JP4417865B2 - 5-Aminolevulinic acid phosphate, method for producing the same, and use thereof - Google Patents
5-Aminolevulinic acid phosphate, method for producing the same, and use thereof Download PDFInfo
- Publication number
- JP4417865B2 JP4417865B2 JP2005051217A JP2005051217A JP4417865B2 JP 4417865 B2 JP4417865 B2 JP 4417865B2 JP 2005051217 A JP2005051217 A JP 2005051217A JP 2005051217 A JP2005051217 A JP 2005051217A JP 4417865 B2 JP4417865 B2 JP 4417865B2
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- JP
- Japan
- Prior art keywords
- group
- aminolevulinic acid
- acid phosphate
- phosphate
- aminolevulinic
- Prior art date
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- XWNWBYZHOAIHTK-UHFFFAOYSA-N 5-amino-4-oxopentanoic acid;phosphoric acid Chemical compound OP(O)(O)=O.NCC(=O)CCC(O)=O XWNWBYZHOAIHTK-UHFFFAOYSA-N 0.000 title claims description 67
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 claims description 60
- -1 2-ethylhexyl group Chemical group 0.000 claims description 51
- 239000007864 aqueous solution Substances 0.000 claims description 33
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 30
- 229960002749 aminolevulinic acid Drugs 0.000 claims description 26
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 239000003729 cation exchange resin Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000002428 photodynamic therapy Methods 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 229950010481 5-aminolevulinic acid hydrochloride Drugs 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 229910001868 water Inorganic materials 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 235000011007 phosphoric acid Nutrition 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 241000196324 Embryophyta Species 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 14
- 210000003491 skin Anatomy 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 238000000855 fermentation Methods 0.000 description 6
- 230000004151 fermentation Effects 0.000 description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 150000003016 phosphoric acids Chemical class 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 239000000032 diagnostic agent Substances 0.000 description 5
- 229940039227 diagnostic agent Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000007794 irritation Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- JYFHYPJRHGVZDY-UHFFFAOYSA-N Dibutyl phosphate Chemical compound CCCCOP(O)(=O)OCCCC JYFHYPJRHGVZDY-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000004040 coloring Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
- 229910001961 silver nitrate Inorganic materials 0.000 description 4
- 239000002689 soil Substances 0.000 description 4
- 210000002105 tongue Anatomy 0.000 description 4
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 244000291564 Allium cepa Species 0.000 description 3
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000220225 Malus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical compound COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 2
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 2
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003337 fertilizer Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 230000015784 hyperosmotic salinity response Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 231100000150 mutagenicity / genotoxicity testing Toxicity 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000011587 new zealand white rabbit Methods 0.000 description 2
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000005962 plant activator Substances 0.000 description 2
- 230000008635 plant growth Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
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- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
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- 239000012086 standard solution Substances 0.000 description 2
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- 238000000967 suction filtration Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 1
- 125000006736 (C6-C20) aryl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- LJKDOMVGKKPJBH-UHFFFAOYSA-N 2-ethylhexyl dihydrogen phosphate Chemical compound CCCCC(CC)COP(O)(O)=O LJKDOMVGKKPJBH-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- ZLHFONARZHCSET-UHFFFAOYSA-N 5-aminolevulinic acid hydrochloride Chemical compound Cl.NCC(=O)CCC(O)=O ZLHFONARZHCSET-UHFFFAOYSA-N 0.000 description 1
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000272201 Columbiformes Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 1
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- 240000007594 Oryza sativa Species 0.000 description 1
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- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
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- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
本発明は、微生物・発酵、動物・医療、植物等の分野において有用な5-アミノレブリン酸リン酸塩、その製造方法、これを含有する医療用組成物及びこれを含有する植物活力剤組成物に関する。 The present invention relates to 5-aminolevulinic acid phosphate useful in the fields of microorganisms / fermentation, animals / medicine, plants, etc., a method for producing the same, a medical composition containing the same, and a plant vital agent composition containing the same. .
5-アミノレブリン酸は、微生物・発酵分野においては、VB12生産、ヘム酵素生産、微生物培養、ポルフィリン生産など、動物・医療分野においては、感染症治療（非特許文献１）、殺菌、ヘモフィラス診断、誘導体原料、除毛、リウマチ治療（非特許文献２）、がん治療（非特許文献３）、血栓治療（非特許文献４）、癌術中診断（非特許文献５）、動物細胞培養、UVカット、ヘム代謝研究、育毛、重金属中毒ポルフィリン症診断、貧血予防などに、植物分野においては農薬などに有用なことが知られている。 5-Aminolevulinic acid is a VB 12 production, a heme enzyme production, a microorganism culture, a porphyrin production, etc. in the field of microorganisms and fermentation. In the animal and medical fields, treatment of infectious diseases (Non-patent Document 1), sterilization, hemophilus diagnosis, Derivative raw material, hair removal, rheumatic treatment (Non-patent document 2), cancer treatment (Non-patent document 3), thrombus treatment (Non-patent document 4), cancer intraoperative diagnosis (Non-patent document 5), animal cell culture, UV cut It is known to be useful for pesticides in the plant field for heme metabolism research, hair growth, heavy metal poisoning porphyria diagnosis, anemia prevention and the like.
一方、5-アミノレブリン酸は塩酸塩としてのみ製造法が知られており、原料として馬尿酸（特許文献１参照）、コハク酸モノエステルクロリド（特許文献２参照）、フルフリルアミン（例えば、特許文献３参照）、ヒドロキシメチルフルフラール（特許文献４参照）、オキソ吉草酸メチルエステル（特許文献５参照）、無水コハク酸（特許文献６参照）を使用する方法が報告されている。 On the other hand, the production method of 5-aminolevulinic acid is known only as hydrochloride, and hippuric acid (see Patent Document 1), succinic acid monoester chloride (see Patent Document 2), and furfurylamine (for example, Patent Document 3) are used as raw materials. Reference), hydroxymethylfurfural (see Patent Document 4), oxovaleric acid methyl ester (see Patent Document 5), and succinic anhydride (see Patent Document 6) have been reported.
しかしながら、5-アミノレブリン酸塩酸塩は塩酸を含んでいるため、製造過程、調剤・分包過程で気化した塩化水素により、装置腐食や刺激性を発生することを考慮する必要があり、これらを防止する措置を講ずることが望ましい。また、5-アミノレブリン酸塩酸塩を、直接、ヒトへの経口投与や皮膚への塗布の場合、舌や皮膚に灼熱感を感じるような刺激性がある。よって、医薬の分野で利用する５−アミノレブリン酸として、５−アミノレブリン酸塩酸塩よりも低刺激性の５−アミノレブリン酸の塩が求められていた。 However, since 5-aminolevulinic acid hydrochloride contains hydrochloric acid, it is necessary to consider that hydrogen chloride vaporized during the manufacturing process, dispensing / packaging process causes equipment corrosion and irritation. It is desirable to take measures. In addition, when 5-aminolevulinic acid hydrochloride is directly orally administered to humans or applied to the skin, it has irritation that makes the tongue and skin feel burning. Therefore, a 5-aminolevulinic acid salt that is less irritating than 5-aminolevulinic acid hydrochloride is required as 5-aminolevulinic acid used in the field of medicine.
また、５−アミノレブリン酸塩酸塩は植物の分野に利用されている（特許文献７参照）が、植物に対して一般的に使用されている殺菌剤成分の硝酸銀等と混合して使用すると、５−アミノレブリン酸塩酸塩と硝酸銀が反応して塩化銀の沈殿が発生する場合があり、噴霧器のノズルが詰まって噴霧できなくなる可能性があり、操作上、注意を要した。
また、５−アミノレブリン酸塩酸塩水溶液を果実へ直接噴霧をした場合、塩化物イオンが存在すると、果実の着色が十分ではない場合があった。
In addition, when a 5-aminolevulinic acid hydrochloride aqueous solution is directly sprayed onto the fruit, the presence of chloride ions may result in insufficient coloring of the fruit.
従って、本発明は低刺激性の5-アミノレブリン酸の新規な塩、その製造方法、これを含有する医療用組成物及びこれを含有する植物活力剤組成物を提供することにある。 Accordingly, it is an object of the present invention to provide a novel salt of 5-aminolevulinic acid with low irritation, a process for producing the same, a medical composition containing the same, and a plant vital agent composition containing the same.
本発明者らは、かかる実情に鑑み鋭意検討を行った結果、陽イオン交換樹脂に吸着した5-アミノレブリン酸を溶出させ、その溶出液をリン酸類と混合することにより、上記要求が満たされる5-アミノレブリン酸リン酸塩が得られることを見出し、本発明を完成させた。 As a result of intensive studies in view of such circumstances, the present inventors have eluted the 5-aminolevulinic acid adsorbed on the cation exchange resin, and the eluate is mixed with phosphoric acids to satisfy the above requirement. The inventors have found that an aminolevulinic acid phosphate can be obtained and have completed the present invention.
すなわち、本発明は、下記一般式（１） That is, the present invention provides the following general formula (1)
HOCOCH2CH2COCH2NH2・HOP(O)(OR1)n(OH)2-n （１） HOCOCH 2 CH 2 COCH 2 NH 2・ HOP (O) (OR 1 ) n (OH) 2-n (1)
（式中、R1は、水素原子又は炭素数１〜18のアルキル基を示し；ｎは０〜２の整数を示す。）で表される5-アミノレブリン酸リン酸塩を提供するものである。 (Wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms; n represents an integer of 0 to 2), and provides a 5-aminolevulinic acid phosphate represented by .
本発明はまた、陽イオン交換樹脂に吸着した5-アミノレブリン酸を溶出させ、その溶出液を、一般式（２）
HOP(O)(OR 1 ) n (OH) 2-n （２）
（式中、R 1 は、水素原子又は炭素数１〜18のアルキル基を示し；ｎは０〜２の整数を示す。）で表されるリン酸類と混合することを特徴とする前記一般式（１）で表される5-アミノレブリン酸リン酸塩の製造方法を提供するものである。
The present invention also elutes 5-aminolevulinic acid adsorbed on the cation exchange resin, and the eluate is represented by the general formula (2).
HOP (O) (OR 1 ) n (OH) 2-n (2)
(Wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms; n represents an integer of 0 to 2) and is mixed with a phosphoric acid represented by the general formula A method for producing a 5-aminolevulinic acid phosphate represented by (1) is provided.
本発明は更に、前記一般式（１）で表される5-アミノレブリン酸リン酸塩を含有する光力学的治療又は光力学的診断用組成物を提供するものである。本発明は更に、前記一般式（１）で表される５−アミノレブリン酸リン酸塩を含有する植物活力剤組成物を提供する
ものである。
The present invention further provides a photodynamic therapeutic or photodynamic diagnostic composition containing the 5-aminolevulinic acid phosphate represented by the general formula (1). The present invention further provides a plant vital agent composition containing the 5-aminolevulinic acid phosphate represented by the general formula (1).
本発明の5-アミノレブリン酸リン酸塩は、臭気が感じられず、そのため取り扱いやすい物質である。しかも、皮膚や舌に対して低刺激性であり、また皮膚等への透過性も良好であることからこれを含有する組成物に光力学的治療又は診断用薬として有用である。本発明の製造方法によれば、簡便かつ効率よく5-アミノレブリン酸リン酸塩を製造することができる。また、水溶液にした場合の塩化物イオン濃度が低いため、植物への投与において、塩素被害が生じにくい。 The 5-aminolevulinic acid phosphate of the present invention is a substance that does not feel odor and is therefore easy to handle. Moreover, since it is hypoallergenic to the skin and tongue and also has good permeability to the skin and the like, it is useful as a photodynamic therapy or diagnostic agent for a composition containing it. According to the production method of the present invention, 5-aminolevulinic acid phosphate can be produced simply and efficiently. Moreover, since the chloride ion density | concentration at the time of using aqueous solution is low, it is hard to produce chlorine damage in the administration to a plant.
前記一般式（１）中、R1で示される炭素数１〜18のアルキル基は、直鎖、分岐鎖又は環状鎖のいずれでもよい。直鎖又は分岐鎖のアルキル基としては、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、tert-ブチル基、n-ペンチル基、イソペンチル基、ネオペンチル基、tert-ペンチル基、2-メチルブチル基、n-ヘキシル基、イソヘキシル基、3-メチルペンチル基、エチルブチル基、n-ヘプチル基、2-メチルヘキシル基、n-オクチル基、イソオクチル基、tert-オクチル基、2-エチルヘキシル基、3-メチルヘプチル基、n-ノニル基、イソノニル基、1-メチルオクチル基、エチルヘプチル基、n-デシル基、1-メチルノニル基、n-ウンデシル基、1,1-ジメチルノニル基、n-ドデシル基、n-トリデシル基、n-テトラデシル基、n-ペンタデシル基、n-ヘキサデシル基、n-ヘプタデシル基、n-オクタデシル基等が挙げられる。環状鎖又は環状鎖を含むアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基、2-シクロプロピルエチル基、2-シクロブチルエチル基、2-シクロペンチルエチル基、シクロヘキシルメチル基、2-シクロヘキシルエチル基、シクロヘプチルメチル基、2-シクロオクチルエチル基、3-メチルシクロヘキシル基、4-メチルシクロヘキシル基、4-エチルシクロヘキシル基、2-メチルシクロオクチル基、3-（3-メチルシクロヘキシル）プロピル基、2-（4-メチルシクロヘキシル）エチル基、2-（4-エチルシクロヘキシル）エチル基、2-（2-メチルシクロオクチル）エチル基等が挙げられる。上記炭素数１〜18のアルキル基としては、炭素数1〜16のアルキル基が好ましく、メチル基、エチル基、n-ブチル基、n-ヘキサデシル基又は2-エチルヘキシル基が特に好ましい。 In the general formula (1), the alkyl group having 1 to 18 carbon atoms represented by R 1 may be linear, branched or cyclic. Examples of the linear or branched alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, and a neopentyl group. Tert-pentyl group, 2-methylbutyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, ethylbutyl group, n-heptyl group, 2-methylhexyl group, n-octyl group, isooctyl group, tert-octyl group Group, 2-ethylhexyl group, 3-methylheptyl group, n-nonyl group, isononyl group, 1-methyloctyl group, ethylheptyl group, n-decyl group, 1-methylnonyl group, n-undecyl group, 1,1- Examples include dimethylnonyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group and the like. Examples of the cyclic chain or an alkyl group containing a cyclic chain include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a 2-cyclopropylethyl group, a 2-cyclobutylethyl group, 2 -Cyclopentylethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, cycloheptylmethyl group, 2-cyclooctylethyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, 4-ethylcyclohexyl group, 2-methylcyclooctyl Group, 3- (3-methylcyclohexyl) propyl group, 2- (4-methylcyclohexyl) ethyl group, 2- (4-ethylcyclohexyl) ethyl group, 2- (2-methylcyclooctyl) ethyl group and the like. . As said C1-C18 alkyl group, a C1-C16 alkyl group is preferable, and a methyl group, an ethyl group, n-butyl group, n-hexadecyl group, or 2-ethylhexyl group is especially preferable.
炭素数２〜18のアルケニル基としては、ビニル基、アリル基、イソプロペニル基、2-ブテニル基、2-メチルアリル基、1,1-ジメチルアリル基、3-メチル-2-ブテニル基、3-メチル-3-ブテニル基、4-ペンテニル基、ヘキセニル基、オクテニル基、ノネニル基、デセニル基、シクロプロペニル基、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基、シクロヘプテニル基、シクロオクテニル基、4-メチルシクロヘキセニル基、4-エチルシクロヘキセニル基、2-シクロペンテニルエチル基、シクロヘキセニルメチル基、シクロヘプテニルメチル基、2-シクロブテニルエチル基、2-シクロオクテニルエチル基、3-（4-メチルシクロヘキセニル）プロピル基、4-シクロプロペニルブチル基、5-（4-エチルシクロヘキセニル）ペンチル基、オレイル基、バクセニル基、リノレイル基、リノレニル基等が挙げられ、オレイル基が好ましい。 Examples of the alkenyl group having 2 to 18 carbon atoms include vinyl group, allyl group, isopropenyl group, 2-butenyl group, 2-methylallyl group, 1,1-dimethylallyl group, 3-methyl-2-butenyl group, 3- Methyl-3-butenyl group, 4-pentenyl group, hexenyl group, octenyl group, nonenyl group, decenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group, 4-methylcyclohexenyl Group, 4-ethylcyclohexenyl group, 2-cyclopentenylethyl group, cyclohexenylmethyl group, cycloheptenylmethyl group, 2-cyclobutenylethyl group, 2-cyclooctenylethyl group, 3- (4-methylcyclohexane) Hexenyl) propyl group, 4-cyclopropenylbutyl group, 5- (4-ethylcyclohexenyl) pentyl group, oleyl group, vacce Group, a linoleyl group, a linolenyl group and the like, oleyl group.
炭素数７〜26のアラルキル基は、炭素数１〜６のアルキル基と炭素数６〜20のアリール基とから構成されるものが好ましい。炭素数１〜６のアルキル基としては、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、tert-ブチル基、n-ペンチル基、n-ヘキシル基、シクロプロピル基、シクロブチル基、シクロヘキシル基等が挙げられ、炭素数６〜20のアリール基としては、フェニル基、ナフチル基等が挙げられる。炭素数７〜26のアラルキル基のうち、ベンジル基又はフェネチル基が好ましく、ベンジル基が特に好ましい。当該アラルキル基のアリール基は、上記記載の炭素数１〜６のアルキル基、メトキシ基、エトキシ基、n-プロポキシ基、n-ブトキシ基、イソブトキシ基、tert-ブトキシ基等の炭素数１〜６のアルコキシ基、水酸基、アミノ基、ニトロ基、シアノ基、フッ素、塩素、臭素、ヨウ素等のハロゲン原子、カルボキシ基等の置換基１〜３個によって置換されていてもよい。 The aralkyl group having 7 to 26 carbon atoms is preferably composed of an alkyl group having 1 to 6 carbon atoms and an aryl group having 6 to 20 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, A cyclopropyl group, a cyclobutyl group, a cyclohexyl group, etc. are mentioned, As a C6-C20 aryl group, a phenyl group, a naphthyl group, etc. are mentioned. Of the aralkyl groups having 7 to 26 carbon atoms, a benzyl group or a phenethyl group is preferable, and a benzyl group is particularly preferable. The aryl group of the aralkyl group is an alkyl group having 1 to 6 carbon atoms described above, a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, or the like. May be substituted by 1 to 3 substituents such as a carboxy group or a halogen atom such as an alkoxy group, a hydroxyl group, an amino group, a nitro group, a cyano group, fluorine, chlorine, bromine or iodine.
一般式（１）で表わされる本発明の5-アミノレブリン酸リン酸塩は、固体でも溶液でもよい。固体とは、結晶を示すが、水和物でもよい。溶液とは、水をはじめとする溶媒に溶解又は分散した状態を示すが、そのpHがpH調整剤等によって調整されたものでもよい。また、水をはじめとする溶媒は、2種以上を混合して使用してもよい。pH調整剤としては、リン酸、ホウ酸、フタル酸、クエン酸、コハク酸、トリス、酢酸、乳酸、酒石酸、シュウ酸、フタル酸、マレイン酸やそれらの塩などを用いた緩衝液又はグッドの緩衝液が挙げられる。 The 5-aminolevulinic acid phosphate of the present invention represented by the general formula (1) may be solid or solution. The solid means a crystal, but may be a hydrate. The solution means a state in which it is dissolved or dispersed in a solvent such as water, but the pH may be adjusted with a pH adjuster or the like. In addition, two or more kinds of solvents including water may be mixed and used. pH adjusters include phosphoric acid, boric acid, phthalic acid, citric acid, succinic acid, tris, acetic acid, lactic acid, tartaric acid, oxalic acid, phthalic acid, maleic acid and their salts. A buffer solution may be mentioned.
溶液形態の5-アミノレブリン酸リン酸塩としては、水溶液が好ましい。該水溶液中の5-アミノレブリン酸リン酸塩濃度は０．０１wt ppm〜１０wt％、さらに０．１wt ppm〜５wt％、特に１wt ppm〜１wt％が好ましい。また、この水溶液のpHは３〜７、さらに３．５〜７、特に４〜７が好ましい。また、この水溶液中には、5-アミノレブリン酸リン酸塩以外の塩が含まれていてもよく、その場合塩化物イオン濃度は5-アミノレブリン酸リン酸塩の５０モル％以下、さらに１０モル％以下、特に３モル％以下が好ましい。 The 5-aminolevulinic acid phosphate in solution form is preferably an aqueous solution. The concentration of 5-aminolevulinic acid phosphate in the aqueous solution is preferably 0.01 wt ppm to 10 wt%, more preferably 0.1 wt ppm to 5 wt%, and particularly preferably 1 wt ppm to 1 wt%. The pH of this aqueous solution is preferably 3-7, more preferably 3.5-7, and particularly preferably 4-7. The aqueous solution may contain a salt other than 5-aminolevulinic acid phosphate, in which case the chloride ion concentration is 50 mol% or less of 5-aminolevulinic acid phosphate, and further 10 mol%. In the following, 3 mol% or less is particularly preferable.
本発明の5-アミノレブリン酸リン酸塩は、陽イオン交換樹脂に吸着した5-アミノレブリン酸をイオン含有水溶液で溶出させ、その溶出液をリン酸類と混合することにより製造することができる。また、その混合液に貧溶媒を加えて結晶化させることにより、5-アミノレブリン酸リン酸塩を固体として得ることができる。陽イオン交換樹脂に吸着させる5-アミノレブリン酸としては、特に制限されず、純度なども制限されない。すなわち、特開昭48-92328号公報、特開昭62-111954号公報、特開平2-76841号公報、特開平6-172281号公報、特開平7-188133号公報等、特開平11-42083号公報に記載の方法に準じて製造したもの、それらの精製前の化学反応溶液や発酵液、また市販品なども使用することができる。尚、好ましくは、5-アミノレブリン酸塩酸塩が用いられる。 The 5-aminolevulinic acid phosphate of the present invention can be produced by eluting 5-aminolevulinic acid adsorbed on a cation exchange resin with an ion-containing aqueous solution and mixing the eluate with phosphoric acids. Moreover, 5-aminolevulinic acid phosphate can be obtained as a solid by adding a poor solvent to the mixed solution and allowing it to crystallize. The 5-aminolevulinic acid adsorbed on the cation exchange resin is not particularly limited, and the purity and the like are not limited. That is, JP-A-48-92328, JP-A-62-111954, JP-A-2-76841, JP-A-6-172281, JP-A-7-188133, etc., JP-A-11-42083 Those manufactured according to the method described in Japanese Patent Publication No. Gazette, chemical reaction solutions and fermentation solutions before purification thereof, and commercial products can also be used. Preferably, 5-aminolevulinic acid hydrochloride is used.
陽イオン交換樹脂としては、強酸性陽イオン交換樹脂又は弱酸性陽イオン交換樹脂のいずれでもよい。また、キレート樹脂も好適に使用できる。これらのうちで、強酸性陽イオン交換樹脂が好ましい。強酸性陽イオン交換樹脂の種類としては、ポリスチレン系樹脂にスルホン酸基が結合したものが好ましい。 The cation exchange resin may be either a strong acid cation exchange resin or a weak acid cation exchange resin. Moreover, chelate resin can also be used conveniently. Of these, strongly acidic cation exchange resins are preferred. As a kind of strong acid cation exchange resin, the thing which the sulfonic acid group couple | bonded with the polystyrene-type resin is preferable.
5-アミノレブリン酸の陽イオン交換樹脂への吸着は、適当な溶媒に溶解した5-アミノレブリン酸溶液を陽イオン交換樹脂に通液することにより実施できる。このような溶媒としては、5-アミノレブリン酸が溶解すれば特に制限されないが、水；ジメチルスルホキシド；メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、イソブタノール等のアルコール系；N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド等のアミド系；ピリジン系などが挙げられ、水、ジメチルスルホキシド、メタノール又はエタノールが好ましく、水、メタノール又はエタノールが特に好ましい。また、２種以上の溶媒を混合して用いてもよい。また、精製前の化学反応溶液や発酵液を使用する場合には、反応溶媒の除去や適当な溶媒による希釈を行ってもよい。なお、上記溶媒、精製前の化学反応溶液や発酵液は、前記pH調整剤により、pH調整してもよい。 Adsorption of 5-aminolevulinic acid to the cation exchange resin can be carried out by passing a 5-aminolevulinic acid solution dissolved in an appropriate solvent through the cation exchange resin. Such a solvent is not particularly limited as long as 5-aminolevulinic acid dissolves, but water; dimethyl sulfoxide; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; N, N-dimethylformamide, N Amides such as N-dimethylacetamide; pyridines and the like, and water, dimethyl sulfoxide, methanol or ethanol are preferred, and water, methanol or ethanol are particularly preferred. Two or more solvents may be mixed and used. In addition, when using a chemical reaction solution or fermentation broth before purification, the reaction solvent may be removed or diluted with an appropriate solvent. In addition, you may adjust pH of the said solvent, the chemical reaction solution before fermentation, and a fermentation liquid with the said pH adjuster.
溶出に用いられるイオン含有水溶液としては特に限定されないが、リン酸、アルカリ金属もしくはアルカリ土類金属の水酸化物又は炭酸塩、アンモニア、アミン、アミノ基を有する化合物を水に溶解したものが好ましく、水酸化リチウム、水酸化ナトリウム、水酸化マグネシウム、水酸化カリウム、水酸化カルシウム、水酸化セシウム、水酸化バリウム、炭酸アンモニウム、炭酸水素アンモニウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸カリウムナトリウム、炭酸水素カリウム、アンモニア、メチルアミン、ジメチルアミン、トリメチルアミン、エチルアミン、ジエチルアミン、トリエチルアミンを水に溶解したものがより好ましく、アンモニアを水に溶解したものが特に好ましい。これらの水溶液は２種以上を組み合わせて使用してもよい。アンモニア水の濃度は、0.01〜10Nが好ましく、0.1〜3Nが特に好ましい。 The ion-containing aqueous solution used for the elution is not particularly limited, but is preferably a phosphoric acid, alkali metal or alkaline earth metal hydroxide or carbonate, ammonia, an amine, a compound having an amino group dissolved in water, Lithium hydroxide, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, barium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium potassium carbonate, carbonic acid What dissolved potassium hydrogen, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, and triethylamine in water is more preferable, and what dissolved ammonia in water is especially preferable. These aqueous solutions may be used in combination of two or more. The concentration of ammonia water is preferably 0.01 to 10N, and particularly preferably 0.1 to 3N.
5-アミノレブリン酸の溶出液と混合されるリン酸類としては、一般式：HOP(O)(OR1)n(OH)2-n（２）〔R1及びｎは前記定義のとおりである。〕で表わされる化合物を使用することができる。このようなリン酸類としては、例えば、リン酸；メチルリン酸、エチルリン酸、n-ブチルリン酸、2-エチルヘキシルリン酸、ヘキサデシルリン酸、ベンジルリン酸、オレイルリン酸、フェニルリン酸等のリン酸モノエステル；ジメチルリン酸、ジエチルリン酸、ジn-ブチルリン酸、ジ（2-エチルヘキシル）リン酸、ジヘキサデシルリン酸、ジベンジルリン酸、ジオレイルリン酸、ジフェニルリン酸等のリン酸ジエステルが挙げられ、メチルリン酸、エチルリン酸、オレイルリン酸、フェニルリン酸、ジメチルリン酸、ジエチルリン酸、ジn-ブチルリン酸、ジ（2-エチルヘキシル）リン酸、ジヘキサデシルリン酸、ジベンジルリン酸、ジオレイルリン酸又はジフェニルリン酸が特に好ましい。また、次亜リン酸又は亜リン酸も好適に使用できる。 The phosphoric acids to be mixed with the eluate of 5-aminolevulinic acid are represented by the general formula: HOP (O) (OR 1 ) n (OH) 2-n (2) [R 1 and n are as defined above. The compound represented by this can be used. Examples of such phosphoric acids include phosphoric acid; monophosphates such as methyl phosphoric acid, ethyl phosphoric acid, n-butyl phosphoric acid, 2-ethylhexyl phosphoric acid, hexadecyl phosphoric acid, benzyl phosphoric acid, oleyl phosphoric acid, and phenyl phosphoric acid. Esters: Phosphoric acid diesters such as dimethyl phosphoric acid, diethyl phosphoric acid, di-n-butyl phosphoric acid, di (2-ethylhexyl) phosphoric acid, dihexadecyl phosphoric acid, dibenzyl phosphoric acid, dioleyl phosphoric acid, diphenyl phosphoric acid, and the like Acid, ethyl phosphate, oleyl phosphate, phenyl phosphate, dimethyl phosphate, diethyl phosphate, di-n-butyl phosphate, di (2-ethylhexyl) phosphate, dihexadecyl phosphate, dibenzyl phosphate, dioleyl phosphate or diphenyl phosphate Is particularly preferred. Moreover, hypophosphorous acid or phosphorous acid can also be used conveniently.
リン酸類は、水和物又は塩のいずれでもよく、また適当な溶媒に溶解又は分散したものも好適に使用できる。リン酸類の混合量は、吸着した5-アミノレブリン酸量から想定される5-アミノレブリン酸溶出量に対して、1〜5000倍モル量が好ましく、より好ましくは1〜500倍モル量、特に1〜50倍モル量が好ましい。なお、吸着した5-アミノレブリン酸量から想定される5-アミノレブリン酸溶出量は、陽イオン交換樹脂や溶出液の種類、溶出液の通流量によっても異なるが、通常、吸着した5-アミノレブリン酸量に対し、90〜100％である。 Phosphoric acids may be either hydrates or salts, and those dissolved or dispersed in a suitable solvent can be suitably used. The mixing amount of the phosphoric acid is preferably 1 to 5000 times the molar amount, more preferably 1 to 500 times the molar amount, particularly 1 to 5 times the 5-aminolevulinic acid elution amount assumed from the adsorbed 5-aminolevulinic acid amount. A 50-fold molar amount is preferred. The elution amount of 5-aminolevulinic acid estimated from the amount of adsorbed 5-aminolevulinic acid varies depending on the type of cation exchange resin, the eluent, and the flow rate of the eluate, but usually the amount of adsorbed 5-aminolevulinic acid In contrast, it is 90 to 100%.
このような溶媒としては、水；ジメチルスルホキシド；メタノール、エタノール、プロパノール、イソプロパノール、n-ブタノール、イソブタノール等のアルコール系；N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド等のアミド系；ピリジン系などが挙げられ、水、ジメチルスルホキシド、メタノール又はエタノールが好ましく、水、メタノール又はエタノールが特に好ましい。また、2種以上の溶媒を混合して用いてもよい。 Examples of such solvents include water; dimethyl sulfoxide; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and isobutanol; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; pyridine Examples thereof include water, dimethyl sulfoxide, methanol or ethanol, and water, methanol or ethanol is particularly preferable. Two or more solvents may be mixed and used.
貧溶媒としては、固体が析出するものであれば特に制限されないが、このような溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、n-ブタノール、イソブタノール等のアルコール系；ジエチルエーテル、ジイソプロピルエーテル、ジオキサン、テトラヒドロフラン、ジメトキシエタン等のエーテル系；酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、γ-ブチロラクトン等のエステル系；アセトン、メチルエチルケトン等のケトン系；アセトニトリル、ベンゾニトリル等のニトリル系などが挙げられ、酢酸メチル、酢酸エチル、γ-ブチロラクトン、アセトン又はアセトニトリルが好ましく、酢酸メチル、γ-ブチロラクトン、アセトン又はアセトニトリルが特に好ましい。また、２種以上の溶媒を混合して用いてもよい。 The poor solvent is not particularly limited as long as a solid is precipitated. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, and isobutanol; diethyl ether, diisopropyl ether, Examples include ethers such as dioxane, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, and γ-butyrolactone; ketones such as acetone and methyl ethyl ketone; and nitriles such as acetonitrile and benzonitrile. Methyl acetate, ethyl acetate, γ-butyrolactone, acetone or acetonitrile are preferred, and methyl acetate, γ-butyrolactone, acetone or acetonitrile are particularly preferred. Two or more solvents may be mixed and used.
イオン含有水溶液による溶出及び溶出液とリン酸類との混合の温度は、溶出液及びリン酸類が固化しない状態において、-20〜60℃が好ましく、-10〜30℃が特に好ましい。 The elution with the ion-containing aqueous solution and the mixing temperature of the eluate and phosphoric acid are preferably −20 to 60 ° C., particularly preferably −10 to 30 ° C. in a state where the eluate and the phosphoric acid are not solidified.
本発明の5-アミノレブリン酸リン酸塩は、5-アミノレブリン酸のアミノ基がアシル基で保護されたものや、アミノ基に1,3-ジオキソ-1,3-ジヒドロ-イソインドール-2-イル型分子骨格となるような保護基が結合したもののように、アミノ基が加水分解可能な保護基で保護された5-アミノレブリン酸から製造してもよい。また、本発明の5-アミノレブリン酸リン酸塩は、本発明以外の製造方法、すなわち、2-フェニル-4-（β-アルコキシカルボニル-プロピオニル）-オキサゾリン-5-オンを所望のリン酸を用いて加水分解する方法や5-アミノレブリン酸塩酸塩等のリン酸塩以外の塩を溶媒中で所望のリン酸類と接触させる方法によっても得てもよい。リン酸類としては前記一般式（２）のもの、反応溶媒としては前記記載のものを使用することができる。 The 5-aminolevulinic acid phosphate of the present invention includes those in which the amino group of 5-aminolevulinic acid is protected with an acyl group, or 1,3-dioxo-1,3-dihydro-isoindol-2-yl in the amino group It may be produced from 5-aminolevulinic acid in which an amino group is protected with a hydrolyzable protecting group, such as those having a protecting group that becomes a type molecular skeleton. In addition, the 5-aminolevulinic acid phosphate of the present invention is produced by a method other than the present invention, that is, using 2-phenyl-4- (β-alkoxycarbonyl-propionyl) -oxazolin-5-one with the desired phosphoric acid. It may also be obtained by a method of hydrolyzing or a method of contacting a salt other than phosphate such as 5-aminolevulinic acid hydrochloride with a desired phosphoric acid in a solvent. As phosphoric acids, those of the general formula (2) can be used, and as the reaction solvent, those described above can be used.
5-アミノレブリン酸リン酸塩（１）は、後記実施例に示すように、5-アミノレブリン酸塩酸塩に比べて、臭気は感じられず、皮膚や舌に対する刺激性が弱く、更に変異原性が認められない。更に、動物の皮膚及び植物の表皮への透過性に優れている。従って、5-アミノレブリン酸リン酸塩は、5-アミノレブリン酸塩酸塩と同様に、ヒトを含む動物における光力学的治療又は光力学的診断剤として有用である。光力学的治療又は診断剤としては、癌、感染症、リウマチ、血栓、にきび等の治療又は診断剤が挙げられる。 As shown in the examples below, 5-aminolevulinic acid phosphate (1) does not feel odor, is less irritating to the skin and tongue, and is more mutagenic than 5-aminolevulinic acid hydrochloride. unacceptable. Furthermore, it has excellent permeability to animal skin and plant epidermis. Therefore, 5-aminolevulinic acid phosphate, like 5-aminolevulinic acid hydrochloride, is useful as a photodynamic therapy or photodynamic diagnostic agent in animals including humans. Examples of the photodynamic therapy or diagnostic agent include those for cancer, infection, rheumatism, thrombus, acne and the like.
5-アミノレブリン酸リン酸塩の光力学的治療剤又は診断剤としての使用に際しては、公知の条件で使用すればよく、具体的には、特表２００１−５０１９７０号公報、特表平４−５００７７０号公報、特表２００５−５０１０５０号公報、特表２００４−５０６００５号公報、特表２００１−５１８４９８号公報、特表平８−５０７７５５号公報に開示されている処方、方法で使用すればよい。 When 5-aminolevulinic acid phosphate is used as a photodynamic therapeutic agent or diagnostic agent, it may be used under known conditions. Specifically, JP 2001-501970 A, JP 4-500770 A No. 2005, No. 2005-501050, No. 2004-506005, No. 2001-518498, and No. 8-507755.
5-アミノレブリン酸リン酸塩を含有する光力学的治療又は光力学的診断用組成物は、皮膚外用剤、注射剤、経口剤、坐剤等の剤形にすることができる。これらの剤形にするにあたっては、薬学的に許容される担体を用いることができる。当該担体としては、水、結合剤、崩壊剤、溶解促進剤、滑沢剤、充填剤、賦形剤等が用いられる。 The composition for photodynamic therapy or photodynamic diagnosis containing 5-aminolevulinic acid phosphate can be made into a dosage form such as an external preparation for skin, an injection, an oral preparation, and a suppository. In preparing these dosage forms, a pharmaceutically acceptable carrier can be used. As the carrier, water, binder, disintegrant, dissolution accelerator, lubricant, filler, excipient and the like are used.
また、5-アミノレブリン酸リン酸塩を例えば、植物用途に使用する場合、一般的に使用される肥料成分等を含有してもよい。肥料成分としては、特許文献７に開示されている物質が挙げられる。
5-アミノレブリン酸リン酸塩は、植物活性化剤としても有用である。植物活性化剤としての使用に際しては、公知の条件で使用すればよく、具体的には、特許文献７に開示されている方法で植物に対して使用すればよい。
Moreover, when using 5-aminolevulinic acid phosphate for a plant use, for example, you may contain the fertilizer component etc. which are generally used. As a fertilizer component, the substance currently indicated by patent documents 7 is mentioned.
5-aminolevulinic acid phosphate is also useful as a plant activator. When used as a plant activator, it may be used under known conditions. Specifically, it may be used for plants by the method disclosed in Patent Document 7.
以下実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
実施例１ 5-アミノレブリン酸リン酸塩の製造
強酸性イオン交換樹脂（AMBERLITE IR120B Na、オルガノ（株）製） 180 mLをカラムに詰めた。イオン交換樹脂は、塩酸処理してナトリウムイオン型から水素イオン型に変換してから使用した。次いで、当該カラムに、5-アミノレブリン酸塩酸塩 20.00 g（119 mmol）をイオン交換水 1000 mLに溶解したものを通液した後、イオン交換水 1000 mLを通液した。次に、1N アンモニア水をゆっくりと通液し、黄色の溶出液 346 mLを採取した。採取した溶出液を85％ リン酸 16mL(H3PO4 238 mmol)に加え、エバポレータで濃縮した。濃縮液にアセトン 400 mLを加え、スタラーで激しく攪拌してから4 ℃で16時間静置した。析出した固体を吸引ろ過で回収し、アセトン 500 mLで洗浄した。得られた固体を12時間減圧乾燥し、目的物 23.04 g(101 mmol)を得た。その物性データを以下に示す。
Example 1 Production of 5-aminolevulinic acid phosphate 180 mL of a strongly acidic ion exchange resin (AMBERLITE IR120B Na, manufactured by Organo Corporation) was packed in a column. The ion exchange resin was used after being treated with hydrochloric acid to convert from a sodium ion type to a hydrogen ion type. Next, a solution of 20.00 g (119 mmol) of 5-aminolevulinic acid hydrochloride in 1000 mL of ion-exchanged water was passed through the column, and then 1000 mL of ion-exchanged water was passed through. Next, 1N aqueous ammonia was slowly passed through to collect 346 mL of a yellow eluate. The collected eluate was added to 16 mL of 85% phosphoric acid (H 3 PO 4 238 mmol) and concentrated by an evaporator. Acetone (400 mL) was added to the concentrate, and the mixture was vigorously stirred with a stirrer and allowed to stand at 4 ° C. for 16 hours. The precipitated solid was collected by suction filtration and washed with 500 mL of acetone. The obtained solid was dried under reduced pressure for 12 hours to obtain 23.04 g (101 mmol) of the desired product. The physical property data is shown below.
融点：108〜109 ℃
1H-NMR(D2O, 400 MHz) δ ppm: 2.67 (t, 2H, CH2), 2.86 (t, 2H, CH2), 4.08 (s, 2H, CH2) 13C-NMR(D2O, 100 MHz) δ ppm: 30 (CH2), 37 (CH2), 50 (CH2), 180 (CO), 207 (COO)元素分析値：C5H9NO3・H3PO4として
理論値：C 26.21％；H 5.28％；N 6.11％
実測値：C 25.6％ ；H 5.2％ ；N 6.1％
イオンクロマトグラフィーによるPO4 3-の含有率：
理論値：41.45％
実測値：43％
イオンクロマトグラフィー分析条件；分離カラム：日本ダイオネクス製 IonPac AS12A、溶離液：Na2CO3とNaHCO3を含有する水溶液（Na2CO3：3.0 mmol/L、NaHCO3：0.5 mmol/L）、流速：1.5 mL/min.、試料導入量：25 μL、カラム温度：35℃、検出器：電気伝導度検出器。
Melting point: 108-109 ° C
1 H-NMR (D 2 O, 400 MHz) δ ppm: 2.67 (t, 2H, CH 2 ), 2.86 (t, 2H, CH 2 ), 4.08 (s, 2H, CH 2 ) 13 C-NMR (D 2 O, 100 MHz) δ ppm: 30 (CH 2 ), 37 (CH 2 ), 50 (CH 2 ), 180 (CO), 207 (COO) Elemental analysis: C 5 H 9 NO 3・ H 3 PO As 4. Theoretical value: C 26.21%; H 5.28%; N 6.11%
Actual measurement: C 25.6%; H 5.2%; N 6.1%
Content of PO 4 3- by ion chromatography:
Theoretical value: 41.45%
Actual value: 43%
Analysis conditions for ion chromatography; separation column: IonPac AS12A manufactured by Nippon Dionex, eluent: aqueous solution containing Na 2 CO 3 and NaHCO 3 (Na 2 CO 3 : 3.0 mmol / L, NaHCO 3 : 0.5 mmol / L), flow rate : 1.5 mL / min., Sample introduction volume: 25 μL, column temperature: 35 ° C, detector: conductivity detector.
実施例２ ５−アミノレブリン酸（リン酸ジ−ｎ−ブチル）塩の製造
強酸性イオン交換樹脂（AMBERLITE IR120B Na、オルガノ（株）製） 180 mLをカラムに詰めた。イオン交換樹脂は、塩酸処理してナトリウムイオン型から水素イオン型に変換してから使用した。次いで、当該カラムに、5-アミノレブリン酸塩酸塩 20.00 g（119 mmol）をイオン交換水 1000 mLに溶解したものを通液した後、イオン交換水 1000 mLを通液した。次に、1N アンモニア水をゆっくりと通液し、黄色の溶出液 321 mLを採取した。採取した溶出液をリン酸ジ−ｎ−ブチル50.00g (238 mmol)に加え、エバポレータで濃縮した。濃縮液にアセトン 400 mLを加え、スタラーで激しく攪拌してから-25 ℃で16時間静置した。析出した固体を吸引ろ過で回収した。得られた固体を12時間減圧乾燥し、目的物 14.67 g(43 mmol)を得た。その物性データを以下に示す。
1H-NMR(D2O, 400MHz)δppm: 0.75(6H, CH3), 1.23(4H, CH2), 1.41(4H, CH2), 2.46(2H, CH2), 2.59(2H, CH2), 3.66(4H, CH2), 3.80(2H, CH2)
13C-NMR(D2O, 100MHz)δppm: 14(CH3), 20(CH2), 29(CH2), 34.2(CH2), 34.3(CH2),36(CH2), 67(CH2O), 176(COO), 204(CO)
Example 2 Production of 5-aminolevulinic acid (di-n-butyl phosphate) 180 mL of a strongly acidic ion exchange resin (AMBERLITE IR120B Na, manufactured by Organo Corporation) was packed in a column. The ion exchange resin was used after being treated with hydrochloric acid to convert from a sodium ion type to a hydrogen ion type. Next, a solution of 20.00 g (119 mmol) of 5-aminolevulinic acid hydrochloride in 1000 mL of ion-exchanged water was passed through the column, and then 1000 mL of ion-exchanged water was passed through. Next, 1N aqueous ammonia was slowly passed through to collect 321 mL of a yellow eluate. The collected eluate was added to 50.00 g (238 mmol) of di-n-butyl phosphate and concentrated by an evaporator. Acetone (400 mL) was added to the concentrate, and the mixture was vigorously stirred with a stirrer and allowed to stand at -25 ° C. for 16 hours. The precipitated solid was collected by suction filtration. The obtained solid was dried under reduced pressure for 12 hours to obtain 14.67 g (43 mmol) of the desired product. The physical property data is shown below.
1 H-NMR (D 2 O, 400 MHz) δppm: 0.75 (6H, CH 3 ), 1.23 (4H, CH 2 ), 1.41 (4H, CH 2 ), 2.46 (2H, CH 2 ), 2.59 (2H, CH 2 ), 3.66 (4H, CH 2 ), 3.80 (2H, CH 2 )
13 C-NMR (D 2 O, 100 MHz) δ ppm: 14 (CH 3 ), 20 (CH 2 ), 29 (CH 2 ), 34.2 (CH 2 ), 34.3 (CH 2 ), 36 (CH 2 ), 67 (CH 2 O), 176 (COO), 204 (CO)
実施例３ 5-アミノレブリン酸リン酸塩の臭気測定
5人の被験者が、実施例１で製造した5-アミノレブリン酸リン酸塩の水溶液（カラムからの溶出液とリン酸の混合液）及びその固体の臭気を直接嗅ぎ、下記の基準に従って臭気を評価した。結果を表1に示す。
Example 3 Odor measurement of 5-aminolevulinic acid phosphate
Five subjects directly smelled the 5-aminolevulinic acid phosphate aqueous solution (mixed solution of eluate from the column and phosphoric acid) prepared in Example 1 and its solid odor, and evaluated the odor according to the following criteria. did. The results are shown in Table 1.
・評価基準
○：臭いが感じられない。
△：臭いはするが不快ではない。
×：不快な臭いがする。
・ Evaluation criteria ○: No odor is felt.
Δ: It smells but is not uncomfortable.
X: There is an unpleasant odor.
比較例１
5-アミノレブリン酸塩酸塩の水溶液及び固体を使用する以外は実施例３と同様にして、臭気を評価した。なお、5-アミノレブリン酸塩酸塩の水溶液は、実施例１の5-アミノレブリン酸塩リン酸塩の水溶液の、5-アミノレブリン酸及びリン酸イオン濃度と、5-アミノレブリン酸及び塩化物イオン濃度とが、それぞれ同モル濃度となるように、5-アミノレブリン酸塩酸塩の固体と塩酸とイオン交換水により、調製した。結果を表１に示す。
Comparative Example 1
Odor was evaluated in the same manner as in Example 3 except that an aqueous solution and a solid of 5-aminolevulinic acid hydrochloride were used. The aqueous solution of 5-aminolevulinic acid hydrochloride had a 5-aminolevulinic acid and phosphate ion concentration and a 5-aminolevulinic acid and chloride ion concentration of the aqueous solution of 5-aminolevulinic acid phosphate of Example 1. These were prepared with a solid of 5-aminolevulinic acid hydrochloride, hydrochloric acid and ion-exchanged water so that each had the same molar concentration. The results are shown in Table 1.
実施例４
5-アミノレブリン酸リン酸塩0.5gを水1mLに溶解した水溶液を使用する以外は実施例３と同様にして、臭気を評価した。結果を表２に示す。
Example 4
Odor was evaluated in the same manner as in Example 3 except that an aqueous solution in which 0.5 g of 5-aminolevulinic acid phosphate was dissolved in 1 mL of water was used. The results are shown in Table 2.
比較例２
5-アミノレブリン酸塩酸塩0.5gを水1mLに溶解した水溶液を使用する以外は実施例３と同様にして、臭気を評価した。結果を表２に示す。
Comparative Example 2
The odor was evaluated in the same manner as in Example 3 except that an aqueous solution in which 0.5 g of 5-aminolevulinic acid hydrochloride was dissolved in 1 mL of water was used. The results are shown in Table 2.
表１、２より、5-アミノレブリン酸リン酸塩の水溶液は、5-アミノレブリン酸塩酸塩の水溶液に比較して臭気が認められなかった。5-アミノレブリン酸塩酸塩の水溶液の製造に必要な臭気対策や腐食性ガス対策が簡略化され、取り扱いがより簡便であった。また、5-アミノレブリン酸リン酸塩の固体も、5-アミノレブリン酸塩酸塩の固体と比べると臭気が認められず、秤量、分封等の取り扱いがより簡便であった。 From Tables 1 and 2, no odor was observed in the aqueous solution of 5-aminolevulinic acid phosphate compared to the aqueous solution of 5-aminolevulinic acid hydrochloride. Odor countermeasures and corrosive gas countermeasures necessary for the production of an aqueous solution of 5-aminolevulinic acid hydrochloride have been simplified, making handling easier. Further, the solid of 5-aminolevulinic acid phosphate did not have odor compared to the solid of 5-aminolevulinic acid hydrochloride, and handling such as weighing and sealing was easier.
実施例５ 5-アミノレブリン酸リン酸塩水溶液の酸性度測定
濃度１〜1000mMの5-アミノレブリン酸リン酸塩水溶液、5-アミノレブリン酸塩酸塩水溶液を各々調製し、その酸性度を25℃にてpHメーターで測定した。結果を図１に示す。図１から明らかなように、同一濃度の場合、5-アミノレブリン酸リン酸塩水溶液の酸性度は、5-アミノレブリン酸塩酸塩水溶液よりも低かった。
Example 5 Acidity Measurement of 5-Aminolevulinic Acid Phosphate Aqueous Solution A 5-aminolevulinic acid phosphate aqueous solution and a 5-aminolevulinic acid phosphate aqueous solution each having a concentration of 1-1000 mM were prepared, and the acidity was adjusted to pH at 25 ° C. Measured with a meter. The results are shown in FIG. As apparent from FIG. 1, the acidity of the 5-aminolevulinic acid phosphate aqueous solution was lower than that of the 5-aminolevulinic acid hydrochloride aqueous solution at the same concentration.
実施例６ 5-アミノレブリン酸リン酸塩の刺激試験
5人の被験者が、実施例１で得た5-アミノレブリン酸リン酸塩の固体 5mgを直接舌にのせ、下記の基準に従って味覚を評価した。結果を表３に示す。
Example 6 Stimulation test of 5-aminolevulinic acid phosphate
Five subjects placed 5 mg of 5-aminolevulinic acid phosphate solid obtained in Example 1 directly on their tongues, and evaluated taste according to the following criteria. The results are shown in Table 3.
・評価基準
○：刺激が感じられない。
△：刺激はあるが弱い。
×：強い刺激がある。
-Evaluation criteria ○: No irritation is felt.
Δ: Stimulation but weak.
X: There is a strong stimulus.
比較例３
5-アミノレブリン酸塩酸塩の固体 5mgを使用する以外は実施例６と同様にして、味覚を評価した。結果を表３に示す。
Comparative Example 3
Taste was evaluated in the same manner as in Example 6 except that 5 mg of 5-aminolevulinic acid hydrochloride solid was used. The results are shown in Table 3.
表３より、5-アミノレブリン酸リン酸塩は、5-アミノレブリン酸塩酸塩と比較して強い刺激が認められなかった。 As shown in Table 3, 5-aminolevulinic acid phosphate was not strongly stimulated as compared with 5-aminolevulinic acid hydrochloride.
実施例７ 微生物（細菌）を用いる変異原性試験（復帰突然変異試験）
試験は、「微生物を用いる変異原性試験の基準」（昭和63年労働省告示第77号）（平成9年労働省告示第67号による一部改正）及び「新規化学物質等に係る試験の方法について」（平成15年11月21日付け：薬食発1121002号、平成15・11・13製局第2号、環保企発第031121002号）の「細菌を用いる復帰突然変異試験」に準拠して行った。5-アミノレブリン酸リン酸塩を蒸留水（和光純薬工業）に5%(w/v)溶解した溶液0.1mLに0.1Mナトリウム−リン酸緩衝液（pH7.4）0.5mL（代謝活性化試験ではS9mix0.5mL）を加え、更に各試験菌液（ヒスチジン要求性のSalmonella typhimurium TA100，TA98，TA1535及びTA1537 ならびにトリプトファン要求性のEscherichia coli WP2 uvrA の5種類の菌株を使用（日本バイオアッセイ研究センター））0.1mLを加え、37℃で20分間振盪しながら、プレインキュベーションした。培養終了後，あらかじめ45℃に保温したトップアガーを2.0mLを加え、最小グルコース寒天平板培地に重層した。また、最小グルコース寒天平板培地は、各用量2枚設けた。ただし、溶媒対照（陰性対照）は3枚設けた。37℃で48時間培養した後、テスト菌株の生育阻害の有無を実体顕微鏡を用いて観察し、出現した復帰変異コロニー数を計数した。計測に際しては自動コロニーアナライザー(CA-11:システムサイエンス(株))を用い86mm径プレート（内径84mm）の約80mm径内を計測し面積補正及び数え落とし補正をパーソナルコンピューターで行い算出した。ただし、コロニー数が1500以上では、自動コロニーアナライザーの信頼性が落ちるため、実体顕微鏡にてプレート内5点をマニュアル測定し平均値に面積補正を行った。用量設定試験は、ガイドライン上定められた最高用量である用量5000 μg/plateを最高とし公比4で希釈した7用量を実施した。その結果、S9 mixの有無によらず、いずれの菌株においても溶媒対照と比較して2倍以上の復帰変異コロニー数の増加は認められなかった。本被験物質の菌に対する生育阻害は認められなかった。本被験物質の沈殿も認められなかった。従って，本試験はガイドライン上定められた最高用量である用量5000 μg/plateを最高とし公比2で希釈した5用量を設定した。その結果、代謝活性の有無によらず、いずれの菌株においても溶媒対照と比較して2倍以上の復帰変異コロニー数の増加は認められなかったことから（表４）、5-アミノレブリン酸リン酸塩は、突然変異誘発能を有さないことが確認された。
Example 7 Mutagenicity test using microorganisms (bacteria) (reverse mutation test)
The test is based on "Standards for mutagenicity tests using microorganisms" (Ministry of Labor Notification No. 77 in 1988) (partially revised by Ministry of Labor Notification No. 67 in 1997) and "Methods for testing new chemical substances, etc." (Based on November 21, 2003: Yakuhin no. 1121002, No. 2, 2003 / November 2003, No. 031121002) It was. 0.1M sodium phosphate buffer solution (pH7.4) 0.5mL (metabolic activation test) in 0.1mL of 5-aminolevulinic acid phosphate dissolved in distilled water (Wako Pure Chemical Industries) 5% (w / v) In addition, S9mix 0.5mL) was added, and each test bacterial solution (Histidine-required Salmonella typhimurium TA100, TA98, TA1535 and TA1537 and tryptophan-required Escherichia coli WP2 uvrA was used (Japan Bioassay Research Center) ) 0.1 mL was added and preincubated with shaking at 37 ° C. for 20 minutes. After completion of the culture, 2.0 mL of top agar previously kept at 45 ° C. was added and overlaid on a minimum glucose agar plate medium. In addition, two minimum glucose agar plates were provided for each dose. However, three solvent controls (negative controls) were provided. After culturing at 37 ° C. for 48 hours, the presence or absence of growth inhibition of the test strain was observed using a stereomicroscope, and the number of revertant colonies that appeared was counted. In the measurement, an automatic colony analyzer (CA-11: System Science Co., Ltd.) was used to measure the inside of an approximately 80 mm diameter of an 86 mm diameter plate (inner diameter 84 mm), and the area correction and count correction were performed by a personal computer. However, when the number of colonies was 1500 or more, the reliability of the automatic colony analyzer decreased. Therefore, 5 points in the plate were manually measured with a stereomicroscope, and the area was corrected to the average value. In the dose setting test, 7 doses, which were the highest dose 5,000 μg / plate defined in the guideline and diluted with a common ratio of 4, were performed. As a result, regardless of the presence or absence of S9 mix, no increase in the number of revertant colonies more than doubled was observed in any strain compared to the solvent control. No growth inhibition of the test substance against bacteria was observed. No precipitation of this test substance was observed. Therefore, in this study, 5 doses were set at the maximum dose of 5000 μg / plate, which was established in the guideline, and diluted at a common ratio of 2. As a result, regardless of the presence or absence of metabolic activity, there was no increase in the number of revertant colonies more than 2-fold in any strain compared to the solvent control (Table 4). 5-aminolevulinic acid phosphate It was confirmed that the salt has no mutagenic potential.
実施例８ 急性経口毒性試験
試験は、OECDガイドラインNo.423「急性経口毒性−急性毒性等級法」（2001年12月17日採択）に準拠して行った。一群3匹の絶食させた雌のラット（Sprague−Dawley CD種）に5−アミノレブリン酸リン酸塩を体重１kg当たり300mgの投与量で処理した。更に別の絶食させた複数郡の雌ラットを体重1kg当たり2000mgの投与量で処理した。投与後2週間連続して観察した。その結果、いずれのラットにおいても死亡が確認されず（表５）、全身毒性の徴候もなく、全てのラットで通常の体重増加が示され(表６)、急性経口半数致死量（LD50）は、体重１kg当たり2500mgより大きいと推定された。
Example 8 Acute oral toxicity test The test was conducted in accordance with OECD guideline No.423 “Acute oral toxicity-acute toxicity grading method” (adopted on December 17, 2001). A group of 3 fasted female rats (Sprague-Dawley CD species) was treated with 5-aminolevulinic acid phosphate at a dose of 300 mg / kg body weight. Yet another fasted group of female rats was treated with a dose of 2000 mg / kg body weight. Observation was continued for 2 weeks after administration. As a result, no death was confirmed in any rat (Table 5), no signs of systemic toxicity, normal weight gain was shown in all rats (Table 6), and the acute oral half-lethal dose (LD50) was , Estimated to be greater than 2500 mg / kg body weight.
実施例９ 急性皮膚刺激性試験
試験は、OECDガイドラインNo.404「急性皮膚刺激性／腐蝕性試験」（1992年7月17日採択）及びEU委員会指令92／69／EEC B4法 急性毒性（皮膚刺激性）に準拠して行った。ニュージーランド白ウサギ3匹（雄）を用い、毛をそった2.5cm四方の無傷な皮膚に5−アミノレブリン酸リン酸塩0.5gを蒸留水0.5mLに溶解したもの（pH3.1）を4時間塗布し、1、24、48、72時間まで観察を行った。その結果、24時間以内でごく軽度な赤斑が観察されたが、48時間後の観察では正常となった（表７、８）。また、ニュージーランド白ウサギ1匹（雄）を用いて、毛をそった2.5cm四方の無傷な皮膚に5−アミノレブリン酸リン酸塩0.5gを蒸留水0.5mLに溶解したもの（pH3.1）を3分、1時間塗布し、1、24、48、72時間まで観察を行った結果では、何の皮膚刺激性も観察されなかった(表７、８)。このことより、P.I.I値（一次皮膚刺激性指数）は0.5であり、現行の国連勧告GHSでの刺激性分類では分類外で刺激性物質には当てはまらないことが確認された。なお、対照として5−アミノレブリン酸塩酸塩0.5gを蒸留水0.5mLに溶解したものは、pHが2.0以下でOECDガイドラインより腐蝕性ありと判断されるため、行わなかった。
Example 9 Acute skin irritation test The test consists of OECD Guideline No. 404 “Acute Skin Irritation / Corrosion Test” (adopted July 17, 1992) and EU Commission Directive 92/69 / EEC B4 Act Acute Toxicity ( Skin irritation). Using 3 New Zealand White Rabbits (male), 2.5 cm square skin with hair and 0.5 g 5-aminolevulinic acid phosphate dissolved in 0.5 mL distilled water (pH 3.1) was applied for 4 hours. The observation was performed until 1, 24, 48, and 72 hours. As a result, very slight red spots were observed within 24 hours, but became normal when observed 48 hours later (Tables 7 and 8). In addition, using a New Zealand White Rabbit (male), a solution of 0.5 g 5-aminolevulinic acid phosphate dissolved in 0.5 mL of distilled water on 2.5 cm square intact skin with hair (pH 3.1) As a result of applying for 3 minutes for 1 hour and observing for 1, 24, 48 and 72 hours, no skin irritation was observed (Tables 7 and 8). From this, the PII value (primary skin irritation index) was 0.5, and it was confirmed that the irritant classification in the current UN recommended GHS is not applicable to irritating substances outside the classification. As a control, 0.5 g of 5-aminolevulinic acid hydrochloride dissolved in 0.5 mL of distilled water was not performed because the pH was 2.0 or less and it was judged corrosive according to the OECD guidelines.
実施例１０ 動物表皮透過性試験
透析セル（有効面積1.13cm2、図２）を用い、受容層にpH6.8の生理食塩水17mLを攪拌しながら37℃に保った。前処理した豚皮全層（表皮＋真皮）をメンブランフィルターにのせ、透析セルに設置した。供与層には、1mMの5-アミノレブリン酸リン酸塩水溶液を0.5mL添加した。所定時間毎に受容層の溶液を0.2mL採取し、新たに生理食塩水を補充した。採取した試料又は標準液それぞれ0.05mLとA液（アセチルアセトン/エタノール/水＝15/10/75（v/v/v）の混合溶液1Lに塩化ナトリウム4g含む）3.5mLとB液（ホルマリン85mLを水で１Lに希釈した溶液）0.45mLを混合し30分間加熱処理し、30分後水冷して5-アミノレブリン酸濃度をＨＰＬＣで測定し（分析条件は、蛍光検出器：励起波長473nm、蛍光波長363nmを用い、溶離液はメタノール/2.5%酢酸水溶液＝40/60(v/v)溶液を用い、カラムはWakosil-II 5C18HG、4.6mφ×150mmを用い、流速は1.0mL/min、温度25℃で行った。）、標準液のピーク面積から各濃度を算出した。
次に、豚皮の替わりにタマネギの表皮を使用して、供与層の5-アミノレブリン酸リン酸塩水溶液の濃度を0.1mMにして同様に行った。その結果を図３、４に示す。図３、４から解るように、豚皮、タマネギ表皮において５−アミノレブリン酸塩酸塩と５−アミノレブリン酸リン酸塩は、同様の透過性を示した。
Example 10 Animal Epidermal Permeability Test Using a dialysis cell (effective area 1.13 cm 2 , FIG. 2), 17 mL of physiological saline with pH 6.8 was kept at 37 ° C. with stirring in the receiving layer. The entire pretreated pig skin (epidermis + dermis) was placed on a membrane filter and placed in a dialysis cell. To the donor layer, 0.5 mL of 1 mM 5-aminolevulinic acid phosphate aqueous solution was added. 0.2 mL of the solution of the receiving layer was collected at predetermined time intervals and supplemented with physiological saline. Collected sample or standard solution 0.05mL and solution A (acetylacetone / ethanol / water = 15/10/75 (v / v / v) mixed solution 1L contains 4g of sodium chloride) 3.5mL and solution B (formalin 85mL 0.45 mL) (solution diluted to 1 L with water) is mixed and heat-treated for 30 minutes. After 30 minutes, it is cooled with water and the 5-aminolevulinic acid concentration is measured by HPLC (analysis conditions are fluorescence detector: excitation wavelength 473 nm, fluorescence wavelength Using 363 nm, eluent is methanol / 2.5% acetic acid aqueous solution = 40/60 (v / v) solution, column is Wakosil-II 5C18HG, 4.6 mφ x 150 mm, flow rate is 1.0 mL / min, temperature is 25 ° C Each concentration was calculated from the peak area of the standard solution.
Next, onion epidermis was used instead of pork skin, and the concentration of the 5-aminolevulinic acid phosphate aqueous solution in the donor layer was changed to 0.1 mM. The results are shown in FIGS. As can be seen from FIGS. 3 and 4, 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid phosphate showed similar permeability in pig skin and onion epidermis.
比較例４
5-アミノレブリン酸リン酸塩の代わりに5-アミノレブリン酸塩酸塩を使用する以外は、実施例１０と同様にして、透過性を測定した。
Comparative Example 4
The permeability was measured in the same manner as in Example 10 except that 5-aminolevulinic acid hydrochloride was used instead of 5-aminolevulinic acid phosphate.
このことより、実施例９で示したように、5-アミノレブリン酸塩酸塩を直接、皮膚に塗布した場合、刺激性があるが、5-アミノレブリン酸リン酸塩では、皮膚刺激性は感じられず、皮膚への透過性が同等であり、5-アミノレブリン酸リン酸塩は、5-アミノレブリン酸塩酸塩以上に医療（光線力学治療や光力学的診断剤）や植物に有効な塩であることが確認できた。 From this, as shown in Example 9, when 5-aminolevulinic acid hydrochloride was applied directly to the skin, there was irritation, but with 5-aminolevulinic acid phosphate, no skin irritation was felt. It has the same permeability to the skin, and 5-aminolevulinic acid phosphate is more effective in medicine (photodynamic therapy and photodynamic diagnostic agent) and plant than 5-aminolevulinic acid hydrochloride. It could be confirmed.
実施例１１ （塩化銀の沈殿発生実験）
5-アミノレブリン酸リン酸塩0.5 gと硝酸銀0.5 gをイオン交換水10 mLに溶解し、５分静置し液の様子を観察した。沈殿の発生は認められなかった。
なお、5-アミノレブリン酸塩酸塩0.5 gと硝酸銀0.5 gをイオン交換水10 mLに溶解し、５分静置し液の様子を観察した。沈殿の発生が認められた。
Example 11 (Silver Chloride Precipitation Experiment)
0.5 g of 5-aminolevulinic acid phosphate and 0.5 g of silver nitrate were dissolved in 10 mL of ion-exchanged water, allowed to stand for 5 minutes, and the state of the liquid was observed. No precipitation was observed.
It should be noted that 0.5 g of 5-aminolevulinic acid hydrochloride and 0.5 g of silver nitrate were dissolved in 10 mL of ion-exchanged water and allowed to stand for 5 minutes to observe the state of the liquid. The occurrence of precipitation was observed.
実施例１２（りんごの着色実験）
実施例１で得られた、5-アミノレブリン酸リン酸塩をイオン交換水に溶解させ、表の所定濃度とした。その液に展着剤（丸和バイオケミカル（株）社製「アプローチBI」）を濃度が0.1重量％となるように加えた。pHはリン酸を用いて調整した。
上記の5-アミノレブリン酸リン酸塩を5-アミノレブリン酸塩酸塩として、またpH調整のリン酸を塩酸とする以外は同様にして5-アミノレブリン酸塩酸塩水溶液を調製した。
りんご「ふじ」の子実が着果し、未だ赤色に着色していない主枝３本に対し、調製した液を１枝当たり2L噴霧した（9月15日）。約2ヵ月後（11月6日）にりんごを収穫し、着色度を調べた。着色の測定にはミノルタ社製、色彩度計CR−200を用いた。結果を表９に示す。
Example 12 (Apple Coloring Experiment)
The 5-aminolevulinic acid phosphate obtained in Example 1 was dissolved in ion-exchanged water to obtain a predetermined concentration in the table. A spreading agent (“Approach BI” manufactured by Maruwa Biochemical Co., Ltd.) was added to the solution so that the concentration was 0.1% by weight. The pH was adjusted using phosphoric acid.
A 5-aminolevulinic acid hydrochloride aqueous solution was prepared in the same manner except that the 5-aminolevulinic acid phosphate was changed to 5-aminolevulinic acid hydrochloride and the pH-adjusted phosphoric acid was hydrochloric acid.
The fruit of the apple “Fuji” came to fruition, and 3 L of the prepared liquid was sprayed onto 3 main branches that were not yet colored red (September 15). About two months later (November 6), apples were harvested and the degree of coloring was examined. For the measurement of coloring, a color saturation meter CR-200 manufactured by Minolta Co., Ltd. was used. The results are shown in Table 9.
表９中のLab値では、Lは明るさ、aは赤、bは黄を表す。従ってaの値が高いほど赤が濃いことになる。5-アミノレブリン塩酸塩よりも5-アミノレブリン酸リン酸塩の方が赤の着色が濃かった。 In the Lab values in Table 9, L represents brightness, a represents red, and b represents yellow. Therefore, the higher the value of a, the darker the red. The 5-aminolevulinic acid phosphate had a darker red color than the 5-aminolevulin hydrochloride.
実施例１３（植物活力効果）
内径１２ｃｍの磁気製ポットに火山灰土壌が600 g充填されかつ、１つのポットに高さ15 cmまで育ったツユクサが１本植えられているものを１２個ずつ用意して20℃の恒温環境におき、１日１回下記散布液による茎葉散布処理を行った。２１日後の葉の様子を観察した。その結果を表１０にまとめた。
Example 13 (plant vitality effect)
Prepare 12 pieces of 12 cm inner diameter magnetic pots filled with 600 g of volcanic ash soil and one potted plant that grows up to a height of 15 cm in a pot and place them in a constant temperature environment of 20 ° C. The foliage spraying treatment with the following spray liquid was performed once a day. The state of the leaves after 21 days was observed. The results are summarized in Table 10.
表１０の結果より、５−アミノレブリン酸リン酸塩に、５−アミノレブリン酸塩酸と同等以上の植物の活力効果が認められた。 From the results shown in Table 10, 5-aminolevulinic acid phosphate was recognized to have a plant vitality effect equivalent to or higher than that of 5-aminolevulinic acid hydrochloric acid.
実施例１４（植物生長調節効果）
イネ種（アキニシキ）をベンレート（住化タケダ園芸（株）製）（200倍）水溶液に一昼夜浸漬し、その後、暗条件、30℃にてインキュベートし催芽した。ハト胸期のステージのそろった種子を選び、カッターナイフで溝をつけた発泡ポリエチレンシートに、ピンセットを用いて1シート当たり１０粒挟み込み、表１１に示す各濃度の５−アミノレブリン酸リン酸塩１５０ｍLを満たした腰高シャーレにこのシートを浮かべ、２５℃、５，０００ルクス連続光照射下で２４時間インキュベートした。反復数は各濃度３反復とした。３日後、調査を行い各区の第一葉鞘長、及び種子根長を測定し無処理区に対する比を算出し、それらの平均値を算出した。その結果を表１１に示す。
Example 14 (Plant growth regulating effect)
Rice seeds (Akinishiki) were immersed in an aqueous solution of benrate (manufactured by Sumika Takeda Horticultural Co., Ltd.) (200 times) overnight, and then incubated at 30 ° C. in dark conditions for germination. Picking out seeds with the same stage of pigeon breast stage, and sandwiching 10 grains per sheet in a foamed polyethylene sheet grooved with a cutter knife, using tweezers, 150 mL of 5-aminolevulinic acid phosphate of each concentration shown in Table 11 This sheet was floated on a petri dish with a waist high, and incubated for 24 hours under continuous light irradiation at 25 ° C. and 5,000 lux. The number of repetitions was 3 for each concentration. Three days later, a survey was conducted to measure the first leaf sheath length and seed root length of each group, and the ratio to the untreated group was calculated, and the average value thereof was calculated. The results are shown in Table 11.
５−アミノレブリン酸リン酸塩は５−アミノレブリン酸塩酸塩と同等以上の植物生長促進効果を示した。 5-Aminolevulinic acid phosphate showed a plant growth promoting effect equivalent to or better than that of 5-aminolevulinic acid hydrochloride.
実施例１５（耐塩性向上効果）
内径１２ｃｍの排水穴のない磁気製ポットに畑土壌を６００ｇ充填し、ワタの種子（品種；M−５ Aｃａｌａ）を７〜８粒播種して１ｃｍ覆土し、温室内で育成させた。その後通常の管理を行い、子葉展開時に、表１２に示す濃度の供試化合物と展着剤（ネオエステリン：クミアイ化学社製）を０．０５％（ｖ／ｖ）含有する耐塩性向上剤を調製し、１０アール当たり１００リットルの散布水量で茎葉に散布処理した。各々の供試化合物は表１２の濃度とした。４日後、表１２に示すように土壌重量当たり０〜１．５重量％に相当する量の塩化ナトリウムを３０ｍＬの水に溶解させて土壌に滴下処理した。更に通常の栽培を続け、２３日後に調査を行った。調査は目視観察によって行い、結果は塩害を以下に示す６段階で評価した。結果を表１２に示す。
Example 15 (Salt tolerance improvement effect)
600 g of field soil was filled in a magnetic pot having an inner diameter of 12 cm and no drain hole, 7 to 8 seeds of cotton (variety: M-5 Acala) were sowed, covered with 1 cm, and grown in a greenhouse. Thereafter, normal management is performed, and a salt tolerance improver containing 0.05% (v / v) of a test compound and a spreading agent (neoesterin: manufactured by Kumiai Chemical Co., Ltd.) having the concentrations shown in Table 12 at the time of cotyledon development. Was sprayed onto the foliage at a spraying water volume of 100 liters per 10 ares. The concentration of each test compound was as shown in Table 12. After 4 days, as shown in Table 12, sodium chloride in an amount corresponding to 0 to 1.5% by weight per soil weight was dissolved in 30 mL of water and dropped onto the soil. Furthermore, normal cultivation was continued and the investigation was conducted after 23 days. The investigation was conducted by visual observation, and the results were evaluated for salt damage according to the following 6 levels. The results are shown in Table 12.
（評価段階）
０：全く塩害が見られない。
１：極弱い塩害が見られる。
２：弱い塩害が見られる。
３：明らかな塩害が見られる。
４：強い塩害が見られる。
５：植物体は塩害により枯死した。
(Evaluation stage)
0: No salt damage is observed.
1: Extremely weak salt damage is observed.
2: Weak salt damage is seen.
3: Obvious salt damage is observed.
4: Strong salt damage is observed.
5: The plant body died due to salt damage.
表１２に示したように、５−アミノレブリン酸リン酸塩は５−アミノレブリン酸塩酸塩と同等以上の耐塩性向上効果を示した。 As shown in Table 12, 5-aminolevulinic acid phosphate showed the same or better salt resistance improvement effect than 5-aminolevulinic acid hydrochloride.
上記実施例で用いた5-アミノレブリン酸リン酸塩水溶液中の塩化物イオン濃度を、以下の条件のイオンクロマト法で測定した結果、いずれも検出限界（０．１ppm）以下であった。
測定条件は、A.分離カラム（日本ダイオネクス製 IonPac AS12A）、B.ガードカラム（日本ダイオネクス製 IonPac AG12A）、C.溶離液（Na2CO3:3.0mmol／L、NaHCO3:0.5mmol／Lからなる水溶液）、D.流量（1.5mL／min）、E.サプレッサ（ASRS（リサイクルモード、電流値50mA））、F.試料導入量（25μL）、G.恒温槽温度（35度）、H.検出器（電気伝導度検出器）による。
As a result of measuring the chloride ion concentration in the aqueous solution of 5-aminolevulinic acid phosphate used in the above examples by ion chromatography under the following conditions, all were below the detection limit (0.1 ppm).
Measurement conditions are A. Separation column (IonPac AS12A manufactured by Nippon Dionex), B. Guard column (IonPac AG12A manufactured by Nippon Dionex), C. Eluent (Na 2 CO 3 : 3.0 mmol / L, NaHCO 3 : 0.5 mmol / L) Solution), D. flow rate (1.5 mL / min), E. suppressor (ASRS (recycle mode, current value 50 mA)), F. sample introduction volume (25 μL), G. temperature chamber temperature (35 degrees), H . By detector (electric conductivity detector).
Claims (8)
HOCOCH2CH2COCH2NH2・HOP(O)(OR1)n(OH)2-n （１）
（式中、R1は、水素原子又は炭素数１〜18のアルキル基を示し；ｎは０〜２の整数を示す。）で表される5-アミノレブリン酸リン酸塩。 The following general formula (1)
HOCOCH 2 CH 2 COCH 2 NH 2・ HOP (O) (OR 1 ) n (OH) 2-n (1)
(Wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms; n represents an integer of 0 to 2).
HOP(O)(OR 1 ) n (OH) 2-n （２）
（式中、R 1 は、水素原子又は炭素数１〜18のアルキル基を示し；ｎは０〜２の整数を示す。）で表されるリン酸類と混合することを特徴とする請求項１〜４のいずれか１項記載の5-アミノレブリン酸リン酸塩の製造方法。 The 5-aminolevulinic acid adsorbed on the cation exchange resin is eluted, and the eluate is expressed by the general formula (2)
HOP (O) (OR 1 ) n (OH) 2-n (2)
(Wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms; n represents an integer of 0 to 2) and is mixed with a phosphoric acid represented by claim 1. The manufacturing method of 5-aminolevulinic acid phosphate of any one of -4.
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| JP2005051217A JP4417865B2 (en) | 2004-03-30 | 2005-02-25 | 5-Aminolevulinic acid phosphate, method for producing the same, and use thereof |
| KR1020067020140A KR101225462B1 (en) | 2004-03-30 | 2005-03-28 | 5-Aminolevulinic acid salt, process for producing the same and use thereof |
| PT05727585T PT1731500E (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid phosphate salt, process for producing the same and use thereof |
| KR1020117013838A KR101267893B1 (en) | 2004-03-30 | 2005-03-28 | 5-Aminolevulinic acid sulfonate and process for producing the same |
| KR1020127030026A KR101312982B1 (en) | 2004-03-30 | 2005-03-28 | 5-Aminolevulinic acid salt, process for producing the same and use thereof |
| DK05727585.1T DK1731500T3 (en) | 2004-03-30 | 2005-03-28 | 5-Aminolevulinic acid phosphate salt, process for its preparation and use thereof |
| CN2005800107065A CN1942430B (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid phosphate, method for producing the same and use thereof |
| AT05727585T ATE493382T1 (en) | 2004-03-30 | 2005-03-28 | 5-AMINOLEVULIC ACID PHOSPHATE SALT, METHOD FOR THE PRODUCTION THEREOF AND ITS USE |
| CN2010102153906A CN101863788B (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid phosphate salt, process for producing the same and use thereof |
| EP05727585A EP1731500B1 (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid phosphate salt, process for producing the same and use thereof |
| PCT/JP2005/005765 WO2005100300A1 (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid salt, process for producing the same and use thereof |
| DE602005025614T DE602005025614D1 (en) | 2004-03-30 | 2005-03-28 | 5-AMINOLEVULIC ACID PHOSPHATE SALT, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF |
| PL05727585T PL1731500T3 (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid phosphate salt, process for producing the same and use thereof |
| CA2562170A CA2562170C (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid salt, process for producing the same and use thereof |
| US10/594,923 US8173839B2 (en) | 2004-03-30 | 2005-03-28 | 5-aminolevulinic acid salt, process for producing the same and use thereof |
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| NO20064373A NO335109B1 (en) | 2004-03-30 | 2006-09-27 | 5-Aminolevulinic acid salt, composition comprising such, process for its preparation and use thereof. |
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| JP4915723B2 (en) | 2006-03-13 | 2012-04-11 | コスモ石油株式会社 | Method for producing amino acid phosphates |
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| CA2715901C (en) | 2008-05-13 | 2016-05-17 | Cosmo Oil Co., Ltd. | Agent for improving lawn grass qualities comprising 5-aminolevulinic acid or a derivative thereof and a gibberellin biosynthesis inhibitor |
| KR101601669B1 (en) | 2008-05-14 | 2016-03-09 | 에스비아이 파마 가부시키가이샤 | Therapeutic agent for male sterility |
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| JP6280117B2 (en) | 2012-08-03 | 2018-02-14 | フォトキュア エイエスエイ | Compound |
| JP5845203B2 (en) * | 2013-03-26 | 2016-01-20 | コスモ石油株式会社 | Process for producing 5-aminolevulinic acid phosphate |
| WO2020218577A1 (en) | 2019-04-26 | 2020-10-29 | ネオファーマジャパン株式会社 | Therapeutic agent for flavivirus infection |
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