in malignant tumor tissues after administration to a living body, and is promptly intracellular. Relates to a 5-aminolevulinic acid derivative or a salt thereof.
近年、日本における悪性新生物（がん）の罹患率又は死亡率は増加の一途をたどっており、日本人の約１／３はがんで死亡するといわれている。がんの撲滅は現代の科学技術をもってしても成し得ることのできない人類共通の課題といえる。日本におけるがん治療法は、外科的切除がその大半を占め、外科的切除単独、及び外科的切除と薬剤投与等との併用療法を合わせると約７割に達する。しかし、外科的切除によるがん治療は、生体侵襲性が高く、臓器の温存ができないなどの問題点がある。また、現代医療においては、患者の生活の質（Quality of Life：ＱＯＬ）の向上が強く要請されており、今後、さらなる高齢化社会を迎えるにあたり、その要請はますます強くなると考えられる。したがって、患者のＱＯＬを考慮した新たながん治療法が求められている。 In recent years, the morbidity rate or mortality rate of malignant neoplasm (cancer) in Japan has been increasing, and it is said that about 1/3 of Japanese people die from cancer. Cancer eradication is a common human issue that cannot be achieved with modern science and technology. The majority of cancer therapies in Japan are surgical resection, and about 70% of surgical resection alone and combined treatment with surgical resection and drug administration. However, cancer treatment by surgical resection has problems such as high invasiveness and inability to preserve organs. Further, in modern medicine, there is a strong demand for improving the quality of life (QOL) of patients, and it is thought that this demand will become stronger in the future as we enter an aging society. Accordingly, there is a need for new cancer treatment methods that take into account the patient's QOL.
光線力学的療法（Photodynamic Therapy：以下「ＰＤＴ」ともいう。）は、光に反応する化合物を投与し、光を照射することにより標的箇所を治療する方法であり、治療が簡便で、生体侵襲性が小さく、臓器温存が可能であることなどから、近年、ＱＯＬを考慮した新たながん治療法として注目されている。ＰＤＴによるがん治療にあたっては、腫瘍親和性を有し、効率よく光に反応する光増感作用を有する化合物を用いることが望まれているが、このような性質を有する化合物として、プロトポルフィリンＩＸ（ＰｐＩＸ）が注目されている。ＰｐＩＸは、ヘムやクロロフィル等の色素の前駆体として知られており、がん組織へ特異的に集積する性質を有し、がん細胞内に蓄積したＰｐＩＸは、光照射されることにより周囲の酸素分子を光励起し、その結果生成する一重項酸素が、その強い酸化力による殺細胞効果を有するとされている。 Photodynamic therapy (hereinafter also referred to as “PDT”) is a method of treating a target site by administering a compound that reacts with light and irradiating light, and is easy to treat and bioinvasive. In recent years, it has attracted attention as a new cancer treatment method considering QOL. In cancer treatment by PDT, it is desired to use a compound having a tumor affinity and having a photosensitizing action that reacts efficiently with light. As a compound having such a property, protoporphyrin IX (PpIX) is drawing attention. PpIX is known as a precursor of pigments such as heme and chlorophyll, and has a property of specifically accumulating in cancer tissues. PpIX accumulated in cancer cells is irradiated with light to irradiate surroundings. It is said that singlet oxygen generated as a result of photoexcitation of oxygen molecules has a cell-killing effect due to its strong oxidizing power.
一方、５−アミノレブリン酸（以下「ＡＬＡ」ともいう）は、色素生合成経路の中間体として知られており、動物や植物や菌類に広く存在し、それ自身は光増感作用を有さないが、色素生合成経路を経てＰｐＩＸを誘導するとされている。かかるＡＬＡ又はその誘導体の投与による効果を利用して開発された、病変の検出及び治療方法等が提案されている（例えば、特許文献１参照）。 On the other hand, 5-aminolevulinic acid (hereinafter also referred to as “ALA”) is known as an intermediate of the pigment biosynthetic pathway and is widely present in animals, plants and fungi, and has no photosensitizing action itself. However, it is said that PpIX is induced through the pigment biosynthesis pathway. A lesion detection and treatment method developed by utilizing the effects of administration of such ALA or a derivative thereof has been proposed (see, for example, Patent Document 1).
ＡＬＡ及びＰｐＩＸを利用したＰＤＴの特長として、１）生体内に存在する化合物であり毒性が低い、２）代謝が速く副作用が少ない、３）経口投与が可能である、４）腫瘍選択性が高い、５）水溶性である点等を挙げることができるといわれているが、生体内に投与後、細胞に取り込まれるＡＬＡ量はわずかであり、治療効果をもたらすためには多量に投薬する必要がある。しかしながら、ＡＬＡを生体内に２０〜６０ｍｇ／ｋｇＢ．Ｗ以上投与すると、日光過敏症や嘔吐、一時的な肝機能障害を引き起こすことが知られており、ＡＬＡの投与量を増加させることなく、細胞内ＰｐＩＸの集積量を増大させ、ＰＤＴ効果を向上させるため、種々の検討がなされている。 The features of PDT using ALA and PpIX are 1) compound existing in the living body and low toxicity, 2) fast metabolism and few side effects, 3) oral administration, 4) high tumor selectivity 5) Although it is said that the water-soluble point can be mentioned, the amount of ALA taken up into cells after administration in vivo is small, and it is necessary to administer a large amount in order to bring about a therapeutic effect is there. However, ALA is 20 to 60 mg / kg B.V. Administration of W or more is known to cause photosensitivity, vomiting, and temporary liver dysfunction. Increases the accumulation of intracellular PpIX and increases the PDT effect without increasing the dose of ALA. Therefore, various studies have been made.
例えば、ＡＬＡにエステル結合を介して長鎖アルコールを結合したＡＬＡエステル（例えば、特許文献２〜４及び非特許文献１〜３参照）や、ＡＬＡにエステル結合を介して芳香族系アルコールを結合したＡＬＡエステル（例えば、非特許文献４参照）が合成され、その細胞内集積性について詳細に報告されている。その結果、これらのＡＬＡエステルは、ＡＬＡと比較して疎水性が高いこと、また細胞内への取込機序がＡＬＡとは異なることなどが確認され、細胞内へのＡＬＡ及びＰｐＩＸの集積性が向上することが明らかにされている。しかし、ＡＬＡと比較して細胞毒性が高くなること、疎水性の増加はＡＬＡ及びＰｐＩＸの正常細胞への集積性も増加させることなどの問題点が指摘されており、それらの問題を生じることなく、ＡＬＡが効率よくがん組織に取り込まれ、ＰｐＩＸが、がん細胞内に蓄積するための新たな方法が求められている。 For example, ALA ester (for example, see Patent Documents 2 to 4 and Non-Patent Documents 1 to 3) in which a long-chain alcohol is bonded to ALA via an ester bond, or an aromatic alcohol is bonded to ALA via an ester bond An ALA ester (see, for example, Non-Patent Document 4) has been synthesized, and its intracellular accumulation has been reported in detail. As a result, it was confirmed that these ALA esters are higher in hydrophobicity than ALA and that the mechanism of intracellular uptake is different from that of ALA. The accumulation of ALA and PpIX into cells is confirmed. Has been shown to improve. However, it has been pointed out that the cytotoxicity is higher than that of ALA, and the increase in hydrophobicity also increases the accumulation of ALA and PpIX in normal cells. Therefore, a new method is required for ALA to be efficiently taken into cancer tissues and PpIX to accumulate in cancer cells.
本発明の課題は、ＡＬＡの投与量を増加させることなく、細胞内のＰｐＩＸの集積量を増大させ、ＰＤＴの効果を向上させることができる、ＡＬＡ誘導体及びその塩を提供することにある。 The subject of this invention is providing the ALA derivative and its salt which can increase the accumulation amount of PpIX in a cell and can improve the effect of PDT, without increasing the dosage of ALA.
本発明者らは、上記課題を解決するため、従来と異なるＡＬＡ誘導体とその生体内における挙動との関係を見出すべく鋭意研究を重ねていたが、ＡＬＡに水溶性を付与したＡＬＡ配糖体との着想に至り、今回、５−アミノレブリン酸アミドと糖の間にスペーサーとしてアルキレン鎖を導入することにより、がん細胞の糖認識部位に結合しやすくなることが期待できる、安定したＡＬＡ誘導体を製造しうることを見出し、本発明を完成するに至った。 In order to solve the above-mentioned problems, the present inventors have conducted intensive research to find out the relationship between ALA derivatives different from conventional ones and their behavior in the living body. However, ALA glycosides that impart water solubility to ALA and This time, by introducing an alkylene chain as a spacer between 5-aminolevulinic acid amide and the sugar, a stable ALA derivative that can be expected to easily bind to the sugar recognition site of cancer cells is produced. As a result, the present invention has been completed.
すなわち本発明は、［１］式（Ｉ）で表される５−アミノレブリン酸誘導体又はその塩； That is, the present invention provides [1] a 5-aminolevulinic acid derivative represented by the formula (I) or a salt thereof;
（式中、Ｑは、単糖残基又はオリゴ糖残基を表し、ｎは、２〜８の整数を表す）や、［２］上記式（Ｉ）中、Ｑで表される単糖残基を提供する単糖が、以下の式（II）で表されることを特徴とする前記［１］記載の化合物又はその塩； (Wherein Q represents a monosaccharide residue or an oligosaccharide residue, and n represents an integer of 2 to 8) or [2] in the above formula (I), the monosaccharide residue represented by Q The monosaccharide which provides a group is represented by the following formula (II):
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、及びＲ７は、互いに独立して、Ｈ、ＯＨ、ＮＨＣＯＲ８、又は保護基を導入したＯＨを表す。但し、Ｒ１とＲ２の少なくとも一方はＨであり、Ｒ３とＲ４の少なくとも一方はＨであり、Ｒ５とＲ６の少なくとも一方はＨである。また、Ｒ８は−（ＣＨ２）ｍ−ＣＨ３を表し、ｍは０〜５の整数を表す）や、［３］上記式（Ｉ）中、Ｑで表される単糖残基が、Ｄ−グルコース、Ｄ−ガラクトース、Ｄ−マンノース、Ｌ−フコース、Ｎ−アセチル−Ｄ−グルコサミン、Ｎ−アセチル−Ｄ−マンノサミン、Ｎ−アセチル−Ｄ−ガラクトサミンからなる群から選択される残基であることを特徴とする前記［１］又は［２］記載の化合物、又はその塩や、［４］上記式（Ｉ）中、ｎが、２又は３であることを特徴とする前記［１］〜［３］のいずれか記載の化合物又はその塩や、［５］式（Ｉ）で表される化合物の塩が、塩酸塩、硫酸塩、酢酸塩又はリン酸塩であることを特徴とする前記［１］〜［４］のいずれか記載の化合物又はその塩に関する。 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each independently represent H, OH, NHCOR 8 , or OH into which a protecting group has been introduced. , R 1 and R 2 are H, at least one of R 3 and R 4 is H, and at least one of R 5 and R 6 is H. R 8 is — (CH 2 ) m represents —CH 3 , m represents an integer of 0 to 5), and [3] In the above formula (I), the monosaccharide residue represented by Q is D-glucose, D-galactose, D— The above [1], which is a residue selected from the group consisting of mannose, L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, N-acetyl-D-galactosamine [2] The compound according to [2] or a salt thereof, or [4] In the above formula (I), n is 2 or 3, wherein the compound according to any one of [1] to [3] or a salt thereof, or [5] a salt of a compound represented by the formula (I) is a hydrochloride or a sulfate. The compound or salt thereof according to any one of [1] to [4], which is an acetate or a phosphate.
さらに本発明は、単糖又はオリゴ糖と、アミノアルコールとを反応させてアミノアルキルグリコシドを得る工程、及び、かかるアミノアルキルグリコシドと５−アミノレブリン酸とを反応させて式（Ｉ）で表される化合物又はその塩を得る工程を有することを特徴とする、式（Ｉ）で表される化合物又はその塩の製造方法； Furthermore, the present invention represents a step of obtaining an aminoalkylglycoside by reacting a monosaccharide or oligosaccharide with an amino alcohol, and reacting such an aminoalkylglycoside with 5-aminolevulinic acid, which is represented by the formula (I). A method for producing a compound represented by formula (I) or a salt thereof, comprising a step of obtaining the compound or a salt thereof;
（式中、Ｑは、単糖残基又はオリゴ糖残基を表し、ｎは、２〜８の整数を表す）に関する。 (Wherein Q represents a monosaccharide residue or an oligosaccharide residue, and n represents an integer of 2 to 8).
本発明の化合物又はその塩は、悪性腫瘍治療剤として有効なＡＬＡ誘導体であって、生体に投与後に悪性腫瘍組織への集積性が高く、細胞内で速やかにＡＬＡが生成し、ＡＬＡの投与量を増加させることなく、細胞内のＰｐＩＸの集積量を増大させ、ＰＤＴの効果を向上させることができる。 The compound of the present invention or a salt thereof is an ALA derivative that is effective as a therapeutic agent for malignant tumors, has high accumulation in a malignant tumor tissue after administration to a living body, rapidly generates ALA in cells, and is administered at a dose of ALA. Without increasing the amount of PpIX, the amount of PpIX accumulated in the cell can be increased, and the effect of PDT can be improved.
本発明の化合物又はその塩としては、式（Ｉ）で表される化合物又はその塩； As the compound of the present invention or a salt thereof, a compound represented by the formula (I) or a salt thereof;
（式中、Ｑは、単糖残基又はオリゴ糖残基を表し、ｎは、２〜８の整数を表す）であれば特に制限されず、上記式（Ｉ）における“Ｑ”、すなわち単糖残基又はオリゴ糖残基としては、還元末端を有する単糖やオリゴ糖由来の残基を例示することができ、上記単糖残基を提供する単糖としては、一例としては、以下の式（II）； (In the formula, Q represents a monosaccharide residue or an oligosaccharide residue, and n represents an integer of 2 to 8.) There is no particular limitation, and “Q” in the above formula (I), that is, simple Examples of the sugar residue or oligosaccharide residue include residues derived from monosaccharides and oligosaccharides having a reducing end. Examples of monosaccharides that provide the above monosaccharide residues include the following: Formula (II);
で表される単糖を挙げることができ、また具体的には、リボース、アラビノース、キシロース、リキソース、アロース、アルトロース、グルコース、マンノース、グロース、イドース、ガラクトース、タロース、タガトース、ラムノース、セドヘプツロース、デオキシリボース、フコース、Ｎ−アセチルグルコサミン、Ｎ−アセチルガラクトサミン、グルクロン酸、フルクトース、キシルロース、リブロース、プシコース、ソルボース、ガラクツロン酸、マンヌロン酸、等のＤ体及びＬ体など、並びにそれらのデオキシ糖、アミノ糖、チオ糖等の誘導体を挙げることができる。また、ヒトの細胞に多く認められることや、市販品として入手がしやすいことから、Ｄ−グルコース、Ｄ−ガラクトース、Ｄ−マンノース、Ｌ−フコース、Ｎ−アセチル−Ｄ−グルコサミン、Ｎ−アセチル−Ｄ−ガラクトサミンを好適に例示することができる。他方、上記オリゴ糖残基を提供するオリゴ糖としては、２個以上３個以下の単糖がグリコシド結合により１分子となった化合物を挙げることができ、例えば、上記１又は複数の単糖が構成成分として選択され、グリコシド結合を形成して１分子となった化合物を挙げることができ、具体的には、ラクトース、マルトース、セロビオース、パラチノース、ゲンチオビオース、スクロース、トレハロース、ニゲロース、ラミナリビオース、コージビオース、イソマルトース、ソホロース、イソマルトトリオース、メリビオース、キトビオース、マルトトリオース、パノース等を挙げることができる。そして、上記還元末端を有する単糖又はオリゴ糖を、α又はβ結合により５−アミノレブリン酸アミドのアミドの部分とアルキレン鎖を介してＯ−グリコシド結合することにより、上記式（Ｉ）で表される化合物又はその塩を形成することができ、また、上記式（Ｉ）中、ｎは、上記式（Ｉ）で表される化合物又はその塩の親水性の維持のため、２〜８が好ましく、２〜５がより好ましく、２又は３が特に好ましい。 And, specifically, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, tagatose, rhamnose, cedheptulose, deoxy Ribose, fucose, N-acetylglucosamine, N-acetylgalactosamine, glucuronic acid, fructose, xylulose, ribulose, psicose, sorbose, galacturonic acid, mannuronic acid, etc., and their deoxy and amino sugars And derivatives such as thiosaccharide. In addition, since it is often observed in human cells and is easily available as a commercial product, D-glucose, D-galactose, D-mannose, L-fucose, N-acetyl-D-glucosamine, N-acetyl- D-galactosamine can be preferably exemplified. On the other hand, examples of the oligosaccharide that provides the oligosaccharide residue include compounds in which 2 or more and 3 or less monosaccharides are converted to one molecule by glycosidic linkage. Examples of the compound selected as a component and forming a glycosidic bond to form one molecule include, specifically, lactose, maltose, cellobiose, palatinose, gentiobiose, sucrose, trehalose, nigerose, laminaribiose, and cordobiose. , Isomaltose, sophorose, isomaltotriose, melibiose, chitobiose, maltotriose, panose and the like. Then, the monosaccharide or oligosaccharide having the reducing end is O-glycosidically bonded to the amide portion of 5-aminolevulinic acid amide through an alkylene chain by an α or β bond, and represented by the above formula (I). In the formula (I), n is preferably 2 to 8 in order to maintain the hydrophilicity of the compound represented by the formula (I) or a salt thereof. 2 to 5 are more preferable, and 2 or 3 is particularly preferable.
上記式（II）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、及び、Ｒ７は、例えば、互いに独立して、Ｈ、ＯＨ、ＮＨＣＯＲ８、又は保護基を導入したＯＨ（水酸基）を表し、Ｒ１とＲ２の少なくとも一方はＨであり、Ｒ３とＲ４の少なくとも一方はＨであり、Ｒ５とＲ６の少なくとも一方はＨであり、また、Ｒ８は−（ＣＨ２）ｍ−ＣＨ３を表し、ｍは０〜５の整数を表し、上記ＯＨ（水酸基）に導入する保護基としては、ピバロイル基、アセチル基、ベンゾイル基、ベンジル基、シリル基、アルキル基等を挙げることができ、また、例えば、上記式（II）で表される単糖がα結合により５−アミノレブリン酸アミドとアルキレン鎖を介してＯ−グリコシド結合した場合は、以下の式（III）にて、 In the above formula (II), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently introduced with H, OH, NHCOR 8 , or a protecting group, for example. OH (hydroxyl group), at least one of R 1 and R 2 is H, at least one of R 3 and R 4 is H, at least one of R 5 and R 6 is H, and R 8 represents — (CH 2 ) m —CH 3 , m represents an integer of 0 to 5, and the protective group introduced into the OH (hydroxyl group) includes pivaloyl group, acetyl group, benzoyl group, benzyl group, silyl group Groups, alkyl groups, and the like, and for example, when the monosaccharide represented by the above formula (II) is O-glycosidically bonded via an α chain to a 5-aminolevulinic acid amide via an alkylene chain, In the formula (III) of
また、上記式（II）で表される単糖がβ結合により５−アミノレブリン酸アミドとアルキレン鎖を介してＯ−グリコシド結合した場合は、以下の式（IV）にて、 Further, when the monosaccharide represented by the above formula (II) is O-glycosidically bonded via a β-bond via a 5-aminolevulinic acid amide and an alkylene chain, the following formula (IV):
上記式（Ｉ）で表される化合物が表現される。 The compound represented by the above formula (I) is represented.
本発明の化合物の塩としては、上記式（Ｉ）で表される化合物と同効であれば特に制限されないが、例えば、薬学的に許容される塩酸塩、臭化水素酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸の酸付加塩や、酢酸塩、乳酸塩、クエン酸塩、酒石酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、アスコルビン酸塩等の有機酸の酸付加塩などを挙げることができ、５−アミノレブリン酸塩酸塩又は５−アミノレブリン酸リン酸塩を好適に例示することができる。なお、本発明の塩は、使用時において水溶液、懸濁液、粉体等として用いることができ、本発明の化合物又はその塩は単独でも２種以上を組み合わせて用いてもよい。 The salt of the compound of the present invention is not particularly limited as long as it has the same effect as the compound represented by the above formula (I). For example, pharmaceutically acceptable hydrochloride, hydrobromide, sulfate, Acid addition salts of inorganic acids such as nitrates and phosphates, and acid additions of organic acids such as acetates, lactates, citrates, tartrate, succinates, maleates, fumarate and ascorbates A salt etc. can be mentioned, 5-aminolevulinic acid hydrochloride or 5-aminolevulinic acid phosphate can be illustrated suitably. In addition, the salt of this invention can be used as aqueous solution, suspension, powder, etc. at the time of use, and the compound of this invention or its salt may be used individually or in combination of 2 or more types.
本発明の化合物又はその塩は、生体内に投与されることで、色素生合成経路を経て腫瘍親和性を有するＰｐＩＸを産生し、ＰｐＩＸが蓄積したがん細胞内にＰＤＴを施すことにより、その結果生成する一重項酸素が、その強い酸化力による殺腫瘍細胞効果をもたらすことが期待される。また、腫瘍細胞は、正常細胞より分裂、増殖が盛んなため貪食性が高く、特にエネルギー源として糖を多量に必要とすること、また腫瘍細胞表面に発現する糖鎖認識タンパク質であるレクチンにより糖が認識されることによって、腫瘍組織に対して能動的、かつ、効率的にＡＬＡが送達されることが期待できる。 When the compound of the present invention or a salt thereof is administered in vivo to produce PpIX having tumor affinity via a pigment biosynthesis pathway, and PDT is applied to cancer cells in which PpIX has accumulated, The resulting singlet oxygen is expected to have a tumoricidal cell effect due to its strong oxidizing power. In addition, tumor cells are more phagocytic because they divide and proliferate more than normal cells. In particular, they require a large amount of sugar as an energy source. Can be expected to deliver ALA actively and efficiently to tumor tissue.
本発明の化合物又はその塩はＰＤＴにおいて光増感剤として用いることができ、光増感剤としてのＰｐＩＸの前駆体として本発明の化合物を用いる場合には、経口又は非経口の形態で投与することができ、本発明の化合物又はその塩を用いた経口投与における剤型としては、粉末、顆粒、錠剤、カプセル剤、シロップ剤、懸濁液等を挙げることができ、本発明の化合物又はその塩を用いた静脈注射、筋肉注射、局所注射等の非経口投与における剤型としては、注射剤、点滴剤等を挙げることができる。また、本発明の化合物又はその塩を用いた光増感剤には、必要に応じて他の薬効成分、栄養剤、担体等の他の成分を添加することができ、例えば、薬学的に許容される通常の担体、結合剤、安定化剤、溶剤、分散媒、増量剤、賦形剤、希釈剤、ｐＨ緩衝剤、崩壊剤、可溶化剤、溶解補助剤、等張剤などの各種調剤用配合成分を添加することができる。 The compound of the present invention or a salt thereof can be used as a photosensitizer in PDT. When the compound of the present invention is used as a precursor of PpIX as a photosensitizer, it is administered in an oral or parenteral form. Examples of the dosage form for oral administration using the compound of the present invention or a salt thereof include powders, granules, tablets, capsules, syrups, suspensions, etc. Examples of dosage forms for parenteral administration such as intravenous injection, intramuscular injection, and local injection using a salt include injections and infusions. In addition, other components such as other medicinal ingredients, nutrients, and carriers can be added to the photosensitizer using the compound of the present invention or a salt thereof as necessary, for example, pharmaceutically acceptable. Various preparations such as ordinary carriers, binders, stabilizers, solvents, dispersion media, extenders, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizers, isotonic agents, etc. Formulation ingredients can be added.
本発明の化合物又はその塩を製造する方法としては、上記式（Ｉ）で表される化合物又はその塩を得ることができる方法であれば特に制限されないが、一例として、単糖又はオリゴ糖とアミノアルコールとを反応させてアミノアルキルグリコシドを得る工程、及び、かかるアミノアルキルグリコシドと５−アミノレブリン酸とを反応させて上記式（Ｉ）で表される化合物又はその塩を得る工程を有することを特徴とする、本発明の化合物又はその塩を製造する方法を挙げることができ、上記各工程において、単糖若しくはオリゴ糖、アミノアルコール、及び／又は５−アミノレブリン酸は、保護基を導入することなく反応に用いてもよいが、慣用に従って、単糖やオリゴ糖のアノマー位の水酸基以外の水酸基、アミノアルコールのアミノ基、及び５−アミノレブリン酸のアミノ基に保護基を導入する工程と、導入した保護基の脱離を行う工程を追加して行うことが、副反応を抑え、目的化合物の収率を増やすことができる点で好ましい。 A method for producing the compound of the present invention or a salt thereof is not particularly limited as long as it is a method capable of obtaining the compound represented by the above formula (I) or a salt thereof. Reacting with an amino alcohol to obtain an aminoalkylglycoside, and reacting such aminoalkylglycoside with 5-aminolevulinic acid to obtain a compound represented by the above formula (I) or a salt thereof. A method for producing the compound of the present invention or a salt thereof, which is characterized, can be mentioned. In each of the above steps, a monosaccharide or oligosaccharide, amino alcohol, and / or 5-aminolevulinic acid is introduced with a protecting group. May be used in the reaction, but in accordance with common practice, a hydroxyl group other than the anomeric hydroxyl group of a monosaccharide or oligosaccharide, And adding a step of introducing a protecting group to the amino group of 5-aminolevulinic acid and a step of removing the introduced protecting group can suppress side reactions and increase the yield of the target compound. This is preferable.
上記式（Ｉ）で表される化合物又はその塩の製造方法に用いられる単糖又はオリゴ糖としては、上記式（Ｉ）における“Ｑ”、すなわち還元末端を有する単糖残基又はオリゴ糖残基を提供する、単糖又はオリゴ糖であれば特に制限されず、単糖又はオリゴ糖のアノマー位以外の水酸基に保護基を導入した単糖又はオリゴ糖誘導体を含み、上記単糖又はオリゴ糖のアノマー位以外の水酸基に保護基を導入する方法としては、例えば、単糖又はオリゴ糖と水酸基の保護剤とを溶媒に溶解して還流し、減圧濃縮後、洗浄・乾燥し、再度、減圧濃縮して、精製をする方法を挙げることができ、上記水酸基の保護基としては、ベンゾイル基、ピバロイル基、アセチル基、ベンジル基、シリル基等を挙げることができるが、上記単糖の場合は、ピバロイル基が好ましく、上記オリゴ糖の場合は、アセチル基又はベンゾイル基が好ましく、上記溶媒としては、ピリジン溶媒を例示することができ、上記精製方法としては、再結晶を例示することができる。 Examples of the monosaccharide or oligosaccharide used in the method for producing the compound represented by the above formula (I) or a salt thereof include “Q” in the above formula (I), that is, a monosaccharide residue or oligosaccharide residue having a reducing end. The monosaccharide or oligosaccharide includes a monosaccharide or oligosaccharide derivative in which a protective group is introduced into a hydroxyl group other than the anomeric position of the monosaccharide or oligosaccharide. As a method for introducing a protecting group into a hydroxyl group other than the anomeric position, for example, a monosaccharide or oligosaccharide and a hydroxyl protecting agent are dissolved in a solvent and refluxed, concentrated under reduced pressure, washed and dried, and then reduced in pressure again. Examples of the protective group for the hydroxyl group include a benzoyl group, a pivaloyl group, an acetyl group, a benzyl group, and a silyl group. In the case of the monosaccharide, , Pivaloyl Preferably, in the case of the oligosaccharides, preferably an acetyl group or a benzoyl group, examples of the solvent can be exemplified by pyridine solvent, as the purification method, can be exemplified recrystallization.
上記式（Ｉ）で表される化合物又はその塩の製造方法に用いられるアミノアルコールとしては、ＨＯ−（ＣＨ２）ｎ−ＮＨ２で表されるアミノアルコールの他、該アミノアルコールのアミノ基に保護基が導入されたアミノアルコール誘導体が含まれ、上記式中、ｎは、２〜８が好ましく、２〜５がより好ましく、２又は３が特に好ましい。かかるアミノアルコールの入手方法としては、市販品を購入する方法や、化学的に合成する方法や、植物体から分離・抽出する方法や、微生物の代謝物より分離・抽出する方法や、酵素的に生産する方法などの公知の方法を含め特に制限されないが、化学的に合成する方法としては、例えば、以下の式（Ｖ）に表されるように、相当するアルケン鎖長を有するジオール化合物から、トシラートを調製して、さらにトシラートのアジド化を経て還元する方法を挙げることができる。 Examples of the amino alcohol used in the method for producing the compound represented by the above formula (I) or a salt thereof include the amino alcohol represented by HO— (CH 2 ) n —NH 2 , and the amino group of the amino alcohol. An amino alcohol derivative into which a protecting group is introduced is included, and in the above formula, n is preferably 2 to 8, more preferably 2 to 5, and particularly preferably 2 or 3. Such amino alcohols can be obtained by purchasing commercially available products, chemically synthesizing, separating and extracting from plants, separating and extracting from microbial metabolites, and enzymatically. Although it does not restrict | limit especially including well-known methods, such as the method to produce, As a method of chemically synthesize | combining, for example, as represented by the following formula (V), from a diol compound having a corresponding alkene chain length, An example is a method in which a tosylate is prepared and further reduced through azidation of the tosylate.
上記アミノアルコールのアミノ基に保護基を導入する方法としては、例えば、アミノアルコールを塩素系溶媒に溶解し、氷冷下で、アミノ基の保護剤を添加し、室温で一晩攪拌し、セライトを通して濾過した後に、濾液を減圧濃縮し、再度、極性溶媒に溶解して酸洗浄した後、乾燥剤で乾燥し、減圧濃縮する方法を挙げることができ、上記アミノ基の保護基としては、２，２，２−トリクロロエトキシカルボニル基（Troc基）、ベンジルオキシカルボニル基（Cbz基）、フタロイル基（Phth基）、フルオレニルメチルオキシカルボニル基（Fmoc基）等を挙げることができるが、Ｔｒｏｃ基が好ましく、上記塩素系溶媒としては、ジクロロメタンを例示することができ、上記乾燥剤としては、硫酸ナトリウムを例示することができる。 As a method for introducing a protective group into the amino group of the amino alcohol, for example, the amino alcohol is dissolved in a chlorinated solvent, an amino group protective agent is added under ice cooling, and the mixture is stirred overnight at room temperature. The filtrate is concentrated under reduced pressure, dissolved in a polar solvent, washed with an acid, dried with a desiccant, and concentrated under reduced pressure. Examples of the amino-protecting group include 2 , 2,2-trichloroethoxycarbonyl group (Troc group), benzyloxycarbonyl group (Cbz group), phthaloyl group (Phth group), fluorenylmethyloxycarbonyl group (Fmoc group) and the like. A group is preferred, and examples of the chlorinated solvent include dichloromethane, and examples of the desiccant include sodium sulfate.
上記式（Ｉ）で表される化合物又はその塩の製造方法における、上記単糖又はオリゴ糖とアミノアルコールとを反応させて、アミノアルキルグリコシドを得る工程としては、例えば、上記アミノアルコールと脱水剤と反応促進剤とを極性溶媒に懸濁し、次に、上記単糖又はオリゴ糖を添加して反応させ、その後、セライトを通して濾過した後に濾液を減圧濃縮し、希釈剤で希釈し、洗浄後、乾燥剤で乾燥・減圧濃縮し、精製してアミノアルキルグリコシドを得る工程を挙げることができる。上記脱水剤としては、モレキュラーシーブス（3A〜5A）を例示することができ、上記反応促進剤としては、銀(Ｉ)−シリカアルミナを例示することができ、上記極性溶媒としては、クロロホルム、ピリジン等を例示することができ、上記希釈剤としては、ジクロロメタンを例示することができ、上記乾燥剤としては、硫酸ナトリウムを例示することができ、上記精製の方法としては、シリカゲルカラムクロマトグラフィを例示することができる。 In the method for producing a compound represented by the above formula (I) or a salt thereof, the step of obtaining the aminoalkyl glycoside by reacting the monosaccharide or oligosaccharide with amino alcohol includes, for example, the amino alcohol and dehydrating agent. And the reaction accelerator suspended in a polar solvent, then added and reacted with the above monosaccharide or oligosaccharide, and then filtered through Celite, and the filtrate was concentrated under reduced pressure, diluted with a diluent, washed, Examples of the step include drying with a desiccant and concentration under reduced pressure, followed by purification to obtain an aminoalkylglycoside. Examples of the dehydrating agent include molecular sieves (3A to 5A). Examples of the reaction accelerator include silver (I) -silica alumina. Examples of the polar solvent include chloroform and pyridine. Examples of the diluent include dichloromethane, examples of the drying agent include sodium sulfate, and examples of the purification method include silica gel column chromatography. be able to.
また、上記単糖又はオリゴ糖とアミノアルコールとを反応させてアミノアルキルグリコシドを得る工程においては、上記単糖又はオリゴ糖のアノマー位の水酸基をハロゲン原子で置換した、単糖又はオリゴ糖のハロゲン化物を用いることが好ましく、上記ハロゲン原子としては、フッ素、塩素、臭素、又はヨウ素等を挙げることができるが、単糖の場合は、臭素が好ましく、オリゴ糖の場合は、臭素又は塩素が好ましい。 In the step of reacting the monosaccharide or oligosaccharide with amino alcohol to obtain an aminoalkylglycoside, the monosaccharide or oligosaccharide halogen is substituted with a halogen atom at the anomeric hydroxyl group of the monosaccharide or oligosaccharide. Preferred examples of the halogen atom include fluorine, chlorine, bromine, and iodine. In the case of a monosaccharide, bromine is preferable, and in the case of an oligosaccharide, bromine or chlorine is preferable. .
上記アミノアルキルグリコシドに保護基が導入されている場合にアミノ基の保護基を脱離する方法としては、例えば、Ｎ−(トリクロロエトキシカルボニル)アミノアルキルグリコシドを亜鉛粉末試薬で処理し、セライトを通して濾過した後に、固形分を塩素系溶媒に溶解して酸洗浄後、水層を洗浄し、乾燥・減圧濃縮し、精製する方法を例示することができ、上記塩素系溶媒としては、ジクロロメタンを例示することができ、上記精製の方法としては、シリカゲルカラムクロマトグラフィを例示することができる。 When a protecting group is introduced into the aminoalkyl glycoside, the amino group protecting group can be removed by, for example, treating N- (trichloroethoxycarbonyl) aminoalkylglycoside with a zinc powder reagent and filtering through celite. Then, after the solid content is dissolved in a chlorinated solvent and washed with an acid, the aqueous layer can be washed, dried and concentrated under reduced pressure, and purified, and the chlorinated solvent is exemplified by dichloromethane. Examples of the purification method include silica gel column chromatography.
上記式（Ｉ）で表される化合物又はその塩の製造方法に用いられる５−アミノレブリン酸としては、以下の式（VI）で表される５−アミノ−４−オキソペンタン酸又はその誘導体及びそれらの塩や、上記５−アミノレブリン酸のアミノ基に保護基を導入した、５−アミノレブリン酸誘導体を含み、かかる５−アミノレブリン酸の入手方法としては、市販品を購入する方法や、化学的に合成する方法（例えば、特開平２−７６８４１号参照）や、植物体から分離・抽出する方法や、微生物の代謝物より分離・抽出する方法（例えば、特開２００８−２９２７２号参照）や、酵素的に生産する方法などの公知の方法を含め特に制限されず、 Examples of 5-aminolevulinic acid used in the method for producing the compound represented by the above formula (I) or a salt thereof include 5-amino-4-oxopentanoic acid represented by the following formula (VI) or a derivative thereof, and those And a 5-aminolevulinic acid derivative in which a protecting group is introduced into the amino group of the above-mentioned 5-aminolevulinic acid. (For example, see JP-A-2-76841), a method for separating / extracting from a plant body, a method for separating / extracting from a metabolite of a microorganism (for example, see JP-A-2008-29272), an enzymatic method There are no particular restrictions including known methods such as
上記５−アミノレブリン酸のアミノ基に保護基を導入する方法としては、例えば、５−アミノレブリン酸塩を極性溶媒に溶解し、アミノ基の保護剤を添加し、室温で数時間攪拌し、セライトを通して濾過した後に、濾液を減圧濃縮し、再度、極性溶媒で希釈し、酸洗浄、乾燥及び減圧濃縮して、精製する方法を例示することができ、５−アミノレブリン酸のアミノ基に導入される保護基としては、Ｔｒｏｃ基、Ｃｂｚ基、フタロイル基（Phth基）、フルオレニルメチルオキシカルボニル基（Fmoc基）等を挙げることができるが、Ｔｒｏｃ基が好ましく、上記極性溶媒としては、テトラヒドロフランを例示することができ、上記精製の方法としては、シリカゲルカラムクロマトグラフィを例示することができる。 As a method for introducing a protecting group into the amino group of the 5-aminolevulinic acid, for example, 5-aminolevulinic acid salt is dissolved in a polar solvent, an amino group protecting agent is added, the mixture is stirred at room temperature for several hours, and passed through Celite. After filtration, the filtrate can be concentrated under reduced pressure, again diluted with a polar solvent, acid washed, dried and concentrated under reduced pressure to illustrate the purification method, and the protection introduced into the amino group of 5-aminolevulinic acid Examples of the group include a Troc group, a Cbz group, a phthaloyl group (Phth group), a fluorenylmethyloxycarbonyl group (Fmoc group), and the like. The Troc group is preferable, and the polar solvent is exemplified by tetrahydrofuran. Examples of the purification method include silica gel column chromatography.
本発明の化合物又はその塩の製造方法における、上記アミノアルキルグリコシドと、上記５−アミノレブリン酸とを反応させて上記式（Ｉ）で表される化合物又はその塩を得る工程としては、例えば、塩基性物質に溶解した５−アミノレブリン酸と、塩素系溶媒に溶解したアミノアルキルグリコシドとを、脱水縮合剤を添加して反応させ、その後、洗浄・乾燥し、減圧濃縮し、精製する方法を挙げることができ、上記塩基性物質としては、４−ジメチルアミノピリジンを例示することができ、上記塩素系溶媒としては、ジクロロメタンを例示することができ、上記脱水縮合剤としては、ジシクロヘキシルカルボジイミド（ＤＣＣ）、又は１−エチル−３−(ジメチルアミノプロピル)カルボジイミド塩酸塩（ＥＤＣ）を例示することができ、上記精製方法としては、シリカゲルカラムクロマトグラフィを例示することができる。 Examples of the step of obtaining the compound represented by the above formula (I) or a salt thereof by reacting the aminoalkylglycoside with the 5-aminolevulinic acid in the method for producing a compound of the present invention or a salt thereof include, for example, a base. Mentioning a method of reacting 5-aminolevulinic acid dissolved in an organic substance with aminoalkylglycoside dissolved in a chlorinated solvent by adding a dehydrating condensing agent, followed by washing, drying, vacuum concentration, and purification. Examples of the basic substance include 4-dimethylaminopyridine, examples of the chlorinated solvent include dichloromethane, examples of the dehydrating condensing agent include dicyclohexylcarbodiimide (DCC), Or 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (EDC) The purification method may be exemplified silica gel column chromatography.
本発明の化合物又はその塩の製造方法における、５−アミノレブリン酸のアミノ基の保護基を脱離する方法としては、例えば、上記式（Ｉ）で表される化合物又はその塩の保護基が導入された誘導体と亜鉛−銅試薬とを酸性溶媒に添加し、室温で反応させ、濾過・減圧濃縮して洗浄後、乾燥剤で乾燥、減圧濃縮し、精製する方法を挙げることができ、上記酸性溶媒としては酢酸を例示することができ、乾燥剤としては硫酸ナトリウムを例示することができ、精製方法としては、シリカゲルカラムクロマトグラフィを例示することができる。さらに、本発明の化合物又はその塩の製造方法における、上記単糖及びオリゴ糖の保護基を脱離する方法としては、上記５−アミノレブリン酸のアミノ基の保護基が脱離した上記式（Ｉ）で表される化合物又はその塩を溶媒に溶かし、加溶媒分解試薬を用いて精製して、上記式（Ｉ）で表される化合物又はその塩を得る方法を例示することができ、上記溶媒としては、メタノールを例示することができ、上記加溶媒分解試薬としては、ナトリウムメトキシドを例示することができ、上記精製方法としては、シリカゲルカラムクロマトグラフィを例示することができる。 Examples of the method for removing the amino protecting group of 5-aminolevulinic acid in the method for producing a compound of the present invention or a salt thereof include, for example, the introduction of a protecting group for the compound represented by the above formula (I) or a salt thereof. The resulting derivative and zinc-copper reagent are added to an acidic solvent, reacted at room temperature, filtered, concentrated under reduced pressure, washed, dried with a desiccant, concentrated under reduced pressure, and purified. Examples of the solvent include acetic acid, examples of the drying agent include sodium sulfate, and examples of the purification method include silica gel column chromatography. Furthermore, in the method for producing the compound of the present invention or a salt thereof, the method for removing the protecting group of the monosaccharide and oligosaccharide may be the above formula (I) wherein the protecting group of the amino group of the 5-aminolevulinic acid is eliminated. ) Or a salt thereof can be dissolved in a solvent and purified using a solvolysis reagent to obtain a compound represented by the above formula (I) or a salt thereof. As an example, methanol can be exemplified. As the solvolysis reagent, sodium methoxide can be exemplified. As the purification method, silica gel column chromatography can be exemplified.
上記式（Ｉ）で表される化合物又はその塩は、５−アミノレブリン酸とアミノアルコールとを反応させる工程の後、単糖又はオリゴ糖とを反応させる工程を経ることによっても製造することができる。各反応は、前記各製造工程に準じて行うことができる。また、上記式（Ｉ）で表される化合物の塩を得る方法としては、上記式（Ｉ）で表される化合物が塩の形で得られる場合には、そのまま精製する方法を挙げることができ、また、遊離の形で得られる場合には、適当な有機溶媒に溶解若しくは懸濁させ、酸を添加して通常の方法により塩を形成させる方法を挙げることができる。 The compound represented by the formula (I) or a salt thereof can also be produced by a step of reacting a monosaccharide or oligosaccharide after a step of reacting 5-aminolevulinic acid and amino alcohol. . Each reaction can be carried out according to the above production steps. In addition, as a method for obtaining a salt of the compound represented by the above formula (I), when the compound represented by the above formula (I) is obtained in the form of a salt, a method for purification as it is can be mentioned. In addition, when it is obtained in a free form, a method of dissolving or suspending in an appropriate organic solvent and adding an acid to form a salt by a usual method can be mentioned.
以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.
［２−（５−アミノレブリニル）アミノエチル−β−Ｄ−グルコピラノシドの合成］
本発明の化合物は、式（VII）〜（XV）で示される以下の工程に従って合成された。
［２−(トリクロロエトキシカルボニル)アミノエタノールの合成］
２−アミノエタノール０．３ｍＬ（５．０ｍｍｏｌ）をジクロロメタン２００ｍＬに溶解し、氷冷下、炭酸ナトリウム１．２ｇ（１１．３ｍｍｏｌ）と２,２,２−トリクロロエトキシカルボニルクロリド０．９５ｍＬ（６．９５ｍｍｏｌ）を添加し、室温で一晩攪拌した。セライトを通して濾過した後に、濾液を減圧濃縮し、ジエチルエーテル１２０ｍＬに溶解し、１Ｎ塩酸１２０ｍＬ、水（３×１２０ｍＬ）で洗浄した。硫酸ナトリウムで乾燥して、減圧濃縮し、シロップとして、２−(トリクロロエトキシカルボニル)アミノエタノール（１）を得た。
[Synthesis of 2- (5-aminolevulinyl) aminoethyl-β-D-glucopyranoside]
The compounds of the present invention were synthesized according to the following steps represented by formulas (VII) to (XV).
[Synthesis of 2- (trichloroethoxycarbonyl) aminoethanol]
Dissolve 0.3 mL (5.0 mmol) of 2-aminoethanol in 200 mL of dichloromethane, and under ice cooling, 1.2 g (11.3 mmol) of sodium carbonate and 0.95 mL of 2,2,2-trichloroethoxycarbonyl chloride (6. 95 mmol) was added and stirred at room temperature overnight. After filtration through celite, the filtrate was concentrated under reduced pressure, dissolved in 120 mL of diethyl ether, and washed with 120 mL of 1N hydrochloric acid and water (3 × 120 mL). The extract was dried over sodium sulfate and concentrated under reduced pressure to give 2- (trichloroethoxycarbonyl) aminoethanol (1) as a syrup.
1H-NMR(400MHz, CDCl3)
δ：3.50(2H, dd, CH 2NH), 3.65(2H, t, CH 2OH), 4.69(2H, s, CH 2CCl3), 6.00(1H, s, NH)
JCH2NH=5.5 Hz, JCH2OH=5.2 Hz
13C-NMR(100MHz, CDCl3)
δ：43.32(CH2NH), 61.25(CH2OH), 74.36(CH2CCl3), 95.34(CCl3), 155.13(CONH)
1 H-NMR (400 MHz, CDCl 3 )
δ: 3.50 (2H, dd, C H 2 NH), 3.65 (2H, t, C H 2 OH), 4.69 (2H, s, C H 2 CCl 3 ), 6.00 (1H, s, NH)
J C H 2NH = 5.5 Hz, J C H 2OH = 5.2 Hz
13 C-NMR (100 MHz, CDCl 3 )
δ: 43.32 ( C H 2 NH), 61.25 ( C H 2 OH), 74.36 ( C H 2 CCl 3 ), 95.34 ( C Cl 3 ), 155.13 ( C ONH)
［ペンタ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシドの合成］
クロロホルム３７．５ｍＬとピリジン２２．５ｍＬに塩化ピバロイル２２．７５ｇ（０．１９ｍｏｌ）を添加し、３０分攪拌し、Ｄ−グルコース５．４５ｇ（０．０３ｍｏｌ）を添加し、２日間還流しながら攪拌した。溶液を減圧濃縮し、ジクロロメタン３８０ｍＬに溶解し、２Ｎ硫酸５４ｍＬ、１０％炭酸水素ナトリウム（５×２７０ｍＬ）、水（２×２７０ｍＬ）で洗浄した。硫酸ナトリウムで乾燥し、減圧濃縮してエタノールから再結晶し、ペンタ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド（２）を白色粉末結晶として得た。
[Synthesis of penta-O-pivaloyl-β-D-glucopyranoside]
Add 22.75 g (0.19 mol) of pivaloyl chloride to 37.5 mL of chloroform and 22.5 mL of pyridine, stir for 30 minutes, add 5.45 g (0.03 mol) of D-glucose, and stir while refluxing for 2 days did. The solution was concentrated under reduced pressure, dissolved in 380 mL of dichloromethane, and washed with 54 mL of 2N sulfuric acid, 10% sodium bicarbonate (5 × 270 mL), and water (2 × 270 mL). The extract was dried over sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain penta-O-pivaloyl-β-D-glucopyranoside (2) as white powder crystals.
1H-NMR(400MHz, CDCl3)
δ：3.83(1H, ddd, H-5), 4.07(1H, dd, H-6a), 4.12(1H, dd, H-6b), 5.10(1H, dd, H-4), 5.18(1H, dd, H-2), 5.34(1H, dd, H-3), 5.66(1H, d, H-1)
J1,2=8.1 Hz, J2,3=10.4 Hz, J3,4=9.1 Hz, J4,5=9.9 Hz, J5,6a=5.1 Hz, J5,6b=2.2 Hz, J6a,6b=12.4 Hz
13C-NMR(100MHz, CDCl3)
δ：27.00, 27.02, 27.05(CH3), 38.68, 38.74, 38.84{COC(CH3)3}, 61.44(C-6), 67.73(C-4), 70.09(C-2), 72.33(C-3), 72.77(C-5), 91.83(C-1), 176.39, 176.41, 177.01, 178.00(C=O)
1 H-NMR (400 MHz, CDCl 3 )
δ: 3.83 (1H, dd, H-5), 4.07 (1H, dd, H-6a), 4.12 (1H, dd, H-6b), 5.10 (1H, dd, H-4), 5.18 (1H, dd, H-2), 5.34 (1H, dd, H-3), 5.66 (1H, d, H-1)
J 1,2 = 8.1 Hz, J 2,3 = 10.4 Hz, J 3,4 = 9.1 Hz, J 4,5 = 9.9 Hz, J 5,6a = 5.1 Hz, J 5,6b = 2.2 Hz, J 6a , 6b = 12.4 Hz
13 C-NMR (100 MHz, CDCl 3 )
δ: 27.00, 27.02, 27.05 (CH 3 ), 38.68, 38.74, 38.84 {CO C (CH 3 ) 3 }, 61.44 (C-6), 67.73 (C-4), 70.09 (C-2), 72.33 ( C-3), 72.77 (C-5), 91.83 (C-1), 176.39, 176.41, 177.01, 178.00 (C = O)
［２，３，４，６−テトラ−Ｏ−ピバロイル−α−Ｄ−グルコピラノシルブロミドの合成］
上記ペンタ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド５ｇ（８．３ｍｏｌ）をジクロロメタン１２ｍＬに溶解し、氷冷下で３０％臭化水素酸‐酢酸溶液１２ｍＬを滴下し、室温で一晩攪拌した。トルエンを添加して濃縮乾固し、ジエチルエーテル１００ｍＬに溶解し、１０％炭酸水素ナトリウム（２×１２０ｍＬ）、水（２×１２０ｍＬ）で洗浄した。硫酸ナトリウムで乾燥し、減圧濃縮して、ヘキサン：酢酸エチル＝４：１から再結晶し、白色粉末結晶として、２，３，４，６−テトラ−Ｏ−ピバロイル−α−Ｄ−グルコピラノシルブロミド（３）を得た。
[Synthesis of 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide]
The above penta-O-pivaloyl-β-D-glucopyranoside (5 g, 8.3 mol) was dissolved in 12 mL of dichloromethane, and 12 mL of 30% hydrobromic acid-acetic acid solution was added dropwise under ice cooling, followed by stirring overnight at room temperature. Toluene was added, concentrated to dryness, dissolved in 100 mL of diethyl ether, and washed with 10% sodium bicarbonate (2 × 120 mL) and water (2 × 120 mL). It was dried over sodium sulfate, concentrated under reduced pressure, recrystallized from hexane: ethyl acetate = 4: 1, and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyrano as white powder crystals. Silbromide (3) was obtained.
1H-NMR(400MHz, CDCl3)
δ：4.09(1H, dd, H-6a), 4.13(1H, dd, H-6b), 4.28(1H, ddd, H-5), 4.78(1H, dd, H-2), 5.18(1H, dd, H-4), 5.59(1H, dt, H-3), 6.58(1H, d, H-1)
J1,2=4.0 Hz, J2,3=9.7 Hz, J3,4=9.9 Hz, J4,5=10.0 Hz, J5,6a=2.0 Hz,J5,6b=2.6 Hz, J6a,6b=8.5 Hz
13C-NMR(100MHz, CDCl3)
δ：26.96, 27.00, 27.04, 27.12(CH3), 38.62, 38.71, 38.86｛COC(CH3)3｝, 60.84(C-6), 66.51(C-4), 69.54(C-3), 70.84(C-2), 72.47(C-5), 86.84(C-1), 176.32, 176.68, 177.24, 177.90(C=O)
1 H-NMR (400 MHz, CDCl 3 )
δ: 4.09 (1H, dd, H-6a), 4.13 (1H, dd, H-6b), 4.28 (1H, ddd, H-5), 4.78 (1H, dd, H-2), 5.18 (1H, dd, H-4), 5.59 (1H, dt, H-3), 6.58 (1H, d, H-1)
J 1,2 = 4.0 Hz, J 2,3 = 9.7 Hz, J 3,4 = 9.9 Hz, J 4,5 = 10.0 Hz, J 5,6a = 2.0 Hz, J 5,6b = 2.6 Hz, J 6a , 6b = 8.5 Hz
13 C-NMR (100 MHz, CDCl 3 )
δ: 26.96, 27.00, 27.04, 27.12 (CH 3 ), 38.62, 38.71, 38.86 {CO C (CH 3 ) 3 }, 60.84 (C-6), 66.51 (C-4), 69.54 (C-3), 70.84 (C-2), 72.47 (C-5), 86.84 (C-1), 176.32, 176.68, 177.24, 177.90 (C = O)
［Ｎ−Ｔｒｏｃ−５−アミノレブリン酸の合成］
５−アミノレブリン酸塩酸塩（コスモ石油株式会社製）１６７．６ｍｇ（１．０ｍｍｏｌ）をテトラヒドロフラン（ＴＨＦ）２０ｍＬに懸濁し、炭酸ナトリウム４８０ｍｇ（４．５２ｍｍｏｌ）と２，２，２−トリクロロエトキシカルボニルクロリド１９０μＬ（１．４２ｍｍｏｌ）を添加し、室温で４時間攪拌した。セライトを通して濾過した後に、濾液を減圧濃縮し、ジクロロメタン３０ｍＬで希釈し、０．０２Ｎ塩酸５０ｍＬで洗浄し、硫酸ナトリウムで乾燥した。減圧濃縮し、シリカゲルカラムクロマトグラフィ（酢酸エチル：アセトニトリル＝１０：１）で精製し、白色粉末結晶としてＮ−Ｔｒｏｃ−５−アミノレブリン酸（４）を得た。
[Synthesis of N-Troc-5-aminolevulinic acid]
167.6 mg (1.0 mmol) of 5-aminolevulinic acid hydrochloride (manufactured by Cosmo Oil Co., Ltd.) was suspended in 20 mL of tetrahydrofuran (THF), 480 mg (4.52 mmol) of sodium carbonate and 2,2,2-trichloroethoxycarbonyl chloride. 190 μL (1.42 mmol) was added and stirred at room temperature for 4 hours. After filtration through celite, the filtrate was concentrated under reduced pressure, diluted with 30 mL of dichloromethane, washed with 50 mL of 0.02N hydrochloric acid, and dried over sodium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: acetonitrile = 10: 1) to obtain N-Troc-5-aminolevulinic acid (4) as white powder crystals.
1H-NMR(400MHz, CDCl3)
δ：2.65(2H, s, COOHCH 2CH2), 2.75(2H, s, CH2CH 2CO), 4.12(1H, t, COCH 2NH), 4.70(2H, s, CH 2CCl3), 5.83(1H, s, NH)
13C-NMR(100MHz, CDCl3)
δ：27.45(COOHCH2CH2), 34.07(CH2 CH2CO), 50.45(COCH2NH), 74.65(CH2CCl3), 95.27(CCl3), 154.45(OCONH), 177.08(COOH), 203.38(CH2 COCH2)
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.65 (2H, s, COOHC H 2 CH 2 ), 2.75 (2H, s, CH 2 C H 2 CO), 4.12 (1H, t, COC H 2 NH), 4.70 (2H, s, C H 2 CCl 3 ), 5.83 (1H, s, NH)
13 C-NMR (100 MHz, CDCl 3 )
δ: 27.45 (COOH C H 2 CH 2 ), 34.07 (CH 2 C H 2 CO), 50.45 (CO C H 2 NH), 74.65 ( C H 2 CCl 3 ), 95.27 (CCl 3 ), 154.45 (O C ONH), 177.08 ( C OOH), 203.38 (CH 2 C OCH 2 )
［２−（トリクロロエトキシカルボニル）アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシドの合成］
上記２−(トリクロロエトキシカルボニル)−アミノエタノール２０４．１ｍｇ（０．８７ｍｍｏｌ）とＭＳ−３Ａ８６２．８ｍｇと銀［Ｉ］−シリカアルミナ１．５５gをジクロロエタン８．６ｍＬに添加し、０℃にて３０分攪拌した。次に、上記２，３，４，６−テトラ−Ｏ−ピバロイル−α−Ｄ−グルコピラノシルブロミド１ｇ（１．７３ｍｍｏｌ）を添加し、０℃にて１時間、１０℃にて１時間、さらに室温にて３０分攪拌した。セライトを通して濾過した後に、濾液を減圧濃縮し、ジクロロメタン１３０ｍＬで希釈し、１０％炭酸水素ナトリウム１３０ｍＬ、水（１３０ｍＬ×２）で洗浄した。硫酸ナトリウムで乾燥し、減圧濃縮し、シリカゲルカラムクロマトグラフィ（トルエン：酢酸エチル＝１０：１）で精製し、シロップとして、２−(トリクロロエトキシカルボニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド（５）を得た。
[Synthesis of 2- (trichloroethoxycarbonyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside]
204.1 mg (0.87 mmol) of the above 2- (trichloroethoxycarbonyl) -aminoethanol, 862.8 mg of MS-3A and 1.55 g of silver [I] -silica alumina were added to 8.6 mL of dichloroethane, and the mixture was stirred at 0 ° C. for 30 minutes. Stir for minutes. Next, 1 g (1.73 mmol) of 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide was added, and the mixture was added at 0 ° C. for 1 hour and at 10 ° C. for 1 hour. The mixture was further stirred at room temperature for 30 minutes. After filtration through celite, the filtrate was concentrated under reduced pressure, diluted with 130 mL of dichloromethane, and washed with 130 mL of 10% sodium bicarbonate and water (130 mL × 2). The extract was dried over sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (toluene: ethyl acetate = 10: 1), and 2- (trichloroethoxycarbonyl) aminoethyl 2,3,4,6-tetra-O as a syrup. -Pivaloyl-β-D-glucopyranoside (5) was obtained.
1H-NMR(400MHz, CDCl3)
δ：3.64(2H, dd, CH 2NH), 3.79(1H, ddd, H-5), 3.97(1H, dd, H-6a), 4.15(1H, dd, H-6b), 4.22(2H, t, OCH2), 4.54(1H, d, H-1), 4.63(2H, d, CH2CCl3), 4.88(1H, dd, H-2), 5.16(1H, dd, H-4), 5.30(1H, dt, H-3)
J1,2=8.0 Hz, J2,3=9.0 Hz, J3,4=9.9 Hz, J4,5=9.5 Hz, J5,6a=4.5 Hz, J5,6b=2.0 Hz, J6a,6b=12.0 Hz
13C-NMR(100MHz, CDCl3)
δ：26.86{C(CH3)3}, 38.45(CH2N), 60.16(C-6), 66.78(OCH2), 67.51(C-4), 71.70(C-2), 72.28(C-3), 73.59(C-5), 74.30(CH2CCl3), 95.18(C-1), 101.01(CCl3), 175.90, 177.78{C(CH3)3}
1 H-NMR (400 MHz, CDCl 3 )
δ: 3.64 (2H, dd, C H 2 NH), 3.79 (1H, ddd, H-5), 3.97 (1H, dd, H-6a), 4.15 (1H, dd, H-6b), 4.22 (2H , t, OCH 2 ), 4.54 (1H, d, H-1), 4.63 (2H, d, CH 2 CCl 3 ), 4.88 (1H, dd, H-2), 5.16 (1H, dd, H-4 ), 5.30 (1H, dt, H-3)
J 1,2 = 8.0 Hz, J 2,3 = 9.0 Hz, J 3,4 = 9.9 Hz, J 4,5 = 9.5 Hz, J 5,6a = 4.5 Hz, J 5,6b = 2.0 Hz, J 6a , 6b = 12.0 Hz
13 C-NMR (100 MHz, CDCl 3 )
δ: 26.86 {C (CH 3 ) 3 }, 38.45 (CH 2 N), 60.16 (C-6), 66.78 (OCH 2 ), 67.51 (C-4), 71.70 (C-2), 72.28 (C- 3), 73.59 (C-5), 74.30 ( C H 2 CCl 3 ), 95.18 (C-1), 101.01 (CCl 3 ), 175.90, 177.78 {C (CH 3 ) 3 }
［２−アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシドの合成］
上記２−(トリクロロエトキシカルボニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド４１１．４ｍｇ（０．５６ｍｍｏｌ）と亜鉛粉末１．７４３ｇ（２６．７ｍｍｏｌ）を酢酸７．５ｍＬに添加し、５０℃にて２時間攪拌した。セライトを通して濾過した後に、濾液を減圧濃縮し、残渣をジクロロメタン３６ｍＬに溶解し、１Ｎ塩酸２４ｍＬで洗浄後、水層をジクロロメタン２５ｍＬと１０％炭酸ナトリウム５０ｍＬで洗浄し、さらに水層をジクロロメタン２０ｍＬと１０％炭酸ナトリウム１５ｍＬで洗浄し、油層を合わせ、１０％炭酸ナトリウム１５ｍＬと水５０ｍＬで洗浄した。硫酸ナトリウムで乾燥し、減圧濃縮し、シリカゲルクロマトグラフィ（トルエン：酢酸エチル＝１０：１、→酢酸エチル：メタノール＝１:１）で精製し、白色粉末結晶として、２−アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド（６）を得た。
[Synthesis of 2-aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside]
The above 2- (trichloroethoxycarbonyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside 411.4 mg (0.56 mmol) and zinc powder 1.743 g (26.7 mmol) were mixed with acetic acid. The mixture was added to 7.5 mL and stirred at 50 ° C. for 2 hours. After filtration through Celite, the filtrate was concentrated under reduced pressure, the residue was dissolved in 36 mL of dichloromethane, washed with 24 mL of 1N hydrochloric acid, the aqueous layer was washed with 25 mL of dichloromethane and 50 mL of 10% sodium carbonate, and the aqueous layer was further diluted with 20 mL and 10 mL of dichloromethane. Washed with 15 mL of% sodium carbonate, combined the oil layers and washed with 15 mL of 10% sodium carbonate and 50 mL of water. The extract was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (toluene: ethyl acetate = 10: 1, then ethyl acetate: methanol = 1: 1) to give 2-aminoethyl 2,3,4 as white powder crystals. , 6-Tetra-O-pivaloyl-β-D-glucopyranoside (6) was obtained.
1H-NMR(400MHz, CDCl3)
δ：3.40(2H, s, NH2), 3.82(1H, dd, H-6a), 3.92(1H, ddd, H-5), 4.12(2H, m, CH 2O), 4.65(1H, d, H-1), 4.76(1H, dd, H-6b), 4.84(1H, dd, H-2), 5.20(1H, dt, H-4), 5.52(1H, dd, H-3)
J1,2=8.0 Hz, J2,3=9.5 Hz, J3,4=9.7 Hz, J4,5=9.5 Hz, J5,6a=3.0 Hz, J5,6b=2.0 Hz, J6a,6b=8.4 Hz
13C-NMR(100MHz, CDCl3)
δ：38.70(CH2N), 61.61(C-6), 67.35(C-4), 70.18(C-2), 70.55(C-3), 72.85(C-5), 90.00(C-1), 176.93, 177.59, 178.25{C(CH3)3}
1 H-NMR (400 MHz, CDCl 3 )
δ: 3.40 (2H, s, NH 2 ), 3.82 (1H, dd, H-6a), 3.92 (1H, ddd, H-5), 4.12 (2H, m, C H 2 O), 4.65 (1H, d, H-1), 4.76 (1H, dd, H-6b), 4.84 (1H, dd, H-2), 5.20 (1H, dt, H-4), 5.52 (1H, dd, H-3)
J 1,2 = 8.0 Hz, J 2,3 = 9.5 Hz, J 3,4 = 9.7 Hz, J 4,5 = 9.5 Hz, J 5,6a = 3.0 Hz, J 5,6b = 2.0 Hz, J 6a , 6b = 8.4 Hz
13 C-NMR (100 MHz, CDCl 3 )
δ: 38.70 (CH 2 N), 61.61 (C-6), 67.35 (C-4), 70.18 (C-2), 70.55 (C-3), 72.85 (C-5), 90.00 (C-1) , 176.93, 177.59, 178.25 { C (CH 3 ) 3 }
［２−(Ｎ−Ｔｒｏｃ−５−アミノレブリニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシドの合成］
上記Ｎ−Ｔｒｏｃ−５−アミノレブリン酸３５．５ｍｇ（０．１２ｍｍｏｌ）と、上記２−アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド６５．４ｍｇ（０．１２ｍｍｏｌ）と、４−ジメチルアミノピリジン４．８ｍｇとをジクロロメタン７．２ｍＬ中に０℃にて溶解した。次に、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド塩酸塩（ＥＤＣ）２４．４ｍｇを添加し、０℃で２時間、次いで室温で一晩攪拌した。酢酸エチル１１ｍＬと水２．５ｍＬで分配し、油層を５％炭酸ナトリウム（２×４．４ｍＬ）、水（３×４．４ｍＬ）で洗浄し、硫酸ナトリウムで乾燥した。減圧濃縮し、シリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝３：４）で精製し、白色粉末として、２−(Ｎ−Ｔｒｏｃ−５−アミノレブリニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド（７）を得た。
[Synthesis of 2- (N-Troc-5-aminolevulinyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside]
35.5 mg (0.12 mmol) of the N-Troc-5-aminolevulinic acid and 65.4 mg (0.12 mmol) of the 2-aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside. ) And 4.8 mg of 4-dimethylaminopyridine were dissolved in 7.2 mL of dichloromethane at 0 ° C. Next, 24.4 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC) was added and stirred at 0 ° C. for 2 hours and then at room temperature overnight. Partitioned between 11 mL ethyl acetate and 2.5 mL water and the oil layer was washed with 5% sodium carbonate (2 × 4.4 mL), water (3 × 4.4 mL) and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 4), and 2- (N-Troc-5-aminolevulinyl) aminoethyl 2,3,4,6-tetra-O— was obtained as a white powder. Pivaloyl-β-D-glucopyranoside (7) was obtained.
1H-NMR(400MHz, CDCl3)
δ：2.51(2H, dt, COCH 2CH2), 2.63(2H, dt, CH2CH 2CO), 3.35(2H, ddd, CH2CH 2NH), 3.68(2H, m, OCH 2CH2), 3.78(1H, ddd, H-5), 4.02(1H, dd, H-6a), 4.07(2H, d, COCH 2NH), 4.12(1H, dd, H-6b), 4.47(1H, d, H-1), 4.67(2H, s, CH 2CCl3), 5.09(1H, dd, H-2), 5.29(1H, t, H-4), 5.44(1H, t, H-3), 5.77(1H, t, COCH2NHCO), 6.13(1H, d, CH2CH2NHCO)
J1,2=8.0 Hz, J2,3=10.0 Hz, J3,4=9.9 Hz, J4,5=9.5 Hz, J5,6a=4.0 Hz, J5,6b=2 Hz, J6a,6b=10.2 Hz
13C-NMR(100MHz, CDCl3)
δ：29.64(COCH2CH2), 33.79(CH2 CH2CO), 38.73, 38.82, 39.26{COC(CH3)3}, 50.39(COCH2NH), 60.32(C-6), 67.15(C-4), 69.35(OCH2CH2), 70.08(C-2), 70.31(C-3), 70.49(C-5), 74.65(OCH2CCl3), 89.05(CCl3), 95.30(C-1), 154.32(NHCOO), 171.11(NHCOCH2), 176.18, 176.71, 177.29 {COC(CH3)3}, 203.85(CH2 COCH2)
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.51 (2H, dt, COC H 2 CH 2 ), 2.63 (2H, dt, CH 2 C H 2 CO), 3.35 (2H, ddd, CH 2 C H 2 NH), 3.68 (2H, m, OC H 2 CH 2 ), 3.78 (1H, ddd, H-5), 4.02 (1H, dd, H-6a), 4.07 (2H, d, COC H 2 NH), 4.12 (1H, dd, H-6b) , 4.47 (1H, d, H-1), 4.67 (2H, s, C H 2 CCl 3 ), 5.09 (1H, dd, H-2), 5.29 (1H, t, H-4), 5.44 (1H , t, H-3), 5.77 (1H, t, COCH 2 N H CO), 6.13 (1H, d, CH 2 CH 2 N H CO)
J 1,2 = 8.0 Hz, J 2,3 = 10.0 Hz, J 3,4 = 9.9 Hz, J 4,5 = 9.5 Hz, J 5,6a = 4.0 Hz, J 5,6b = 2 Hz, J 6a , 6b = 10.2 Hz
13 C-NMR (100 MHz, CDCl 3 )
δ: 29.64 (CO C H 2 CH 2 ), 33.79 (CH 2 C H 2 CO), 38.73, 38.82, 39.26 {CO C (CH 3 ) 3 }, 50.39 (CO C H 2 NH), 60.32 (C- 6), 67.15 (C-4), 69.35 (O C H 2 CH 2 ), 70.08 (C-2), 70.31 (C-3), 70.49 (C-5), 74.65 (O C H 2 CCl 3 ) , 89.05 (C Cl 3 ), 95.30 (C-1), 154.32 (NHCOO), 171.11 (NH C OCH 2 ), 176.18, 176.71, 177.29 { C OC (CH 3 ) 3 }, 203.85 (CH 2 C OCH 2 )
［２−(５−アミノレブリニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシドの合成］
上記２−(Ｎ−Ｔｒｏｃ−５−アミノレブリニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド９３ｍｇ（０．１１ｍｍｏｌ）と亜鉛−銅試薬を酢酸４ｍＬ中に添加し、室温で１．５時間反応させた。セライトを通して濾過した後に、濾液を減圧濃縮し、トルエン（３×１４ｍＬ）で共沸後、酢酸エチル４７ｍＬに溶解し、１０％炭酸水素ナトリウム２３ｍＬ及び食塩水２３ｍＬで洗浄し、硫酸ナトリウムで乾燥した。その後、減圧濃縮し、シリカゲルカラムクロマトグラフィ（酢酸エチル：メタノール＝４：１）で精製し、無色シロップとして、２−(５−アミノレブリニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシドを得た。
[Synthesis of 2- (5-aminolevulinyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside]
93 mg (0.11 mmol) of 2- (N-Troc-5-aminolevulinyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside and zinc-copper reagent were added to 4 mL of acetic acid. And allowed to react for 1.5 hours at room temperature. After filtration through Celite, the filtrate was concentrated under reduced pressure, azeotroped with toluene (3 × 14 mL), dissolved in 47 mL of ethyl acetate, washed with 23 mL of 10% sodium bicarbonate and 23 mL of brine, and dried over sodium sulfate. Thereafter, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: methanol = 4: 1), and 2- (5-aminolevulinyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl- was obtained as a colorless syrup. β-D-glucopyranoside was obtained.
1H-NMR(400 MHz, CD3OD)
δ：2.41(2H, dt, COCH 2CH2), 2.72(2H, dt, CH2CH 2CO), 3.25(2H, m, OCH 2CH2), 3.81(1H, ddd, H-5), 3.87(1H, dd, H-6a), 3.99(1H, ddd, CH2CH 2NH), 4.03(1H, dd, H-6b), 4.16(2H, d, COCH 2NH), 4.64(1H, d, H-1), 4.95(1H, dd, H-2), 5.07(1H, dt, H-4), 5.35(1H, dd, H-3),5.76(1H, t, COCH2NHCO), 6.00(1H, t, CH2CH2NHCO)
J1,2=8.4 Hz, J2,3=10.0 Hz, J3,4=10.0 Hz, J4,5=10.0 Hz, J5,6a=2 Hz, J5,6b=7.5 Hz,J6a,6b=11 Hz
1 H-NMR (400 MHz, CD 3 OD)
δ: 2.41 (2H, dt, COC H 2 CH 2 ), 2.72 (2H, dt, CH 2 C H 2 CO), 3.25 (2H, m, OC H 2 CH 2 ), 3.81 (1H, ddd, H- 5), 3.87 (1H, dd, H-6a), 3.99 (1H, ddd, CH 2 C H 2 NH), 4.03 (1H, dd, H-6b), 4.16 (2H, d, COC H 2 NH) , 4.64 (1H, d, H-1), 4.95 (1H, dd, H-2), 5.07 (1H, dt, H-4), 5.35 (1H, dd, H-3), 5.76 (1H, t , COCH 2 N H CO), 6.00 (1H, t, CH 2 CH 2 N H CO)
J 1,2 = 8.4 Hz, J 2,3 = 10.0 Hz, J 3,4 = 10.0 Hz, J 4,5 = 10.0 Hz, J 5,6a = 2 Hz, J 5,6b = 7.5 Hz, J 6a , 6b = 11 Hz
［２−（５−アミノレブリニル）アミノエチル β−Ｄ−グルコピラノシドの合成］
上記２−(５−アミノレブリニル)アミノエチル ２，３，４，６−テトラ−Ｏ−ピバロイル−β−Ｄ−グルコピラノシド１０．４ｍｇをメタノール１．０ｍＬに溶解し、２８％ナトリウムメトキシド４８μＬを添加し、室温で２時間反応させた。シリカゲルカラムクロマトグラフィ（メタノール）で精製し、２−（５−アミノレブリニル）アミノエチル β−Ｄ−グルコピラノシド（９）を得た。
[Synthesis of 2- (5-aminolevulinyl) aminoethyl β-D-glucopyranoside]
10.2 mg of the above 2- (5-aminolevulinyl) aminoethyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside is dissolved in 1.0 mL of methanol, and 48 μL of 28% sodium methoxide is added. And allowed to react at room temperature for 2 hours. Purification by silica gel column chromatography (methanol) gave 2- (5-aminolevulinyl) aminoethyl β-D-glucopyranoside (9).
1H-NMR (400MHz, CD3OD)
δ：2.1及び2.3 (2 × 1H, m, NHCOCH 2 ), 2.46 (2H, m, NHCOCH2CH 2 ), 2.75 (1H, dd, H-3), 2.89 (1H, dd, H-4), 3.09 (2H, m, OCH 2 CH2), 3.18 (1H, dd, H-2), 3.26 (1H, m, H-5), 3.4 (2H, m, OCH2CH 2 ), 3.69 (1H, m, H-6a), 3.84 (1H, dd, H-6b), 4.18 (2H, m, COCH 2 NH2), 4.28 (1H, d, H-1)
J1,2= 8.0 Hz, J2,3= 9.0 Hz, J3,4= 8.0 Hz, J5,6a= 4.0 Hz, J5,6b= 1.5 Hz, J6a,6b= 10.0 Hz
13C-NMR (100MHz, CD3OD)
δ：25.12 (NHCOCH2), 30.58 (NHCOCH2 CH2), 58.21 (OCH2), 62.71 (C-6), 67.92 (COCH2NH2), 74.92 (C-2), 78.08 (C-5), 104.34 (C-1), 104.49 (CONH), 179.61 (CH2 COCH2)
1 H-NMR (400MHz, CD 3 OD)
δ: 2.1 and 2.3 (2 × 1H, m, NHCOC H 2 ), 2.46 (2H, m, NHCOCH 2 C H 2 ), 2.75 (1H, dd, H-3), 2.89 (1H, dd, H-4 ), 3.09 (2H, m, OC H 2 CH 2 ), 3.18 (1H, dd, H-2), 3.26 (1H, m, H-5), 3.4 (2H, m, OCH 2 C H 2 ), 3.69 (1H, m, H-6a), 3.84 (1H, dd, H-6b), 4.18 (2H, m, COC H 2 NH 2 ), 4.28 (1H, d, H-1)
J 1,2 = 8.0 Hz, J 2,3 = 9.0 Hz, J 3,4 = 8.0 Hz, J 5,6a = 4.0 Hz, J 5,6b = 1.5 Hz, J 6a, 6b = 10.0 Hz
13 C-NMR (100MHz, CD 3 OD)
δ: 25.12 (NHCO C H 2 ), 30.58 (NHCOCH 2 C H 2), 58.21 (O C H 2), 62.71 (C-6), 67.92 (CO C H 2 NH 2), 74.92 (C-2) , 78.08 (C-5), 104.34 (C-1), 104.49 (CONH), 179.61 (CH 2 C OCH 2 )
Claims (6)
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| JP2014079552A (en) * | 2012-10-16 | 2014-05-08 | Beijing Top Grade-Kang Ming Medical Devices Inc | A series of medicines with phytochrome catalyzing decomposition of hydrogen peroxide |
| US9757357B2 (en) * | 2011-05-06 | 2017-09-12 | Tokyo Institute Of Technology | Photodynamic therapy or diagnostic agent, using infrared-spectrum light |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9757357B2 (en) * | 2011-05-06 | 2017-09-12 | Tokyo Institute Of Technology | Photodynamic therapy or diagnostic agent, using infrared-spectrum light |
| JP2014079552A (en) * | 2012-10-16 | 2014-05-08 | Beijing Top Grade-Kang Ming Medical Devices Inc | A series of medicines with phytochrome catalyzing decomposition of hydrogen peroxide |
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