JP2022071097A - Allergen activity inhibitor and applications thereof - Google Patents
Allergen activity inhibitor and applications thereof Download PDFInfo
- Publication number
- JP2022071097A JP2022071097A JP2022031570A JP2022031570A JP2022071097A JP 2022071097 A JP2022071097 A JP 2022071097A JP 2022031570 A JP2022031570 A JP 2022031570A JP 2022031570 A JP2022031570 A JP 2022031570A JP 2022071097 A JP2022071097 A JP 2022071097A
- Authority
- JP
- Japan
- Prior art keywords
- group
- allergen
- egcg
- activity
- acyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000694 effects Effects 0.000 title claims abstract description 110
- 239000013566 allergen Substances 0.000 title claims abstract description 103
- 239000003112 inhibitor Substances 0.000 title abstract description 44
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical class O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 claims abstract description 80
- 239000000126 substance Substances 0.000 claims abstract description 35
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 18
- 125000002252 acyl group Chemical group 0.000 claims description 104
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 238000000034 method Methods 0.000 description 35
- 102000004882 Lipase Human genes 0.000 description 33
- 108090001060 Lipase Proteins 0.000 description 33
- 239000004367 Lipase Substances 0.000 description 33
- 235000019421 lipase Nutrition 0.000 description 33
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 31
- 229940030275 epigallocatechin gallate Drugs 0.000 description 31
- 206010020751 Hypersensitivity Diseases 0.000 description 27
- 240000005109 Cryptomeria japonica Species 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 208000030961 allergic reaction Diseases 0.000 description 18
- -1 inorganic acid salt Chemical class 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000523 sample Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 150000001765 catechin Chemical class 0.000 description 12
- 229960004784 allergens Drugs 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 241000238876 Acari Species 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 241000238631 Hexapoda Species 0.000 description 5
- 241000238711 Pyroglyphidae Species 0.000 description 5
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 5
- 235000005487 catechin Nutrition 0.000 description 5
- 229940046533 house dust mites Drugs 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 125000004663 dialkyl amino group Chemical group 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000006911 enzymatic reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000222175 Diutina rugosa Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 102000009438 IgE Receptors Human genes 0.000 description 3
- 108010073816 IgE Receptors Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 2
- 241000588986 Alcaligenes Species 0.000 description 2
- 241000228245 Aspergillus niger Species 0.000 description 2
- 241001674044 Blattodea Species 0.000 description 2
- 241001453380 Burkholderia Species 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241001661345 Moesziomyces antarcticus Species 0.000 description 2
- 235000011613 Pinus brutia Nutrition 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000179532 [Candida] cylindracea Species 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229950001002 cianidanol Drugs 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000006872 improvement Effects 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
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 229940051866 mouthwash Drugs 0.000 description 2
- 125000004108 n-butyl group Chemical group [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
- 239000007922 nasal spray Substances 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 235000021118 plant-derived protein Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000013076 target substance Substances 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
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010001742 Allergy to animal Diseases 0.000 description 1
- 244000036975 Ambrosia artemisiifolia Species 0.000 description 1
- 235000003129 Ambrosia artemisiifolia var elatior Nutrition 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- 240000006891 Artemisia vulgaris Species 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000589513 Burkholderia cepacia Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241001177891 Cheyletidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000005956 Cosmos caudatus Nutrition 0.000 description 1
- 241000218691 Cupressaceae Species 0.000 description 1
- 208000001840 Dandruff Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010052140 Eye pruritus Diseases 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 208000035533 House dust allergy Diseases 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282373 Panthera pardus Species 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 241000218641 Pinaceae Species 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 108010064851 Plant Proteins Proteins 0.000 description 1
- 241000209504 Poaceae Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589540 Pseudomonas fluorescens Species 0.000 description 1
- 241000589614 Pseudomonas stutzeri Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 206010048908 Seasonal allergy Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241000611866 Tyrophagus putrescentiae Species 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000003484 annual ragweed Nutrition 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000006263 bur ragweed Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012459 cleaning agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000003488 common ragweed Nutrition 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 125000002704 decyl group Chemical group [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])* 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [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])* 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 125000005644 linolenyl group Chemical group 0.000 description 1
- 125000005645 linoleyl group Chemical group 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 125000000628 margaroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229940062713 mite extract Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000001421 myristyl 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])[H] 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 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 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 125000002958 pentadecyl 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])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 235000009736 ragweed Nutrition 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000002889 tridecyl 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])[H] 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl 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])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K3/00—Materials not provided for elsewhere
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
本発明は、アレルゲン活性を抑制するアレルゲン活性の抑制剤に関する。 The present invention relates to an allergen activity inhibitor that suppresses allergen activity.
アレルギー反応は、一般に、外来物質がアレルゲンとなり引き起こされる過剰な免疫反応である。近年では、特に、ダニおよび花粉等のアレルゲンによってアレルギー症状を引き起こす患者の数が著しく増加している。このため、アレルギー反応を抑制する有効物質の探索は、非常に重要視されている。 An allergic reaction is generally an excessive immune reaction caused by an allergen caused by a foreign substance. In recent years, in particular, the number of patients who cause allergic symptoms due to allergens such as mites and pollen has increased remarkably. Therefore, the search for an effective substance that suppresses allergic reactions is very important.
アレルギー反応は、例えば、次の機序で起こると考えられている。まず、ダニの死骸、糞および花粉等に由来するタンパク質（アレルゲン）が、ヒトの鼻および喉等の粘膜に付着し、リンパ球により異物として認識される。そして、前記リンパ球は、前記アレルゲンを異物として認識すると、ＩｇＥ抗体を産生し、産生された前記ＩｇＥ抗体は、肥満細胞の表面のレセプターに結合して提示される。これによって、その後、同じタンパク質が前記粘膜に付着すると、前記タンパク質がアレルゲンとして前記肥満細胞上の前記ＩｇＥ抗体に作用し、前記肥満細胞からヒスタミン等の化学物質が放出される。そして、これらの化学物質が、アレルギー反応を惹起して、くしゃみ、鼻水・鼻づまり、目のかゆみ、目の充血および涙目等のアレルギー症状を引き起こす。 Allergic reactions are thought to occur, for example, by the following mechanisms: First, proteins (allergens) derived from dead mites, feces, pollen, etc. adhere to the mucous membranes of human nose and throat, and are recognized as foreign substances by lymphocytes. Then, when the lymphocyte recognizes the allergen as a foreign substance, it produces an IgE antibody, and the produced IgE antibody is presented by binding to a receptor on the surface of mast cells. As a result, when the same protein subsequently adheres to the mucous membrane, the protein acts as an allergen on the IgE antibody on the mast cell, and a chemical substance such as histamine is released from the mast cell. These chemical substances cause allergic reactions and cause allergic symptoms such as sneezing, runny nose / stuffy nose, itchy eyes, red eyes and teary eyes.
近年、前記アレルギー反応の抑制物質として、カテキン（特許文献１）およびメチル化カテキン類等が報告されている。これらの抑制物質の作用機序は、ＩｇＥ受容体であるＦｃεＲＩの発現抑制等であり、一連のアレルギー反応における一部の反応工程を抑制するものである（非特許文献１）。 In recent years, catechin (Patent Document 1), methylated catechins and the like have been reported as substances that suppress the allergic reaction. The mechanism of action of these inhibitors is suppression of the expression of FcεRI, which is an IgE receptor, and suppresses some reaction steps in a series of allergic reactions (Non-Patent Document 1).
しかしながら、本願発明者らが確認したところ、実際には、前述のようなカテキンおよびメチル化カテキンでは、アレルゲンによるアレルギー反応の発生を十分に抑制できないことがわかった。 However, as confirmed by the inventors of the present application, it was found that, in fact, the above-mentioned catechins and methylated catechins cannot sufficiently suppress the occurrence of allergic reactions caused by allergens.
そこで、本発明は、安全性を維持し且つアレルゲンの活性を抑制できる新たな有効物質の提供を目的とする。 Therefore, an object of the present invention is to provide a new effective substance capable of maintaining safety and suppressing the activity of allergens.
前記目的を達成するために、本発明のアレルゲン活性の抑制剤は、下記化学式（１）で表されるエピガロカテキンガレート（ＥＧＣＧ）の誘導体、もしくはその異性体またはそれらの塩を含むことを特徴とする。
Ｒ１～Ｒ６、Ｒ１２およびＲ１４は、それぞれ水素原子、ハロゲン、ナトリウム、カリウムまたは直鎖もしくは分枝状の飽和もしくは不飽和アシル基であり、同一でも異なっていてもよく、前記アシル基は、さらに１または複数の置換基で置換されていてもよく、前記Ｒ１～Ｒ６、Ｒ１２およびＲ１４の少なくとも１つが前記アシル基であり、Ｒ７～Ｒ１１、Ｒ１３、Ｒ１５およびＲ１６は、水素原子、ハロゲン、ナトリウムまたはカリウムであり、同一でも異なっていてもよい。
In order to achieve the above object, the allergen activity inhibitor of the present invention is characterized by containing a derivative of epigallocatechin gallate (EGCG) represented by the following chemical formula (1), an isomer thereof, or a salt thereof. And.
R 1 to R 6 , R 12 and R 14 are hydrogen atoms, halogens, sodium, potassium or linear or branched saturated or unsaturated acyl groups, respectively, and may be the same or different, and the acyl group is described above. May be further substituted with one or more substituents, wherein at least one of the R 1 to R 6 , R 12 and R 14 is the acyl group, R 7 to R 11 , R 13 and R 15 . And R 16 are hydrogen atoms, halogens, sodium or potassium and may be the same or different.
本発明のアレルゲン活性の抑制方法は、アレルゲンに前記本発明のアレルゲン活性の抑制剤を接触させることを特徴とする。 The method for suppressing allergen activity of the present invention is characterized in that the allergen is brought into contact with the agent for suppressing allergen activity of the present invention.
本発明のアレルギー反応の抑制方法は、被検体に前記本発明のアレルゲン活性の抑制剤を投与することを特徴とする。 The method for suppressing an allergic reaction of the present invention is characterized by administering the agent for suppressing allergen activity of the present invention to a subject.
本発明によれば、アレルギー反応を、安全且つ効果的に防止できる。このため、本発明は、医療分野、食品衛生分野等において、有用といえる。 According to the present invention, allergic reactions can be prevented safely and effectively. Therefore, it can be said that the present invention is useful in the medical field, food hygiene field, and the like.
＜アレルゲン活性の抑制剤＞
本発明のアレルゲン活性の抑制剤（以下、「活性抑制剤」ともいう。）は、前述のように、下記化学式（１）で表されるエピガロカテキンガレートの誘導体、もしくはその異性体またはそれらの塩を含むことを特徴とする。
Ｒ１～Ｒ６、Ｒ１２およびＲ１４は、それぞれ水素原子、ハロゲン、ナトリウム、カリウムまたは直鎖もしくは分枝状の飽和もしくは不飽和アシル基であり、同一でも異なっていてもよく、前記アシル基は、さらに１または複数の置換基で置換されていてもよく、前記Ｒ１～Ｒ６、Ｒ１２およびＲ１４の少なくとも１つが前記アシル基であり、Ｒ７～Ｒ１１、Ｒ１３、Ｒ１５およびＲ１６は、水素原子、ハロゲン、ナトリウムまたはカリウムであり、同一でも異なっていてもよい。
<Inhibitor of allergen activity>
As described above, the agent for suppressing allergen activity of the present invention (hereinafter, also referred to as “activity inhibitor”) is a derivative of epigallocatechin gallate represented by the following chemical formula (1), an isomer thereof, or an isomer thereof. It is characterized by containing salt.
R 1 to R 6 , R 12 and R 14 are hydrogen atoms, halogens, sodium, potassium or linear or branched saturated or unsaturated acyl groups, respectively, and may be the same or different, and the acyl group is described above. May be further substituted with one or more substituents, wherein at least one of the R 1 to R 6 , R 12 and R 14 is the acyl group, R 7 to R 11 , R 13 and R 15 . And R 16 are hydrogen atoms, halogens, sodium or potassium and may be the same or different.
なお、前記化学式（１）において、「Ａ～Ｄ」は、エピガロカテキンガレートにおける各環の表記である。本発明において、以下、エピガロカテキンガレート、は「ＥＧＣＧ」といい、ＥＧＣＧの誘導体は、「ＥＧＣＧ誘導体」という。 In the chemical formula (1), "A to D" is a notation of each ring in epigallocatechin gallate. In the present invention, epigallocatechin gallate is hereinafter referred to as "EGCG", and the derivative of EGCG is referred to as "EGCG derivative".
本発明において、「アレルゲン活性の抑制」とは、例えば、アレルゲン本来の活性が抑制されていることの他、アレルゲン活性の失活等であってもよい。 In the present invention, "suppression of allergen activity" may mean, for example, suppression of the original activity of the allergen, deactivation of the allergen activity, or the like.
本発明において、ＥＧＣＧ誘導体には、例えば、前記化学式（１）で表される化合物の塩、互変異性体、立体異性体、光学異性体、幾何異性体等の異性体、異性体混合物も含まれる。前記塩とは、特に制限されず、例えば、無機酸塩、有機酸塩、無機塩基塩、有機塩基塩、酸性または塩基性アミノ酸塩等があげられる。前記異性体は、例えば、各種クロマトグラフィー等の従来公知の分離方法により、精製することも可能である。また、本発明において、前記ＥＧＣＧ誘導体は、例えば、前記化学式（１）で表される化合物を、酸化、還元、加水分解、抱合等の代謝をうけて、生成する化合物も含む。 In the present invention, the EGCG derivative also includes, for example, a salt of the compound represented by the chemical formula (1), an isomer such as a metavariant, a stereoisomer, an optical isomer, a geometric isomer, or a mixture of isomers. Is done. The salt is not particularly limited, and examples thereof include an inorganic acid salt, an organic acid salt, an inorganic base salt, an organic base salt, an acidic or basic amino acid salt, and the like. The isomer can also be purified by a conventionally known separation method such as various chromatographies. Further, in the present invention, the EGCG derivative also includes, for example, a compound produced by undergoing metabolism such as oxidation, reduction, hydrolysis and conjugation of the compound represented by the chemical formula (1).
Ｒ１～Ｒ６において、前記アシル基の主鎖長は、特に制限されないが、例えば、カルボニル炭素を含み原子数６～１８であり、好ましくは１２～１８であり、より好ましくは１２、１６または１８であり、特に好ましくは、１２である。なお、前記アシル基の主鎖長とは、アシル基において最も長い鎖の原子数をいい、例えば、前記炭素原子の他に、窒素原子、硫黄原子、リン原子、酸素原子、ホウ素原子等を含んでもよい。前記アシル基の主鎖長は、例えば、飽和であっても不飽和であってもよい。 In R 1 to R 6 , the main chain length of the acyl group is not particularly limited, but for example, it contains carbonyl carbon and has 6 to 18 atoms, preferably 12 to 18, and more preferably 12, 16 or. It is 18, and particularly preferably 12. The main chain length of the acyl group means the number of atoms of the longest chain in the acyl group, and includes, for example, a nitrogen atom, a sulfur atom, a phosphorus atom, an oxygen atom, a boron atom and the like in addition to the carbon atom. But it may be. The main chain length of the acyl group may be, for example, saturated or unsaturated.
Ｒ１～Ｒ６において、前記アシル基の原子数は、特に制限されない。前記アシル基の原子数（例えば、炭素原子数）は、例えば、カルボニル炭素を含み２～２０であり、好ましくは４～２０、より好ましくは８～１８、１２～１８であり、具体的に、例えば、８、１２、１６または１８が好ましい。なお、前記アシル基が、さらに前記置換基で置換されている場合、前記炭素原子数は、例えば、前記置換基の炭素原子数を含まない数であることが好ましい。また、前記不飽和アシル基は、例えば、シスでもトランスでもよい。 In R 1 to R 6 , the number of atoms of the acyl group is not particularly limited. The number of atoms (for example, the number of carbon atoms) of the acyl group is, for example, 2 to 20 including carbonyl carbon, preferably 4 to 20, more preferably 8 to 18, 12 to 18, and specifically. For example, 8, 12, 16 or 18 are preferred. When the acyl group is further substituted with the substituent, the number of carbon atoms is preferably, for example, a number not including the number of carbon atoms of the substituent. Further, the unsaturated acyl group may be, for example, cis or trans.
前記アシル基としては、特に限定されないが、例えば、ホルミル基（Ｃ１）、アセチル基（Ｃ２）、プロピオニル基（Ｃ３）、ブチリル基（Ｃ４）、イソブチリル基（Ｃ４）、バレリル基（Ｃ５）、イソバレリル基（Ｃ５）、ピバロイル基（Ｃ５）、ヘキサノイル基（Ｃ６）、２－エチルヘキシル基（Ｃ８）、オクタノイル基（Ｃ８）、ゲラノイル基（３，７－ジメチルオクタ－２，６－ジエノイル基）（Ｃ１０）、トランス－８－メチル－６－ノネノイル基（Ｃ１０）、ウンデカノイル基（Ｃ１１）、ラウロイル基（ドデカノイル基）（Ｃ１２）、トリデカノイル基（Ｃ１３）、１２－（ジメチルアミノ）ラウロイル基（１２－（ジメチルアミノ）ドデカノイル基）（Ｃ１４）、ファルネソイル基（３，７，１１－トリメチルドデカ－２，６，１０－トリエノイル基（Ｃ１５）、パルミトイル基（ヘキサデカノイル基）（Ｃ１６）、ヘプタデカノイル基（Ｃ１７）、ステアロイル基（オクタデカノイル基）（Ｃ１８）、リノレイル基（Ｃ１８）、リノレニル基（Ｃ１８）、ノナデカノイル基（Ｃ１９）、エイコサノイル基（イコサノイル基）（Ｃ２０）等があげられる。なお、列挙したアシル基のかっこ内の「Ｃ」は、カルボニル炭素を含む炭素原子数を示す。 The acyl group is not particularly limited, but for example, a formyl group (C1), an acetyl group (C2), a propionyl group (C3), a butyryl group (C4), an isobutyryl group (C4), a valeryl group (C5), and an isovaleryl. Group (C5), Pivaloyl group (C5), Hexanoyl group (C6), 2-Ethylhexyl group (C8), Octanoyl group (C8), Geranoyl group (3,7-dimethylocta-2,6-dienoyl group) (C10) ), Trans-8-methyl-6-nonenoyl group (C10), undecanoyl group (C11), lauroyl group (dodecanoyl group) (C12), tridecanoyl group (C13), 12- (dimethylamino) lauroyl group (12- (12- ( Dimethylamino) dodecanoyl group) (C14), farnesoyl group (3,7,11-trimethyldodeca-2,6,10-trienoyl group (C15), palmitoyl group (hexadecanoyl group) (C16), heptadecanoyl group (C17) ), Stearoyl group (octadecanoyl group) (C18), linoleyl group (C18), linolenyl group (C18), nonadecanoyle group (C19), eikosanoyl group (icosanoyl group) (C20) and the like are listed. "C" in parentheses of the acyl group indicates the number of carbon atoms including carbonyl carbon.
前記アシル基の中でも、例えば、下記化学式に示すアシル基等が特に好ましい。下記アシル基のうち不飽和アシル基における不飽和結合の位置は、これらには制限されない。具体例として、トランス－８－メチル－ノネノイル基（Ｃ１０）の不飽和結合（二重結合）は、以下に示す６位には制限されず、例えば、２～５位および７位のいずれであってもよい。 Among the acyl groups, for example, the acyl group represented by the following chemical formula is particularly preferable. Of the following acyl groups, the position of the unsaturated bond in the unsaturated acyl group is not limited thereto. As a specific example, the unsaturated bond (double bond) of the trans-8-methyl-nonenoyl group (C10) is not limited to the 6-position shown below, and is, for example, any of the 2-5-position and the 7-position. You may.
前記アシル基の種類は、特に制限されず、前述のように、不飽和のアシル基、飽和のアシル基のいずれであってもよい。前記アシル基における不飽和結合の数は、特に制限されないが、例えば、１、２、３である。 The type of the acyl group is not particularly limited, and as described above, it may be either an unsaturated acyl group or a saturated acyl group. The number of unsaturated bonds in the acyl group is not particularly limited, but is, for example, 1, 2, or 3.
前記化学式（１）において、例えば、Ｒ１～Ｒ６、Ｒ１２およびＲ１４のうち、または、Ｒ１～Ｒ６のうち、いずれか１カ所のみが前記アシル基でもよいし、いずれか２カ所以上が前記アシル基でもよい。２カ所以上が前記アシル基の場合、各部位における前記アシル基は、例えば、同じでもよいし、異なってもよい。前記化学式（１）において、前記アシル基以外のＲは、特に制限されず、例えば、水素原子が好ましい。 In the chemical formula (1), for example, only one of R 1 to R 6 , R 12 and R 14 , or any one of R 1 to R 6 may be the acyl group, or any two of them. The above may be the acyl group. When two or more sites are the acyl groups, the acyl groups at each site may be the same or different, for example. In the chemical formula (1), R other than the acyl group is not particularly limited, and for example, a hydrogen atom is preferable.
前記化学式（１）において、Ｒ１～Ｒ６、Ｒ１２およびＲ１４のうち、または、Ｒ１～Ｒ６のうち、アシル基の部位は、特に制限されない。具体例として、例えば、Ｂ環のＲ１およびＲ２ならびにＤ環のＲ５およびＲ６のうち少なくとも１カ所が前記アシル基を有することが好ましく、特に、Ｒ１、Ｒ２、Ｒ５およびＲ６のうちいずれか１カ所が前記アシル基を有することが好ましい。この際、他のＲは、特に制限されず、例えば、水素原子であることが好ましい。 In the chemical formula (1), the site of the acyl group among R 1 to R 6 , R 12 and R 14 , or R 1 to R 6 is not particularly limited. As a specific example, for example, it is preferable that at least one of R 1 and R 2 of the B ring and R 5 and R 6 of the D ring has the acyl group, and in particular, R 1 , R 2 , R 5 and R. It is preferable that any one of 6 has the acyl group. At this time, the other R is not particularly limited, and is preferably a hydrogen atom, for example.
また、前記化学式（１）において、Ｂ環のＲ１、Ｒ２およびＲ３のうち少なくとも１カ所が前記アシル基であることが好ましく、より好ましくは、Ｂ環のＲ１、Ｒ２およびＲ３のうち１カ所のみがアシル基であることが好ましい。前記化学式（１）において、Ｄ環のＲ４、Ｒ５およびＲ６のうち少なくとも１カ所が前記アシル基であることが好ましく、より好ましくは、Ｄ環のＲ４、Ｒ５およびＲ６のうち１カ所のみがアシル基であることが好ましい。 Further, in the chemical formula (1), it is preferable that at least one of R 1 , R 2 and R 3 of the B ring is the acyl group, and more preferably R 1 , R 2 and R 3 of the B ring. It is preferable that only one of them is an acyl group. In the chemical formula (1), it is preferable that at least one of R 4 , R 5 and R 6 of the D ring is the acyl group, and more preferably, of R 4 , R 5 and R 6 of the D ring. It is preferable that only one place is an acyl group.
前記化学式（１）において、Ｂ環は、例えば、Ｂ環とＣ環との間の単結合を軸に回転する。このため、Ｒ１にアシル基を有する誘導体は、例えば、Ｒ３にアシル基を有する誘導体と実質的に同一である。また、前記化学式（１）において、Ｄ環は、例えば、Ｄ環とエステルとの間の単結合を軸に回転する。このため、Ｒ６にアシル基を有する誘導体は、例えば、Ｒ４にアシル基を有する誘導体と実質的に同一である。 In the chemical formula (1), the B ring rotates about, for example, a single bond between the B ring and the C ring. Therefore, the derivative having an acyl group at R 1 is substantially the same as, for example, the derivative having an acyl group at R 3 . Further, in the chemical formula (1), the D ring rotates about, for example, a single bond between the D ring and the ester. Therefore, the derivative having an acyl group at R 6 is substantially the same as, for example, the derivative having an acyl group at R 4 .
前記化学式（１）において、「Ｒ７～Ｒ１１、Ｒ１３、Ｒ１５およびＲ１６」、または、「Ｒ７～Ｒ１６」は、前述のように、水素原子、ハロゲン、ナトリウム（Ｎａ）またはカリウム（Ｋ）であり、同一でも異なっていてもよく、例えば、下記化学式（２）に示すように、水素原子であることが好ましい。下記化学式（２）において、例えば、Ｒ１～Ｒ６のいずれが前記アシル基であってもよい。具体例として、例えば、Ｒ１～Ｒ６のうち、いずれか１カ所のみまたは２カ所以上が、前述したアシル基であることが好ましく、より好ましくは、Ｒ１、Ｒ２、Ｒ５およびＲ６のうち、いずれか１カ所のみまたは２カ所以上が、前述したアシル基であることが好ましい。
前記化学式（１）のＲ１～Ｒ６において、前記アシル基は、前述のように、１または複数の置換基で置換されてもよく、具体的には、例えば、前記アシル基の水素原子が、前記置換基で置換されてもよい。前記置換基は、特に制限されず、例えば、アルキル基、アミノ基、アルキルアミノ基およびジアルキルアミノ基等があげられる。 In R 1 to R 6 of the chemical formula (1), the acyl group may be substituted with one or a plurality of substituents as described above, and specifically, for example, the hydrogen atom of the acyl group may be substituted. , May be substituted with the substituent. The substituent is not particularly limited, and examples thereof include an alkyl group, an amino group, an alkylamino group, and a dialkylamino group.
前記アルキル基は、例えば、炭素原子数１～６の直鎖もしくは分枝アルキル基があげられ、好ましくはメチル基である。また、前記アルキルアミノ基におけるアルキル基としては、例えば、炭素原子数１～６の直鎖もしくは分枝アルキル基があげられ、好ましくはメチルアミノ基である。前記ジアルキルアミノ基におけるアルキル基としては、例えば、炭素原子数１～６の直鎖もしくは分枝アルキル基があげられ、好ましくはジメチルアミノ基である。これらは、同一でも異なっていてもよい。 Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, and a methyl group is preferable. Examples of the alkyl group in the alkylamino group include a linear or branched alkyl group having 1 to 6 carbon atoms, and a methylamino group is preferable. Examples of the alkyl group in the dialkylamino group include a linear or branched alkyl group having 1 to 6 carbon atoms, and a dimethylamino group is preferable. These may be the same or different.
置換基等が鎖状構造を有する基の場合、具体的に、例えば、アルキル基、アルキルアミノ基、ジアルキルアミノ基、アルコキシ基、カルボキシアルキル基、アルコキシカルボニルアルキル基、アルコキシアルキル基、アルケノキシアルキル基等の場合、特に制限されず、直鎖状でも分枝状でもよい。置換基等の一部に鎖状構造を含む場合、例えば、置換アルキル基または置換アリール基等における置換基が鎖状構造を含む場合も同様である。置換基等に異性体が存在する場合、特に制限されず、どの異性体でもよい。例えば、単に「プロピル基」という場合、n－プロピル基およびイソプロピル基のどちらでもよく、単に「ブチル基」という場合、n－ブチル基、イソブチル基、ｓｅｃ－ブチル基およびｔｅｒｔ－ブチル基のいずれでもよく、単に「ナフチル基」という場合、１－ナフチル基および２－ナフチル基のどちらでもよい。 When the substituent or the like has a chain structure, specifically, for example, an alkyl group, an alkylamino group, a dialkylamino group, an alkoxy group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an alkoxyalkyl group, or an alkyloxyalkyl group. In the case of a group or the like, there is no particular limitation, and it may be linear or branched. The same applies when a part of the substituent or the like contains a chain structure, for example, when the substituent in the substituted alkyl group or the substituted aryl group or the like contains a chain structure. When an isomer is present in the substituent or the like, the isomer is not particularly limited and may be any isomer. For example, the term "propyl group" may be either an n-propyl group or an isopropyl group, and the term "butyl group" may be any of an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. Often, the term "naphthyl group" may be either a 1-naphthyl group or a 2-naphthyl group.
本発明において、「ハロゲン」とは、任意のハロゲン元素を指す。前記ハロゲンは、例えば、フッ素、塩素、臭素およびヨウ素があげられる。また、本発明において、「アルキル基」とは、特に限定されない。前記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、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基、ヘプタデシル基、オクタデシル基、ノナデシル基、イコシル基等があげられる。アルキル基を構造中に含む基またはアルキル基から誘導される基（アルキルアミノ基、ジアルキルアミノ基、アルコキシ基、カルボキシアルキル基、アルコキシカルボニルアルキル基、アルコキシアルキル基、アルケノキシアルキル基等）についても同様である。 In the present invention, "halogen" refers to any halogen element. Examples of the halogen include fluorine, chlorine, bromine and iodine. Further, in the present invention, the "alkyl group" is not particularly limited. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group and an octyl. Examples thereof include a group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecil group and an icosyl group. Groups containing an alkyl group in the structure or derived from an alkyl group (alkylamino group, dialkylamino group, alkoxy group, carboxyalkyl group, alkoxycarbonylalkyl group, alkoxyalkyl group, alkenoxyalkyl group, etc.) The same is true.
本発明における前記ＥＧＣＧ誘導体が、例えば、前記式（１）または前記式（２）において、Ｒ１、Ｒ２、Ｒ５およびＲ６のうち、いずれか１カ所のみに前記アシル基を有する場合、前記アシル基は、例えば、以下のようなアシル基が好ましい。この場合、Ｒ１、Ｒ２、Ｒ５およびＲ６のうち、前記アシル基以外は、例えば、水素、ハロゲン、および、Ｎａ、Ｋ等のアルカリ金属等があげられる。 When the EGCG derivative in the present invention has the acyl group in only one of R 1 , R 2 , R 5 and R 6 in the formula (1) or the formula (2), for example. As the acyl group, for example, the following acyl groups are preferable. In this case, among R 1 , R 2 , R 5 and R 6 , other than the acyl group, for example, hydrogen, halogen, and alkali metals such as Na and K can be mentioned.
第１の形態として、前記アシル基が直鎖の飽和アシル基の場合、例えば、主鎖の炭素数は、８～１８の範囲、１２～１８の範囲が好ましく、具体例としては、主鎖の炭素数１２、１６または１８のアシル基があげられる。第１の形態は、例えば、アレルゲンがダニおよび花粉等に適している。 As the first embodiment, when the acyl group is a linear saturated acyl group, for example, the number of carbon atoms in the main chain is preferably in the range of 8 to 18 and preferably in the range of 12 to 18, and specific examples thereof include the main chain. Acyl groups having 12, 16 or 18 carbon atoms can be mentioned. In the first form, for example, the allergen is suitable for mites, pollen and the like.
第２の形態として、前記アシル基が不飽和アシル基の場合、例えば、主鎖の炭素数は、１２～１８の範囲が好ましく、不飽和結合は、二か所に－Ｃ＝Ｃ－を有することが好ましく、具体例としては、主鎖の炭素数が１８であり、二か所に－Ｃ＝Ｃ－を有するアシル基があげられる。第２の形態は、例えば、アレルゲンがダニおよび花粉等に適している。 As a second embodiment, when the acyl group is an unsaturated acyl group, for example, the carbon number of the main chain is preferably in the range of 12 to 18, and the unsaturated bond has -C = C- in two places. It is preferable, and specific examples thereof include an acyl group having 18 carbon atoms in the main chain and having -C = C- in two places. In the second form, for example, the allergen is suitable for mites, pollen and the like.
第３の形態として、前記アシル基が分岐の飽和アシル基の場合、例えば、主鎖の炭素数は、６～２０の範囲が好ましく、分岐鎖の炭素数は、１～４の範囲が好ましく、分岐鎖の数は、１～３が好ましく、具体例としては、主鎖の炭素数が６であり、分岐鎖の炭素数が１であり、分岐鎖の数が２であるアシル基があげられる。 As a third embodiment, when the acyl group is a branched saturated acyl group, for example, the carbon number of the main chain is preferably in the range of 6 to 20, and the carbon number of the branched chain is preferably in the range of 1 to 4. The number of branched chains is preferably 1 to 3, and specific examples thereof include an acyl group having 6 carbon atoms in the main chain, 1 carbon atom in the branched chain, and 2 carbon atoms in the branched chain. ..
本発明における前記ＥＧＣＧ誘導体が、例えば、前記式（１）または前記式（２）において、Ｒ１、Ｒ２、Ｒ５およびＲ６のうち、いずれか２カ所のみに前記アシル基を有する場合、前記アシル基は、例えば、以下のようなアシル基が好ましい。この場合、Ｒ１、Ｒ２、Ｒ５およびＲ６のうち、前記アシル基以外は、例えば、水素、ハロゲン、および、Ｎａ、Ｋ等のアルカリ金属等があげられる。 When the EGCG derivative in the present invention has the acyl group only in any two of R 1 , R 2 , R 5 and R 6 in the formula (1) or the formula (2), for example. As the acyl group, for example, the following acyl groups are preferable. In this case, among R 1 , R 2 , R 5 and R 6 , other than the acyl group, for example, hydrogen, halogen, and alkali metals such as Na and K can be mentioned.
第４の形態として、前記アシル基が直鎖の飽和アシル基の場合、例えば、２カ所の各アシル基は、主鎖の炭素数が、８～１８の範囲が好ましく、具体例としては、主鎖の炭素数８のアシル基があげられる。第４の形態は、例えば、アレルゲンがダニおよび花粉等に適している。 As a fourth embodiment, when the acyl group is a linear saturated acyl group, for example, each of the two acyl groups preferably has a main chain having a carbon number of 8 to 18, and as a specific example, the main chain has a carbon number of 8 to 18. An acyl group having 8 carbon atoms in the chain can be mentioned. In the fourth form, for example, the allergen is suitable for mites, pollen and the like.
本発明におけるＥＧＣＧ誘導体は、例えば、１種類でもよいし、２種類以上を併用してもよい。例えば、Ｒ１～Ｒ６のうち異なる部位にアシル基を有する２種類以上のＥＧＣＧ誘導体でもよいし、異なるアシル基を有する２種類以上のＥＧＣＧ誘導体でもよい。具体例として、Ｂ環のＲ１が前記アシル基であるＥＧＣＧ誘導体、Ｒ２が前記アシル基であるＥＧＣＧ誘導体、Ｒ３が前記アシル基であるＥＧＣＧ誘導体のうち、いずれか２種類以上、または、３種類全てを含む混合物であってもよく、Ｄ環のＲ４が前記アシル基であるＥＧＣＧ誘導体、Ｒ５が前記アシル基であるＥＧＣＧ誘導体、Ｒ６が前記アシル基であるＥＧＣＧ誘導体のうち、いずれか２種類以上、または、３種類全てを含む混合物であってもよい。また、Ｂ環のＲ１～Ｒ３の少なくともいずれかが前記アシル基であるＥＧＣＧ誘導体と、Ｄ環のＲ４～Ｒ６の少なくともいずれかが前記アシル基であるＥＧＣＧ誘導体との混合物であってもよい。 The EGCG derivative in the present invention may be, for example, one type or a combination of two or more types. For example, two or more types of EGCG derivatives having an acyl group at different sites of R 1 to R 6 may be used, or two or more types of EGCG derivatives having different acyl groups may be used. As a specific example, any two or more of the EGCG derivative in which R 1 of the B ring is the acyl group, the EGCG derivative in which R 2 is the acyl group, and the EGCG derivative in which R 3 is the acyl group, or It may be a mixture containing all three types, and among the EGCG derivative in which R4 of the D ring is the acyl group, the EGCG derivative in which R5 is the acyl group, and the EGCG derivative in which R6 is the acyl group. It may be a mixture containing any two or more kinds or all three kinds. Further, a mixture of an EGCG derivative in which at least one of R 1 to R 3 of the B ring is the acyl group and an EGCG derivative in which at least one of R 4 to R 6 of the D ring is the acyl group. May be good.
本発明の活性抑制剤は、前述のようにアレルゲンに対して使用できる。前記アレルゲンは、例えば、ヒトおよび非ヒト動物に対してアレルギー反応を引き起こす原因となるものであり、特に制限されない。前記アレルゲンの具体例は、例えば、ハウスダスト、花粉、昆虫由来タンパク質ならびに植物由来タンパク質等があげられる。ハウスダストは、例えば、動物の皮膚（フケを含む）；ダニ、その虫体、その死骸およびその糞；カビならびに細菌等があげられる。前記動物は、例えば、ヒト、またはイヌおよびネコ等の非ヒト動物があげられる。前記ダニは、例えば、コナヒョウヒナニ等のヒョウヒダニ（チリダニ）類、ケナガコナダニ等のコナダニ類、フトツメダニ等のツメダニ類、イエダニ等のイエダニ類等があげられる。前記花粉は、例えば、スギ等のヒノキ科、ブタクサおよびヨモギ等のキク科、マツ等のマツ科、イネ等のイネ科等の植物の花粉があげられる。前記昆虫由来タンパク質は、例えば、ゴキブリ等のタンパク質があげられる。前記植物由来タンパク質は、例えば、ダイズ、卵、牛乳等のタンパク質があげられる。 The activity inhibitor of the present invention can be used for allergens as described above. The allergen causes, for example, an allergic reaction to humans and non-human animals, and is not particularly limited. Specific examples of the allergen include house dust, pollen, insect-derived protein, plant-derived protein and the like. House dust includes, for example, animal skin (including dandruff); mites, their insect bodies, their carcasses and their feces; molds and bacteria. Examples of the animal include humans and non-human animals such as dogs and cats. Examples of the mites include house dust mites (dust mites) such as house dust mites, house dust mites such as Tyrophagus putrescentiae, cheyletidae such as chyletidae, and house dust mites such as house dust mites. Examples of the pollen include pollen of plants such as Cupressaceae such as Sugi, Asteraceae such as ragweed and mugwort, Pinaceae such as pine, and Gramineae such as rice. Examples of the insect-derived protein include proteins such as cockroach. Examples of the plant-derived protein include proteins such as soybean, egg, and milk.
本発明の活性抑制剤は、例えば、アレルギー反応の発症の予防ならびにアレルギー反応の治療に使用することができる。具体的には、例えば、アレルゲンと前記活性抑制剤とを接触させることによって、前記アレルゲンの活性を抑制し、その結果、アレルギー反応の発症の抑制等を行うことができる。 The activity inhibitor of the present invention can be used, for example, for prevention of the onset of allergic reaction and treatment of allergic reaction. Specifically, for example, by contacting the allergen with the activity inhibitor, the activity of the allergen can be suppressed, and as a result, the onset of an allergic reaction can be suppressed.
本発明の活性抑制剤は、前記ＥＧＣＧ誘導体を含んでいればよく、その形態は何ら制限されない。前記形態としては、例えば、溶液や分散液等の液体、固体、粉末等があげられる。また、剤形は、特に制限されず、例えば、使用方法に応じて適宜設定でき、例えば、液剤、カプセル剤、錠剤、粒剤（細粒剤）、散剤等があげられる。 The activity inhibitor of the present invention may contain the EGCG derivative, and its form is not limited at all. Examples of the form include liquids such as solutions and dispersions, solids, and powders. The dosage form is not particularly limited and can be appropriately set according to the method of use. Examples thereof include liquids, capsules, tablets, granules (fine granules) and powders.
前記使用方法としては、例えば、アレルギー反応を生じる可能性がある被検体に前記活性抑制剤を投与する方法があげられる。前記被検体は、例えば、アレルゲンによりアレルギー反応を生じる可能性がある動物である。前記投与方法は、特に制限されず、非経口投与、経口投与があげられる。前記非経口投与としては、例えば、経皮投与、腹腔内投与、静脈注射等の静脈内投与、筋肉投与、皮下注射等の皮下投与、直腸投与等があげられ、好ましくは、経皮投与である。前記経皮投与は、特に制限されず、例えば、皮膚の他、粘膜等も含まれる。本発明の活性抑制剤は、例えば、これらの投与形態に応じて、例えば、前記ＥＧＣＧ誘導体を含む塗り薬、点鼻薬、鼻腔塗布薬、鼻腔洗浄薬、口腔洗浄薬、うがい薬、舌下剤、内服薬、手指等の消毒剤等として投与でき、また、ＥＧＣＧ誘導体もしくはそれを含む溶液または分散液として、ネブライザー、吸引器、注射等を用いて投与できる。また、前記ＥＧＣＧ誘導体またはそれを含む粉末として、例えば、ネブライザー、吸引器等を用いて投与できる。 Examples of the method of use include a method of administering the activity inhibitor to a subject who may cause an allergic reaction. The subject is, for example, an animal that may cause an allergic reaction due to an allergen. The administration method is not particularly limited, and examples thereof include parenteral administration and oral administration. Examples of the parenteral administration include transdermal administration, intraperitoneal administration, intravenous administration such as intravenous injection, intramuscular administration, subcutaneous administration such as subcutaneous injection, rectal administration and the like, and transdermal administration is preferable. .. The transdermal administration is not particularly limited, and includes, for example, mucous membranes as well as skin. The activity inhibitor of the present invention is, for example, depending on these administration forms, for example, an ointment containing the EGCG derivative, a nasal spray, a nasal liniment, a nasal lavage agent, an oral lavage agent, a mouthwash, a sublingual agent, an internal medicine, and the like. It can be administered as a disinfectant for fingers and the like, and can also be administered as an EGCG derivative or a solution or dispersion containing the same using a nebulizer, an aspirator, an injection or the like. Further, the EGCG derivative or the powder containing the EGCG derivative can be administered using, for example, a nebulizer, an aspirator or the like.
前記動物は、例えば、ヒト、または非ヒト動物があげられる。前記非ヒト動物は、例えば、ブタ、フェレット、ラット、マウス、ウシ等の非ヒト哺乳類、アヒル、ニワトリ等の鳥類等があげられる。 Examples of the animal include humans and non-human animals. Examples of the non-human animal include non-human mammals such as pigs, ferrets, rats, mice and cows, and birds such as ducks and chickens.
前記本発明の活性抑制剤は、例えば、前記動物等の被検体とアレルゲンとが接触する前に、前記被検体と接触させてもよいし、前記被検体と前記アレルゲンとが接触した後に、前記被検体と接触させてもよい。アレルゲン活性の抑制により前記被検体におけるアレルギー反応の発症をより効果的に抑制できることから、前者のように、前記被検体と前記アレルゲンとが接触する前に、前記被検体と前記活性抑制剤とを接触させることが好ましい。 The activity inhibitor of the present invention may be brought into contact with the subject before the allergen comes into contact with the subject such as the animal, or after the subject comes into contact with the allergen. It may be brought into contact with the subject. Since the onset of allergic reaction in the subject can be more effectively suppressed by suppressing the allergen activity, the subject and the activity inhibitor are combined before the subject and the allergen come into contact with each other as in the former case. It is preferable to bring them into contact.
前記使用方法としては、その他に、例えば、アレルゲンが存在する可能性がある被検体を前記活性抑制剤で処理する方法があげられ、前記被検体は、例えば、アレルゲンが存在する可能性がある環境であり、後述するようなものが例示される。この場合、本発明の活性抑制剤は、例えば、前記ＥＧＣＧ誘導体を含む手洗い剤、ふき取り剤、洗濯剤等の洗浄剤の形態があげられる。このように、本発明の活性抑制剤によって、例えば、手および机等、アレルゲンが存在すると思われる箇所を処理することで、存在するアレルゲンの活性を抑制し、アレルギー反応の発症の予防を図ることも可能である。また、本発明の活性抑制剤を、例えば、衣類；布団および枕等の寝具；畳、カーペット、机、椅子、ベッド等の家具、ならびにマスク等に担持させてもよい。その他にも、本発明の活性抑制剤で、例えば、エアコンまたは空気洗浄機中のフィルターを処理してもよい。この場合、例えば、本発明の活性抑制剤を前記フィルターに担持させてもよいし、本発明の活性抑制剤で前記フィルターを洗浄してもよい。 Other examples of the method of use include a method of treating a subject in which an allergen may be present with the activity inhibitor, and the subject is, for example, an environment in which an allergen may be present. This is an example of what will be described later. In this case, the activity inhibitor of the present invention may be, for example, in the form of a cleaning agent such as a hand-washing agent containing the EGCG derivative, a wiping agent, or a washing agent. As described above, the activity inhibitor of the present invention is used to suppress the activity of existing allergens and prevent the onset of allergic reactions by treating, for example, hands and desks where allergens are thought to be present. Is also possible. Further, the activity inhibitor of the present invention may be carried on, for example, clothing; bedding such as futons and pillows; furniture such as tatami mats, carpets, desks, chairs and beds, and masks. In addition, the activity inhibitor of the present invention may be used to treat, for example, a filter in an air conditioner or an air purifier. In this case, for example, the activity inhibitor of the present invention may be supported on the filter, or the filter may be washed with the activity inhibitor of the present invention.
また、前記被検体は、例えば、前記動物の生体そのものでもよいし、前記生体から採取した細胞および組織、それらの培養物でもよい。前記被検体が、例えば、前記細胞、組織等の場合、前記活性抑制剤の投与方法は、特に制限されず、例えば、培地等への添加があげられる。 Further, the subject may be, for example, the living body of the animal itself, cells and tissues collected from the living body, or a culture thereof. When the subject is, for example, the cells, tissues, or the like, the method of administering the activity inhibitor is not particularly limited, and examples thereof include addition to a medium or the like.
本発明の活性抑制剤において、前記ＥＧＣＧ誘導体の含有量は、特に制限されず、例えば、使用目的や使用方法に応じて適宜決定できる。本発明の活性抑制剤がうがい薬の場合、例えば、一回あたり１０～１００μｍｏｌの前記ＥＧＣＧ誘導体を含むことが好ましい。また、本発明の活性抑制剤が点鼻薬の場合、例えば、一回あたり１０～１００μｍｏｌの前記ＥＧＣＧ誘導体を含むことが好ましい。 In the activity inhibitor of the present invention, the content of the EGCG derivative is not particularly limited and can be appropriately determined, for example, according to the purpose of use and the method of use. When the activity inhibitor of the present invention is a mouthwash, it is preferable to contain, for example, 10 to 100 μmol of the EGCG derivative at a time. When the activity inhibitor of the present invention is a nasal spray, it is preferable to contain, for example, 10 to 100 μmol of the EGCG derivative at a time.
本発明の活性抑制剤は、例えば、その剤形や使用方法に応じて、適宜、添加剤や基剤等をさらに含んでもよい。前記添加剤としては、例えば、賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味剤、矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤、吸収促進剤等があげられる。これらの添加割合は、特に制限されず、前記ＥＧＣＧ誘導体の効果を損なわない範囲で添加することができる。 The activity inhibitor of the present invention may further contain additives, bases and the like, as appropriate, depending on, for example, its dosage form and method of use. Examples of the additive include excipients, binders, lubricants, disintegrants, colorants, flavoring agents, odorants, emulsifiers, surfactants, solubilizing agents, suspending agents, and tonicity agents. , Buffering agents, preservatives, antioxidants, stabilizers, absorption promoters and the like. The addition ratio of these is not particularly limited, and can be added within a range that does not impair the effect of the EGCG derivative.
本発明の活性抑制剤は、さらに、その他の抗アレルゲン活性を有する剤を含んでもよく、具体例としては、例えば、タンニン酸等の有機系抗アレルゲン剤、ゼオライト、銀等の無機系抗アレルゲン剤等があげられる。また、これらは、本発明の活性抑制剤に含まれてもよいし、本発明の活性抑制剤と併用してもよい。 The activity inhibitor of the present invention may further contain other agents having anti-allergen activity, and specific examples thereof include organic anti-allergen agents such as tannic acid and inorganic anti-allergen agents such as zeolite and silver. And so on. Further, these may be contained in the activity inhibitor of the present invention, or may be used in combination with the activity inhibitor of the present invention.
本発明におけるＥＧＣＧ誘導体の製造方法は、特に制限されない。前記方法としては、例えば、有機合成法、酵素等を利用する化学合成法等、従来公知の方法が採用できる。前記酵素を利用する化学合成法としては、特に制限されないが、例えば、ＷＯ２００７／１０５２８０に開示された、リパーゼを利用する方法があげられる。すなわち、有機溶媒中、ＥＧＣＧとアシル基供与体とを基質としてリパーゼにより酵素反応を行い、ＥＧＣＧをアシル化する方法である。この方法によれば、例えば、ＥＧＣＧを選択的にアシル化することができる。なお、以下に、一例として、リパーゼを使用する方法を例示するが、本発明は、ＥＧＣＧ誘導体の製造方法には、何ら制限されない。 The method for producing an EGCG derivative in the present invention is not particularly limited. As the method, conventionally known methods such as an organic synthesis method and a chemical synthesis method using an enzyme or the like can be adopted. The chemical synthesis method using the enzyme is not particularly limited, and examples thereof include a method using lipase disclosed in WO2007 / 105280. That is, it is a method of acylating EGCG by performing an enzymatic reaction with lipase using EGCG and an acyl group donor as substrates in an organic solvent. According to this method, for example, EGCG can be selectively acylated. In the following, a method using lipase will be exemplified as an example, but the present invention is not limited to the method for producing an EGCG derivative.
前記リパーゼとしては、例えば、ＩＵＢ Ｎｏ．３．１．１．３．のリパーゼが使用できる。具体例として、Aspergillus niger等のAspergillus属由来リパーゼ；Candida rugosa、Candida cylindracea、Candida antarctica等のCandida属由来リパーゼ；Pseudomonas fluorescens、Pseudomonas cepacia、Pseudomonas stutzeri等のPseudomonas属由来リパーゼ；Alcaligenes属由来リパーゼ；Burkholderia cepacia等のBurkholderia属由来リパーゼ；ブタ膵臓由来のリパーゼ等があげられる。これらは、従来公知の方法により調製することもできるが、例えば、Lipase AS“AMANO”、Lipase AYS“AMANO”、Lipase PS“AMANO”、Lipase AK“AMANO”20、Lipase AH“AMANO”（全て商品名：天野エンザイム社製）、Lipase MY、Lipase OF、Lipase PL、Lipase PLC、Lipase PLG、Lipase QLM、Lipase QLC、Lipase QLG、Lipase SL、Lipase TL（全て商品名：名糖産業社製）、Lipase PPL、L4777 Lipase acrylic resin from Candida Antarctica、L3126 Lipase from porcine pancreas（全て商品名：シグマアルドリッチ社製）等の市販品も使用できる。なお、各市販品の物理化学的性質は、それぞれの商品説明書に記載の通りであり、同様の物理化学的性質を示す酵素も同様に使用できる。 Examples of the lipase include IUB No. 3.1.1.3. Lipase can be used. Specific examples include lipases derived from the genus Aspergillus such as Aspergillus niger ; lipases derived from the genus Candida such as Candida rugosa , Candida cylindracea , and Candida antarctica ; Burkholderia -derived lipases such as; Pseudomonas-derived lipases and the like. These can be prepared by conventionally known methods, for example, Lipase AS “AMANO”, Lipase AYS “AMANO”, Lipase PS “AMANO”, Lipase AK “AMANO” 20, Lipase AH “AMANO” (all products). Name: Amano Enzyme), Lipase MY, Lipase OF, Lipase PL, Lipase PLC, Lipase PLG, Lipase QLM, Lipase QLC, Lipase QLG, Lipase SL, Lipase TL (all product names: Lipase TL), Lipase Commercial products such as PPL, L4777 Lipase acrylic resin from Candida Antarctica, and L3126 Lipase from porcine pancreas (all trade names: manufactured by Sigma Aldrich) can also be used. The physicochemical properties of each commercially available product are as described in the respective product manuals, and enzymes exhibiting similar physicochemical properties can also be used in the same manner.
また、以下に示すような（１）～（８）の何れかの物理化学的特性および酵素学的特性を有するリパーゼであってもよい。
（１）分子量３５，０００、等電点４．１０（例えば、Aspergillus niger由来）
（２）分子量６４，０００、等電点４．３０、８０℃１０分間の処理で不活性化（例えば、Candida rugosa由来）
（３）至適ｐＨ８、至適温度６０℃、ｐＨ４～１０の範囲で特に安定、７０℃以下で特に安定（例えば、Pseudomonas fluorescens由来）
（４）分子量６０，０００、至適ｐＨ６～７、ｐＨ安定性３～８、至適温度４０～５０℃、３７℃以下において溶液状態で特に安定（例えば、Candida cylindracea由来、Candida rugosa由来）
（５）分子量３０，０００、等電点４．５、至適ｐＨ８～９．５、ｐＨ安定性７～１０、至適温度５０℃、４０℃以下において特に安定（例えば、Alcaligenes属由来）
（６）分子量３１，０００、等電点４．９、至適ｐＨ７～９、ｐＨ安定性６～１０、至適温度６５～７０℃、５０℃以下において特に安定（例えば、Alcaligenes属由来）
（７）分子量３１，０００、等電点５．２、至適ｐＨ７～９、ｐＨ安定性６～１０、至適温度６５～７０℃、６０℃以下において特に安定（例えば、Pseudomonas cepacia由来、Burkholderia cepacia由来）
（８）分子量２７，０００、等電点６．６、至適ｐＨ７～８、ｐＨ安定性６～９、至適温度５０℃、４０℃以下において特に安定（例えば、Pseudomonas stutzeri由来）
Further, it may be a lipase having the physicochemical property and the enzymatic property according to any one of (1) to (8) as shown below.
(1) Molecular weight 35,000, isoelectric point 4.10 (for example, derived from Aspergillus niger )
(2) Inactivation by treatment with a molecular weight of 64,000, an isoelectric point of 4.30, and 80 ° C. for 10 minutes (for example, derived from Candida rugosa ).
(3) Especially stable in the range of optimum pH 8,
(4) Especially stable in solution at molecular weight 60,000, optimum pH 6-7, pH stability 3-8, optimum temperature 40-50 ° C, 37 ° C or lower (for example, derived from Candida cylindracea , derived from Candida rugosa ).
(5) Especially stable at a molecular weight of 30,000, an isoelectric point of 4.5, an optimum pH of 8 to 9.5, a pH stability of 7 to 10, an optimum temperature of 50 ° C. and 40 ° C. or lower (for example, derived from the genus Alcaligenes ).
(6) Especially stable at a molecular weight of 31,000, an isoelectric point of 4.9, an optimum pH of 7 to 9, a pH stability of 6 to 10, an optimum temperature of 65 to 70 ° C., and 50 ° C. or lower (for example, derived from the genus Alcaligenes ).
(7) Molecular weight 31,000, isoelectric point 5.2, optimum pH 7-9, pH stability 6-10, optimum temperature 65-70 ° C, particularly stable at 60 ° C or lower (for example, derived from Pseudomonas cepacia , Burkholderia ) From cepacia )
(8) Especially stable at a molecular weight of 27,000, an isoelectric point of 6.6, an optimum pH of 7 to 8, pH stability of 6 to 9, an optimum temperature of 50 ° C. and 40 ° C. or lower (for example, derived from Pseudomonas stutzeri ).
前記有機溶媒としては、特に制限されず、例えば、アセトニトリル、アセトン、ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）等が使用できる。また、例えば、疎水性を示すパラメータ（ｌｏｇＰ値）が－０．３５～０．２８の範囲の有機溶媒でもよく、このような有機溶媒としては、前述のアセトニトリル（ｌｏｇＰ値：－０．４５～０．１９）、アセトン（ｌｏｇＰ値：－０．１６～０．１９）、ＤＭＦ（ｌｏｇＰ値：－１．０１～０．２８）、ＤＭＳＯ（ｌｏｇＰ値：－１．３５～０．２８）があげられる。これらの他にも、前記パラメータを満たす従来公知の溶媒が使用できる。前記ｌｏｇＰは、溶媒固有の値であるため、当該技術分野における当業者であれば、前記パラメータを満たす溶媒を選択することが可能である。なお、ｌｏｇＰとは、目的物質をオクタノールと水との混合溶液に添加し、平衡に達した時のオクタノール層と水層とにおける前記目的物質の濃度比を常用対数で表示したものであり、前述のように、物質の疎水性を示すパラメータとして一般的である。 The organic solvent is not particularly limited, and for example, acetonitrile, acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like can be used. Further, for example, an organic solvent having a hydrophobicity parameter (logP value) in the range of −0.35 to 0.28 may be used, and as such an organic solvent, the above-mentioned acetonitrile (logP value: −0.45 to 0.19), acetone (logP value: -0.16 to 0.19), DMF (logP value: -1.01 to 0.28), DMSO (logP value: -1.35 to 0.28) can give. In addition to these, conventionally known solvents that satisfy the above parameters can be used. Since the logP is a solvent-specific value, a person skilled in the art can select a solvent that satisfies the above parameters. Note that logP refers to the concentration ratio of the target substance in the octanol layer and the aqueous layer when the target substance is added to a mixed solution of octanol and water and reaches equilibrium, and is expressed by a common logarithm. As a parameter indicating the hydrophobicity of a substance, such as.
本発明において、アシル基（Ｒ－ＣＯ－）供与体としては、例えば、カルボン酸ビニルエステル（Ｒ－ＣＯ－Ｏ－ＣＨ＝ＣＨ２）があげられる。なお、前記アシル基としては、前述のような直鎖もしくは分枝状の飽和もしくは不飽和アシル基があげられる。 In the present invention, examples of the acyl group (R-CO-) donor include carboxylic acid vinyl ester (R-CO-O-CH = CH 2 ). Examples of the acyl group include the above-mentioned linear or branched saturated or unsaturated acyl group.
前記酵素反応溶液にＤＭＦを用いた場合、ＥＧＣＧの添加割合は、特に制限されないが、例えば、０．２～１００ｍｍｏｌ／Ｌであり、好ましくは０．５～５０ｍｍｏｌ／Ｌ、より好ましくは０．５～２０ｍｍｏｌ／Ｌである。アシル基供与体の添加割合は、特に制限されず、例えば、反応液におけるＥＧＣＧの添加割合に応じて適宜決定できる。具体例として、ＥＧＣＧとアシル基供与体との添加割合（モル比）は、例えば、１：１～１：１０であり、好ましくは１：１～１：５、より好ましくは１：１～１：３である。また、反応液におけるリパーゼの添加割合は、例えば、ＥＧＣＧやアシル基供与体の添加割合、リパーゼの比活性等に応じて適宜決定でき、特に制限されないが、例えば、ＥＧＣＧ１ｍｍｏｌ／Ｌに対して、例えば、５００～５０,０００Ｕ／Ｌであり、好ましくは５００～５,０００Ｕ／Ｌ、より好ましくは１,０００～２,５００Ｕ／Ｌである。 When DMF is used as the enzyme reaction solution, the addition ratio of EGCG is not particularly limited, but is, for example, 0.2 to 100 mmol / L, preferably 0.5 to 50 mmol / L, and more preferably 0.5. It is ~ 20 mmol / L. The addition ratio of the acyl group donor is not particularly limited, and can be appropriately determined, for example, according to the addition ratio of EGCG in the reaction solution. As a specific example, the addition ratio (molar ratio) of EGCG and the acyl group donor is, for example, 1: 1 to 1:10, preferably 1: 1 to 1: 5, and more preferably 1: 1 to 1. : 3. The addition ratio of lipase in the reaction solution can be appropriately determined depending on, for example, the addition ratio of EGCG or the acyl group donor, the specific activity of lipase, etc., and is not particularly limited. For example, with respect to 1 mmol / L of EGCG, for example. , 500 to 50,000 U / L, preferably 500 to 5,000 U / L, and more preferably 1,000 to 2,500 U / L.
酵素反応の条件は特に制限されないが、反応温度は、例えば、４５～７５℃の範囲である。前記反応時間は、例えば、基質や酵素の量によって適宜決定でき、特に制限されないが、例えば、３０分～２４時間（１４４０分）であり、好ましくは１時間（６０分）～３時間（１８０分）、より好ましくは１．５時間（９０分）～３時間（１８０分）である。 The conditions of the enzymatic reaction are not particularly limited, but the reaction temperature is, for example, in the range of 45 to 75 ° C. The reaction time can be appropriately determined, for example, depending on the amount of the substrate and the enzyme, and is not particularly limited, but is, for example, 30 minutes to 24 hours (1440 minutes), preferably 1 hour (60 minutes) to 3 hours (180 minutes). ), More preferably 1.5 hours (90 minutes) to 3 hours (180 minutes).
前記反応液には、さらに、塩基性触媒を添加してもよい。前記塩基性触媒としては、例えば、トリエチルアミン等の３級アミン、ピリジン等があげられる。反応液における塩基性触媒の添加割合は、特に制限されないが、例えば、５～７２０ｍｍｏｌ／Ｌであり、好ましくは１２～２４０ｍｍｏｌ／Ｌ、より好ましくは１２～４８ｍｍｏｌ／Ｌである。 A basic catalyst may be further added to the reaction solution. Examples of the basic catalyst include tertiary amines such as triethylamine and pyridine. The addition ratio of the basic catalyst in the reaction solution is not particularly limited, but is, for example, 5 to 720 mmol / L, preferably 12 to 240 mmol / L, and more preferably 12 to 48 mmol / L.
ＥＧＣＧにおいて前記アシル基が導入される位置は、例えば、使用するリパーゼの種類によって選択できる。また、ＥＧＣＧに導入するアシル基の数は、例えば、使用する有機溶媒の種類や反応時間によって決定することが可能である。例えば、有機溶媒の疎水性が相対的に高い程（親水性が相対的に低い程）、導入されるアシル基の数を相対的に低減でき、有機溶媒の親水性が相対的に高い程（疎水性が相対的に低い程）、導入されるアシル基の数を相対的に増加できる。また、二種類以上の有機溶媒を混合して用いることによっても、導入されるアシル基の数を調節することができる。具体例としては、例えば、１個のアシル基を導入する際には、アセトニトリル等を使用することが好ましく、例えば、１～２個のアシル基を導入する際には、アセトン、アセトニトリル等を使用することが好ましく、例えば、３～５個のアシル基を導入する際には、ＤＭＳＯ、ＤＭＦ等を使用することが好ましい。 The position in which the acyl group is introduced in EGCG can be selected, for example, depending on the type of lipase used. Further, the number of acyl groups to be introduced into EGCG can be determined, for example, by the type of organic solvent used and the reaction time. For example, the higher the hydrophobicity of the organic solvent (relatively low hydrophilicity), the more the number of acyl groups introduced can be relatively reduced, and the higher the hydrophilicity of the organic solvent (relatively low hydrophilicity). The relatively lower the hydrophobicity), the more the number of acyl groups introduced can be relatively increased. The number of acyl groups introduced can also be adjusted by using a mixture of two or more kinds of organic solvents. As a specific example, for example, acetonitrile or the like is preferably used when introducing one acyl group, and acetone, acetonitrile or the like is used when introducing one or two acyl groups, for example. For example, when introducing 3 to 5 acyl groups, it is preferable to use DMSO, DMF, or the like.
さらに、同じ有機溶媒を用いる場合でも、温度時間や反応温度の制御と組合せること等によって、導入するアシル基数を調節することもできる。以下にその例を示すが、これには限定されない。ＤＭＦを使用する場合、例えば、反応温度を約５７℃～約７０℃の範囲に設定し、反応温度を長くする（例えば、約３～５時間）ことによって、ＥＧＣＧに２個のアシル基が選択的に導入された誘導体を優先的に得ることができ、他方、反応温度を低下させ（例えば、５７℃から約５℃低い温度）、反応時間を短くする（例えば、約１～３時間）ことによって、１個のアシル基を選択的に導入することができる。また、アセトンとＤＭＦを同量（質量）混合した混合溶媒を使用することによっても、ＥＧＣＧに１個のアシル基を選択的に導入することができる。 Further, even when the same organic solvent is used, the number of acyl groups to be introduced can be adjusted by combining with the control of the temperature time and the reaction temperature. An example is shown below, but the present invention is not limited to this. When using DMF, for example, by setting the reaction temperature in the range of about 57 ° C to about 70 ° C and increasing the reaction temperature (for example, about 3 to 5 hours), two acyl groups are selected for EGCG. Introduced derivatives can be preferentially obtained, while lowering the reaction temperature (eg, 57 ° C to about 5 ° C lower) and shortening the reaction time (eg, about 1-3 hours). Allows one acyl group to be selectively introduced. In addition, one acyl group can be selectively introduced into EGCG by using a mixed solvent in which acetone and DMF are mixed in the same amount (mass).
また、導入するアシル基の数は、反応液に前述の塩基性触媒を添加することによって増加させることができる。この場合、ＥＧＣＧにおけるどの部位にアシル基がさらに導入されるかは、例えば、リパーゼの位置選択性に依存する。 Further, the number of acyl groups to be introduced can be increased by adding the above-mentioned basic catalyst to the reaction solution. In this case, at which site in EGCG the acyl group is further introduced depends, for example, on the regioselectivity of the lipase.
前記酵素反応によるＥＧＣＧ誘導体の収率は、例えば、反応温度を相対的に高く設定することによって、相対的に向上させることができる。反応温度は、通常、前述のように、４５～７５℃であるが、収率向上の点から、好ましくは５７～７５℃であり、より好ましくは５７～７０℃である。特に、反応温度が、５７～７０℃の場合、前記ＥＧＣＧアシル化誘導体の収率は、約３５～４５％を実現することが可能である。なお、前記収率とは、反応に使用したＥＧＣＧを１００％とした場合のＥＧＣＧアシル化誘導体（例えば、全モノアシル化誘導体）の割合（変換効率）を意味する。 The yield of the EGCG derivative by the enzymatic reaction can be relatively improved, for example, by setting the reaction temperature relatively high. The reaction temperature is usually 45 to 75 ° C. as described above, but is preferably 57 to 75 ° C., more preferably 57 to 70 ° C. from the viewpoint of improving the yield. In particular, when the reaction temperature is 57 to 70 ° C., the yield of the EGCG acylated derivative can be about 35 to 45%. The yield means the ratio (conversion efficiency) of the EGCG acylated derivative (for example, the total monoacylated derivative) when the EGCG used in the reaction is 100%.
本発明において、ＥＧＣＧ誘導体は、例えば、前述のように、いずれか一種類を用いてもよいし、二種類以上の混合物を用いてもよい。前記混合物から一種類のＥＧＣＧ誘導体を単離する場合は、例えば、クロマトグラフィー等を用いる従来公知の方法により、調製可能である。 In the present invention, for example, as described above, any one of the EGCG derivatives may be used, or a mixture of two or more kinds may be used. When one kind of EGCG derivative is isolated from the mixture, it can be prepared by, for example, a conventionally known method using chromatography or the like.
＜アレルゲン活性の抑制方法＞
本発明のアレルゲン活性の抑制方法は、前述のように、アレルゲンに前記本発明の活性抑制剤を接触させることを特徴とする。本発明の抑制方法は、前記本発明の活性抑制剤を使用することが特徴であって、その他の構成や条件等は、何ら制限されない。前記本発明の活性抑制剤およびその使用方法等は、例えば、前述と同様であり、全て援用できる。
<Method of suppressing allergen activity>
As described above, the method for suppressing the activity of the allergen of the present invention is characterized by contacting the allergen with the agent for suppressing the activity of the present invention. The suppression method of the present invention is characterized by using the activity inhibitor of the present invention, and other configurations, conditions and the like are not limited in any way. The activity inhibitor of the present invention and the method of using the same are, for example, the same as described above, and all of them can be incorporated.
本発明において、前記アレルゲンと前記活性抑制剤の接触方法は、特に制限されない。前述ように、例えば、被検体に投与して、前記動物が有する前記アレルゲンと前記活性抑制剤を接触させてもよいし、前記アレルゲンが存在する可能性がある被検体を前記活性抑制剤で処理することにより、前記アレルゲンと前記活性抑制剤とを接触させてもよい。前者において、前記被検体は、例えば、前述のような、動物（ヒトまたは非ヒト動物）であり、後者において、前記被検体は、例えば、アレルゲンが存在する可能性がある環境であり、具体例として、前述の衣類、寝具等の例示が援用できる。 In the present invention, the contact method between the allergen and the activity inhibitor is not particularly limited. As described above, for example, the allergen possessed by the animal may be brought into contact with the activity inhibitor by administration to the subject, or the subject in which the allergen may be present may be treated with the activity inhibitor. By doing so, the allergen and the activity inhibitor may be brought into contact with each other. In the former, the subject is, for example, an animal (human or non-human animal) as described above, and in the latter, the subject is, for example, an environment in which an allergen may be present, and a specific example. As the above-mentioned examples of clothing, bedding and the like can be used.
＜アレルギー反応の抑制方法＞
本発明のアレルギー反応の抑制方法は、前述のように、被検体に前記本発明の活性抑制剤を投与することを特徴とする。本発明は、前記本発明の活性抑制剤を使用することが特徴であって、その他の構成や条件等は、何ら制限されない。前記本発明の活性抑制剤およびその使用方法等は、例えば、前述と同様であり、全て援用できる。また、本発明のアレルギー反応の抑制方法は、例えば、前記本発明のアレルゲン活性の抑制方法における記載も援用できる。
<Method of suppressing allergic reaction>
As described above, the method for suppressing an allergic reaction of the present invention is characterized by administering the activity inhibitor of the present invention to a subject. The present invention is characterized in that the activity inhibitor of the present invention is used, and other configurations, conditions and the like are not limited in any way. The activity inhibitor of the present invention and the method of using the same are, for example, the same as described above, and all of them can be incorporated. Further, as the method for suppressing an allergic reaction of the present invention, for example, the description in the above-mentioned method for suppressing allergen activity of the present invention can also be incorporated.
本発明のアレルギー反応の抑制方法は、例えば、前記本発明の活性抑制剤を投与することにより、前記被検体におけるアレルギー反応に由来する疾患を治療できる。このため、本発明のアレルギー反応の抑制方法は、例えば、アレルギー性疾患の治療方法ということもできる。本発明において、「治療」は、例えば、前記疾患の予防、前記疾患の改善、前記疾患の予後の改善の意味を含み、いずれでもよい。 The method for suppressing an allergic reaction of the present invention can treat a disease derived from the allergic reaction in the subject by, for example, administering the activity inhibitor of the present invention. Therefore, the method for suppressing an allergic reaction of the present invention can be said to be, for example, a method for treating an allergic disease. In the present invention, "treatment" includes, for example, the meaning of prevention of the disease, improvement of the disease, and improvement of the prognosis of the disease, and may be any of them.
前記アレルギー性疾患は、特に制限されず、例えば、花粉症、アレルギー性鼻炎、蕁麻疹、動物アレルギー、食物アレルギー、ゴキブリ等の昆虫に対する昆虫アレルギー、ハウスダストアレルギー等があげられる。 The allergic disease is not particularly limited, and examples thereof include pollinosis, allergic rhinitis, urticaria, animal allergies, food allergies, insect allergies to insects such as cockroaches, and house dust allergies.
前記被検体に対する前記活性抑制剤の投与時期は、特に制限されず、例えば、アレルゲンと接触する前でもよいし、アレルゲンと接触した後でもよい。 The time of administration of the activity inhibitor to the subject is not particularly limited, and may be, for example, before or after contact with the allergen.
＜アレルギー活性の抑制剤の使用＞
本発明は、アレルギー反応を抑制するための前記本発明の活性抑制剤の使用、アレルギー性疾患を治療するための前記本発明の活性抑制剤の使用である。また、本発明は、アレルギー反応用医薬の製造のための前記本発明の活性抑制剤の使用、アレルギー性疾患用医薬の製造のための前記本発明の活性抑制剤の使用である。
<Use of agents that suppress allergic activity>
The present invention is the use of the activity inhibitor of the present invention for suppressing an allergic reaction, and the use of the activity inhibitor of the present invention for treating an allergic disease. Further, the present invention is the use of the activity inhibitor of the present invention for the production of a drug for allergic reaction, and the use of the activity suppressant of the present invention for the production of a drug for allergic diseases.
つぎに、本発明の実施例について説明する。ただし、本発明は、下記実施例により制限されない。 Next, examples of the present invention will be described. However, the present invention is not limited by the following examples.
化合物として、実施例に該当するアシル化ＥＧＣＧ誘導体、比較例に該当するＥＧＣＧおよびメチル化カテキンを準備した。 As the compound, an acylated EGCG derivative corresponding to the example, an EGCG corresponding to the comparative example, and a methylated catechin were prepared.
（１）アシル化ＥＧＣＧ誘導体
下記化学式（２）において、Ｒ１～Ｒ６のいずれか一カ所または二か所が以下のアシル基であるＥＧＣＧ誘導体を使用した（全て、プロテクティア社製）。なお、アシル基以外のＲ１～Ｒ６は、水素原子とした。
ＥＧＣＧ－Ｃ１２、ＥＧＣＧ－Ｃ１６、ＥＧＣＧ－Ｃ１８、ＥＧＣＧ－Ｃ１８ＤＥおよびＥＧＣＧ－ＥＨは、それぞれ、Ｒ１のアシル化誘導体、Ｒ２のアシル化誘導体、Ｒ５のアシル化誘導体およびＲ６のアシル化誘導体の４種類の混合物である。また、ＥＧＣＧ－Ｃ８×２は、Ｒ１とＲ５とのアシル化誘導体、Ｒ１とＲ６とのアシル化誘導体、Ｒ２とＲ５とのアシル化誘導体、Ｒ２とＲ６とのアシル化誘導体、Ｒ１とＲ２とのアシル化誘導体、Ｒ１とＲ３とのアシル化誘導体、Ｒ４とＲ５とのアシル化誘導体およびＲ４とＲ６とのアシル化誘導体の８種類の混合物である。 EGCG-C12, EGCG-C16, EGCG-C18, EGCG-C18DE and EGCG-EH are an acylated derivative of R 1 , an acylated derivative of R 2 , an acylated derivative of R 5 and an acylated derivative of R 6 , respectively. It is a mixture of four kinds of. EGCG-C8 × 2 is an acylated derivative of R 1 and R 5 , an acylated derivative of R 1 and R 6 , an acylated derivative of R 2 and R 5 , and an acylation of R 2 and R 6 . Eight kinds of chemical derivatives, acylated derivatives of R 1 and R 2 , acylated derivatives of R 1 and R 3 , acylated derivatives of R 4 and R 5 , and acylated derivatives of R 4 and R 6 . It is a mixture.
（２）ＥＧＣＧ
前記化学式（２）において、Ｒ１～Ｒ６が全て水素原子（非アシル基）である天然型のＥＧＣＧ（商品名サンフェノンＥＧＣＧ、太陽化学株式会社製）を使用した。
(2) EGCG
In the chemical formula (2), a natural type EGCG (trade name: Sanphenon EGCG, manufactured by Taiyo Kagaku Co., Ltd.) in which all R 1 to R 6 are hydrogen atoms (non-acyl groups) was used.
（３）メチル化カテキン
前記式（２）において、Ｒ５のみがメチル基（非アシル基）であるモノメチル化カテキン（プロテクティア社製）、および、Ｒ２およびＲ５がメチル基であるジメチル化カテキン（プロテクティア社製）を用いた。なお、メチル基以外のＲ１～Ｒ６は、水素原子とした。
(3) Methylated catechin In the above formula (2), monomethylated catechin (manufactured by Protectia) in which only R 5 is a methyl group (non-acyl group), and dimethylation in which R 2 and R 5 are methyl groups. Catechin (manufactured by Protectia) was used. R 1 to R 6 other than the methyl group were hydrogen atoms.
［実施例１］
アシル化ＥＧＣＧ誘導体について、各種アレルゲンに対する活性抑制能を確認した。
（１）ダニアレルゲン活性の抑制試験
コナヒョウダニ抽出物（商品名Ｍｉｔｅ Ｅｘｔｒａｃｔ Ｄｆ、コスモ・バイオ社製）を、カルシウムイオンおよびマグネシウムイオン未含有のＤｕｌｂｅｃｃｏリン酸生理緩衝液（Ｄ－ＰＢＳ（－）、和光純薬製）で終濃度１００μｇ／ｍＬになるよう希釈して、ダニアレルゲン溶液を調製した。また、１０ｍｍｏｌ／Ｌの前記アシル化ＥＧＣＧ誘導体を含むＤＭＳＯ溶液を、リン酸生理緩衝液（ＰＢＳ）で終濃度１１１μｍｏｌ／Ｌになるよう希釈して、実施例サンプルを調製した。
[Example 1]
Regarding the acylated EGCG derivative, the ability to suppress the activity against various allergens was confirmed.
(1) Suppression test of dania allergen activity Kona leopard mite extract (trade name: Mite Exect Df, manufactured by Cosmo Bio Co., Ltd.) was used as a calcium ion-free and magnesium ion-free Dulvecco phosphate buffer solution (D-PBS (-), sum. A dania allergen solution was prepared by diluting with (manufactured by Kojunyaku) to a final concentration of 100 μg / mL. Further, a DMSO solution containing the 10 mmol / L acylated EGCG derivative was diluted with phosphate buffered buffer (PBS) to a final concentration of 111 μmol / L to prepare an example sample.
前記ダニアレルゲン溶液５０μＬと前記サンプル４５０μＬとをチューブ内で混合し、これを室温で２時間インキュベートした。その後、前記混合液に残存するダニアレルゲン活性を、ダニアレルゲン測定用ＥＬＩＳＡキット（商品名ダニアレルゲン（Ｄｅｒｆ１）測定キット、ニチニチ製薬社製）を用いて測定した。前記キットによる測定は、使用説明書に従って行った。 50 μL of the mite allergen solution and 450 μL of the sample were mixed in a tube and incubated at room temperature for 2 hours. Then, the mite allergen activity remaining in the mixed solution was measured using an ELISA kit for mite allergen measurement (trade name: mite allergen (Derf1) measurement kit, manufactured by Nichinichi Pharmaceutical Co., Ltd.). The measurement with the kit was performed according to the instruction manual.
また、コントロールは、前記実施例サンプルに代えてＰＢＳまたは１％ＤＭＳＯ溶液（以下、１％ＤＭＳＯという）をコントロールサンプルとして使用し、同様にして、ダニアレルゲン活性を測定した。比較例は、前記実施例サンプルに代えて天然ＥＧＣＧを比較例サンプルとして使用し、同様にしてサンプルを調製して、ダニアレルゲン活性を測定した。 In addition, as a control, PBS or 1% DMSO solution (hereinafter referred to as 1% DMSO) was used as a control sample in place of the Example sample, and mite allergen activity was measured in the same manner. In Comparative Example, natural EGCG was used as the Comparative Example sample in place of the Example sample, and a sample was prepared in the same manner to measure the mite allergen activity.
そして、前記コントロールのダニアレルゲン活性を１００％として、前記実施例および比較例のダニアレルゲン活性の相対値（％）をそれぞれ算出し、これをダニアレルゲン活性残存率（％）とした。本実施例においては、１サンプルごとに２回の測定を個別に行い、平均値を結果とした。 Then, assuming that the mite allergen activity of the control was 100%, the relative value (%) of the mite allergen activity of the Examples and Comparative Examples was calculated, and this was taken as the mite allergen activity residual rate (%). In this example, two measurements were individually performed for each sample, and the average value was used as the result.
これらの結果を、図１に示す。図１は、ダニアレルゲンのアレルゲン活性残存率（％）を示すグラフである。図１において、Ｙ軸が、アレルゲン活性残存率（％）であり、Ｃ１２は、ＥＧＣＧ－Ｃ１２、Ｃ１６は、ＥＧＣＧ－Ｃ１６、Ｃ１８は、ＥＧＣＧ－Ｃ１８、Ｃ１８ＤＥは、ＥＧＣＧ－Ｃ１８ＤＥ、ＥＨは、ＥＧＣＧ－ＥＨ、Ｃ８×２は、ＥＧＣＧ－Ｃ８×２の結果を示す。図１において、ダニアレルゲン活性残存率が低いほど、サンプルによるダニアレルゲンの活性抑制効果が優れることを意味する。図１に示すように、天然のＥＧＣＧは、ダニアレルゲンに対して活性抑制効果をほとんど示さなかったのに対し、ＥＧＣＧ誘導体（Ｃ１２、Ｃ１６、Ｃ１８、Ｃ１８ＤＥ、ＥＨ、Ｃ８×２）は、それぞれ、ダニアレルゲンに対して有意な活性抑制効果を示した。中でも、Ｃ１２およびＣ１８ＤＥは、ダニアレルゲンに対する非常に優れた活性抑制効果を示し、特にＣ１２は、ダニアレルゲン活性を約１０％にまで抑制しており、極めて優れていることがわかった。 These results are shown in FIG. FIG. 1 is a graph showing the residual rate (%) of allergen activity of mite allergen. In FIG. 1, the Y-axis is the residual rate of allergen activity (%), C12 is EGCG-C12, C16 is EGCG-C16, C18 is EGCG-C18, C18DE is EGCG-C18DE, and EH is EGCG. -EH, C8x2 indicate the result of EGCG-C8x2. In FIG. 1, the lower the residual rate of mite allergen activity, the better the effect of suppressing the activity of mite allergen by the sample. As shown in FIG. 1, the natural EGCG showed almost no activity-suppressing effect on mite allergens, whereas the EGCG derivatives (C12, C16, C18, C18DE, EH, C8 × 2) showed little effect, respectively. It showed a significant activity-suppressing effect on mite allergens. Among them, C12 and C18DE showed a very excellent activity-suppressing effect on mite allergen, and in particular, C12 suppressed mite allergen activity to about 10%, and it was found to be extremely excellent.
（２）スギアレルゲン活性の抑制試験
スギ花粉抗原（商品名精製スギ花粉抗原 Ｃｒｙｊ１、フナコシ社製）を、前記Ｄ－ＰＢＳ（－）で終濃度５００ｎｇ／ｍＬになるよう希釈して、スギアレルゲン溶液を調製した。また、前記（１）で調製した、前記アシル化ＥＧＣＧ誘導体の実施例サンプルを使用した。
(2) Sugi allergen activity suppression test Sugi pollen antigen (trade name: purified Sugi pollen antigen Cryj1, manufactured by Funakoshi Co., Ltd.) is diluted with the above D-PBS (-) to a final concentration of 500 ng / mL, and a Sugi allergen solution is used. Was prepared. Moreover, the example sample of the acylated EGCG derivative prepared in the above (1) was used.
前記スギアレルゲン溶液５０μＬと前記サンプル４５０μＬとをチューブ内で混合し、これを室温で２時間インキュベートした。その後、前記混合液に残存するスギアレルゲン活性を、スギ花粉抗原測定用ＥＬＩＳＡキット（商品名スギ花粉抗原（Ｃｒｙｊ１）測定キット、ニチニチ製薬社製）を用いて測定した。前記キットによる測定は、使用説明書に従って行った。また、コントロールおよび比較例は、前記（１）と同様とした。 50 μL of the Sugi allergen solution and 450 μL of the sample were mixed in a tube and incubated at room temperature for 2 hours. Then, the sugi allergen activity remaining in the mixed solution was measured using an ELISA kit for measuring sugi pollen antigen (trade name: sugi pollen antigen (Cryj1) measuring kit, manufactured by Nichinichi Pharmaceutical Co., Ltd.). The measurement with the kit was performed according to the instruction manual. The controls and comparative examples were the same as in (1) above.
これらの結果を、図２に示す。図２は、スギアレルゲンのアレルゲン活性残存率（％）を示すグラフである。図２において、Ｙ軸が、アレルゲン活性残存率（％）であり、Ｃ１２は、ＥＧＣＧ－Ｃ１２、Ｃ１６は、ＥＧＣＧ－Ｃ１６、Ｃ１８は、ＥＧＣＧ－Ｃ１８、Ｃ１８ＤＥは、ＥＧＣＧ－Ｃ１８ＤＥ、Ｃ８×２は、ＥＧＣＧ－Ｃ８×２の結果を示す。図１において、スギアレルゲン活性残存率が低いほど、サンプルによるスギアレルゲンに対する活性抑制効果が優れることを意味する。図２に示すように、天然のＥＧＣＧは、スギアレルゲンに対する活性抑制効果をほとんど示さなかったのに対し、ＥＧＣＧ誘導体（Ｃ１２、Ｃ１６、Ｃ１８、Ｃ１８ＤＥ、Ｃ８×２）は、それぞれ、スギアレルゲンに対して有意な活性抑制効果を示した。 These results are shown in FIG. FIG. 2 is a graph showing the residual rate (%) of allergen activity of Sugi allergen. In FIG. 2, the Y-axis is the residual rate of allergen activity (%), C12 is EGCG-C12, C16 is EGCG-C16, C18 is EGCG-C18, C18DE is EGCG-C18DE, and C8 × 2 is. , EGCG-C8 × 2 results are shown. In FIG. 1, the lower the residual rate of sugi allergen activity, the better the activity-suppressing effect of the sample on sugi allergen. As shown in FIG. 2, natural EGCG showed almost no activity-suppressing effect on sugi allergen, whereas EGCG derivatives (C12, C16, C18, C18DE, C8 × 2) had little effect on sugi allergen, respectively. Showed a significant activity-suppressing effect.
また、比較例として、前記アシル化ＥＧＣＧ誘導体にかえて、抗アレルギー効果が報告されている前記メチル化カテキンを用いて、スギアレルゲンに対する活性抑制能を確認した。この比較例サンプルは、前記アシル化ＥＧＣＧ誘導体に代えて、前記メチル化カテキン（モノメチル化カテキンまたはジメチル化カテキン）を使用し、終濃度を５０μｍｏｌ／Ｌまたは１００μｍｏｌ／Ｌとした以外は、前記実施例サンプルと同様にして調製した。そして、前記比較例サンプルを用いて、前述と同様にして、スギアレルゲン活性を測定し、アレルゲン活性残存率を求めた。なお、アレルゲン活性残存率は、１％ＤＭＳＯのアレルゲン活性を１００％として、相対値（％）を求めた。 Further, as a comparative example, the ability to suppress the activity against sugi allergen was confirmed by using the methylated catechin, which has been reported to have an antiallergic effect, instead of the acylated EGCG derivative. This Comparative Example sample uses the methylated catechin (monomethylated catechin or dimethylated catechin) in place of the acylated EGCG derivative, except that the final concentration is 50 μmol / L or 100 μmol / L. Prepared in the same manner as the sample. Then, using the comparative example sample, the sugi allergen activity was measured in the same manner as described above, and the allergen activity residual rate was determined. The allergen activity residual rate was determined as a relative value (%) with the allergen activity of 1% DMSO as 100%.
これらの結果を、図３に示す。図３は、スギアレルゲン活性残存率（％）を示すグラフである。図３において、Ｙ軸が、アレルゲン活性残存率（％）であり、ｍＭ ＥＧＣＧは、モノメチル化カテキン、ｄＭ ＥＧＣＧは、ジメチル化カテキンであり、μＭ（μｍｏｌ／Ｌ）は、サンプルにおけるメチル化カテキンの濃度を示す。図３において、スギアレルゲン活性残存率が低いほど、スギアレルゲンに対する活性抑制効果が優れることを意味する。図３に示すように、メチル化カテキンは、いずれの濃度においても、アレルゲン活性残存率が１００％を超え、アレルゲンに対する活性抑制効果を示さなかった。 These results are shown in FIG. FIG. 3 is a graph showing the residual rate of Sugi allergen activity (%). In FIG. 3, the Y-axis is the residual rate of allergen activity (%), mM EGCG is monomethylated catechin, dM EGCG is dimethylated catechin, and μM (μmol / L) is the methylated catechin in the sample. Indicates the concentration. In FIG. 3, the lower the residual rate of sugi allergen activity, the better the activity-suppressing effect on sugi allergen. As shown in FIG. 3, the methylated catechin had an allergen activity residual rate of more than 100% at any concentration and did not show an activity-suppressing effect on the allergen.
本発明によれば、アレルギー反応を、安全且つ効果的に防止できる。このため、本発明は、医療分野、食品衛生分野等において、有用といえる。 According to the present invention, allergic reactions can be prevented safely and effectively. Therefore, it can be said that the present invention is useful in the medical field, food hygiene field, and the like.
Claims (1)
Ｒ１～Ｒ６は、
それぞれ水素原子、ハロゲン、ナトリウム、カリウムまたは直鎖もしくは分枝状の飽和もしくは不飽和アシル基であり、同一でも異なっていてもよく、
前記アシル基は、さらに１または複数の置換基で置換されていてもよく、
前記Ｒ１～Ｒ６の少なくとも１つが前記アシル基であり、
Ｒ７～Ｒ１６は、水素原子、ハロゲン、ナトリウムまたはカリウムであり、同一でも異なっていてもよい。 An agent for suppressing the allergen activity of an allergen, which comprises an epigallocatechin gallate derivative represented by the following chemical formula (1), an isomer thereof, or a salt thereof:
R1 to R6 are
They are hydrogen atoms, halogens, sodium, potassium or linear or branched saturated or unsaturated acyl groups, respectively, which may be the same or different.
The acyl group may be further substituted with one or more substituents.
At least one of the R 1 to R 6 is the acyl group,
R 7 to R 16 are hydrogen atoms, halogens, sodium or potassium, and may be the same or different.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014151095 | 2014-07-24 | ||
| JP2014151095 | 2014-07-24 | ||
| JP2020081491A JP7035109B2 (en) | 2014-07-24 | 2020-05-01 | Allergen activity inhibitor and its uses |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020081491A Division JP7035109B2 (en) | 2014-07-24 | 2020-05-01 | Allergen activity inhibitor and its uses |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2022071097A true JP2022071097A (en) | 2022-05-13 |
| JP7419416B2 JP7419416B2 (en) | 2024-01-22 |
Family
ID=55163176
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016535991A Active JP6731340B2 (en) | 2014-07-24 | 2015-07-24 | Inhibitor of allergen activity and use thereof |
| JP2020081491A Active JP7035109B2 (en) | 2014-07-24 | 2020-05-01 | Allergen activity inhibitor and its uses |
| JP2022031570A Active JP7419416B2 (en) | 2014-07-24 | 2022-03-02 | Allergen activity inhibitors and their uses |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016535991A Active JP6731340B2 (en) | 2014-07-24 | 2015-07-24 | Inhibitor of allergen activity and use thereof |
| JP2020081491A Active JP7035109B2 (en) | 2014-07-24 | 2020-05-01 | Allergen activity inhibitor and its uses |
Country Status (2)
| Country | Link |
|---|---|
| JP (3) | JP6731340B2 (en) |
| WO (1) | WO2016013654A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6731340B2 (en) * | 2014-07-24 | 2020-07-29 | 株式会社プロテクティア | Inhibitor of allergen activity and use thereof |
| JP6505905B2 (en) * | 2017-04-14 | 2019-04-24 | 株式会社プロテクティア | Cosmetics of catechin fatty acid derivatives |
| EP3801496A4 (en) | 2018-06-05 | 2022-07-06 | Flagship Pioneering Innovations V, Inc. | Active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03157330A (en) * | 1989-11-13 | 1991-07-05 | Itouen:Kk | Antiallergic agent |
| JPH06279273A (en) * | 1993-03-30 | 1994-10-04 | Earth Chem Corp Ltd | Method for removing allergen from environment and antiallergic composition |
| JP2002255811A (en) * | 2001-02-28 | 2002-09-11 | Mg Seiyaku Kk | Protein conjugate-forming agent |
| WO2007125731A1 (en) * | 2006-04-28 | 2007-11-08 | Menicon Co., Ltd. | Soft contact lens solution, drug-sustained release soft contact lens prepared by using the solution |
| JP2008050743A (en) * | 2006-07-26 | 2008-03-06 | Idemitsu Technofine Co Ltd | Method for fixing polyphenols to fiber aggregate, its fiber aggregate and fiber-treating agent |
| WO2009096581A1 (en) * | 2008-02-01 | 2009-08-06 | Kunihiro Kaihatsu | Membrane fusion inhibitor |
| WO2016013654A1 (en) * | 2014-07-24 | 2016-01-28 | 株式会社プロテクティア | Allergen activity inhibitor and use thereof |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001048799A (en) * | 1999-08-12 | 2001-02-20 | Taiyo Kagaku Co Ltd | Medicine for treating tick allergy |
| JP3525182B2 (en) * | 2000-02-16 | 2004-05-10 | 独立行政法人産業技術総合研究所 | New anti-leukemia cell agent |
| JP2005273099A (en) * | 2004-03-26 | 2005-10-06 | Shinto Fine Co Ltd | Anti-allergen textile product |
| EP1849779A4 (en) * | 2005-01-26 | 2010-07-14 | Suntory Holdings Ltd | Esterified catechin, process for producing the same, food and drink or cosmetic containing the same |
| JP2006205083A (en) * | 2005-01-28 | 2006-08-10 | Kao Corp | Method for accommodating bedding |
| WO2007105280A1 (en) * | 2006-03-10 | 2007-09-20 | Osaka University | Process for production of acylated derivative of epigallocatechin gallate |
| JP5128826B2 (en) * | 2007-02-07 | 2013-01-23 | 独立行政法人農業・食品産業技術総合研究機構 | Novel methylated catechins and compositions containing them |
| JP2009084266A (en) * | 2007-09-14 | 2009-04-23 | Osaka Univ | Carcinostatic agent utilizing acyl derivative of epigallocatechin gallate |
| JP5434192B2 (en) * | 2009-03-30 | 2014-03-05 | 東亞合成株式会社 | Anti-allergenic composition and anti-allergenic product |
| EP2460405B8 (en) | 2009-07-31 | 2016-07-06 | Protectea Ltd. | Epigallocatechin gallate derivative as antibacterial agent |
| EP2619194A4 (en) * | 2010-04-08 | 2014-09-10 | Genesis Group Inc | Fatty acid derivatives of catechins and methods of their use |
| JP6027741B2 (en) * | 2011-01-12 | 2016-11-16 | 住友化学株式会社 | Control methods for harmful arthropods, compositions, electrostatic sprayers |
| JP2014042514A (en) * | 2012-07-30 | 2014-03-13 | Yoshiaki Nagaura | Formation of antigen-antibody complex by which human body acquires autoimmunity, using blood collected from mammal such as human body and swine or poultry infected with hiv, ifv, new coronavirus, sars coronavirus or other virus, or malaria parasite, and formation method thereof |
| JP6040674B2 (en) * | 2012-09-26 | 2016-12-07 | 大日本印刷株式会社 | Method for measuring allergen performance |
-
2015
- 2015-07-24 JP JP2016535991A patent/JP6731340B2/en active Active
- 2015-07-24 WO PCT/JP2015/071101 patent/WO2016013654A1/en active Application Filing
-
2020
- 2020-05-01 JP JP2020081491A patent/JP7035109B2/en active Active
-
2022
- 2022-03-02 JP JP2022031570A patent/JP7419416B2/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03157330A (en) * | 1989-11-13 | 1991-07-05 | Itouen:Kk | Antiallergic agent |
| JPH06279273A (en) * | 1993-03-30 | 1994-10-04 | Earth Chem Corp Ltd | Method for removing allergen from environment and antiallergic composition |
| JP2002255811A (en) * | 2001-02-28 | 2002-09-11 | Mg Seiyaku Kk | Protein conjugate-forming agent |
| WO2007125731A1 (en) * | 2006-04-28 | 2007-11-08 | Menicon Co., Ltd. | Soft contact lens solution, drug-sustained release soft contact lens prepared by using the solution |
| JP2008050743A (en) * | 2006-07-26 | 2008-03-06 | Idemitsu Technofine Co Ltd | Method for fixing polyphenols to fiber aggregate, its fiber aggregate and fiber-treating agent |
| WO2009096581A1 (en) * | 2008-02-01 | 2009-08-06 | Kunihiro Kaihatsu | Membrane fusion inhibitor |
| WO2016013654A1 (en) * | 2014-07-24 | 2016-01-28 | 株式会社プロテクティア | Allergen activity inhibitor and use thereof |
| JP2020127418A (en) * | 2014-07-24 | 2020-08-27 | 株式会社プロテクティア | Allergen activity inhibitor and use therefor |
Non-Patent Citations (4)
| Title |
|---|
| "蛍光分析法を利用したアシル化カテキンと血清アルブミンの相互作用の検討", 日本食品科学工学会第59回大会講演集, JPN6023017568, 2012, pages 152, ISSN: 0005054417 * |
| アレルギー, vol. 29, no. 8, JPN6023017564, 1980, pages 763 - 772, ISSN: 0005054414 * |
| アレルギー, vol. 45, no. 4, JPN6023017566, 1996, pages 416 - 421, ISSN: 0005054415 * |
| 日本花粉学会会誌, vol. 46, no. 1, JPN6023017567, 2000, pages 29 - 38, ISSN: 0005054416 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP7035109B2 (en) | 2022-03-14 |
| JPWO2016013654A1 (en) | 2017-06-08 |
| JP2020127418A (en) | 2020-08-27 |
| WO2016013654A1 (en) | 2016-01-28 |
| JP6731340B2 (en) | 2020-07-29 |
| JP7419416B2 (en) | 2024-01-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7419416B2 (en) | Allergen activity inhibitors and their uses | |
| JP5579449B2 (en) | Membrane fusion inhibitor | |
| JP5279054B2 (en) | Antibacterial agent | |
| KR20160055916A (en) | Deoxynojirimycin derivatives and methods of their using | |
| JP2001031566A (en) | Inhibitory composition for problematic behavior of pet | |
| Négrel et al. | Synthesis and biological activities of naturally functionalized polyamines: An overview | |
| JP5281234B2 (en) | Orally administered composition for the improvement and prevention of fatigued eyes due to ciliary overtension | |
| TWI594755B (en) | Administration of eritoran or pharmaceutically acceptable salts thereof to treat orthomyxovirus infections | |
| WO2016041013A1 (en) | Glycerolipids and uses therefor | |
| Hwang et al. | Isodihydrocapsiate stimulates plasma glucose uptake by activation of AMP-activated protein kinase | |
| US20230102247A1 (en) | Methods and compositions relating to ionic liquid adjuvants | |
| AU2021400851A1 (en) | Cath2 derivatives for stimulating innate immune memory | |
| CN102379296A (en) | Novel use of ginkgolide C | |
| WO2014157622A1 (en) | Antiviral agent against non-enveloped viruses and use thereof | |
| WO2022158602A1 (en) | Composition having antiviral activity | |
| US9226509B2 (en) | Phagodeterrent compounds of fungal origin | |
| MA33512B1 (en) | INHIBITORS OF CATHEPSIN C | |
| JP2004345971A (en) | Anti-influenza virus agent using chlorogenate derivative | |
| MA34961B1 (en) | INHIBITORS OF CATHEPSIN C | |
| KR20140138920A (en) | A mixture of polar glycolipids for use in the treatment of pain and COPD | |
| Wang | Perfluorooctane sulfonate and bisphenol a strongly interact with bacterial antigens and adversely modulate host immunity | |
| KR20230058590A (en) | Respiratory therapy using Salmonaceae oil compositions | |
| RU2021101682A (en) | COMPOSITIONS AND METHODS FOR EYE TREATMENT | |
| JP2021046451A (en) | Fatty acid composition and method for producing the same, and skin external preparation, quasi drug and cosmetic preparation containing the fatty acid composition | |
| JP2001292706A (en) | Feed additive containing enzyme-treated product of fagopyrum tataricum (l.) gaertn and feed |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220331 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220413 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230509 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230706 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231010 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231129 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231212 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240110 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7419416 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |