JPS6341421A - Anticataract agent - Google Patents
Anticataract agentInfo
- Publication number
- JPS6341421A JPS6341421A JP61184127A JP18412786A JPS6341421A JP S6341421 A JPS6341421 A JP S6341421A JP 61184127 A JP61184127 A JP 61184127A JP 18412786 A JP18412786 A JP 18412786A JP S6341421 A JPS6341421 A JP S6341421A
- Authority
- JP
- Japan
- Prior art keywords
- pqq
- tyrosinase
- cataract
- agent
- cataracts
- 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
- 229940124428 anticataract agent Drugs 0.000 title claims abstract description 7
- MMXZSJMASHPLLR-UHFFFAOYSA-N pyrroloquinoline quinone Chemical compound C12=C(C(O)=O)C=C(C(O)=O)N=C2C(=O)C(=O)C2=C1NC(C(=O)O)=C2 MMXZSJMASHPLLR-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000000126 substance Substances 0.000 claims abstract description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract 2
- 150000001340 alkali metals Chemical class 0.000 claims abstract 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract 2
- 239000004480 active ingredient Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 208000002177 Cataract Diseases 0.000 abstract description 15
- 102000003425 Tyrosinase Human genes 0.000 abstract description 14
- 108060008724 Tyrosinase Proteins 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 102000004169 proteins and genes Human genes 0.000 abstract description 7
- 108090000623 proteins and genes Proteins 0.000 abstract description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 abstract description 4
- 239000008103 glucose Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 244000005700 microbiome Species 0.000 abstract description 3
- 150000001299 aldehydes Chemical class 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 11
- 108010053754 Aldehyde reductase Proteins 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 7
- 210000000695 crystalline len Anatomy 0.000 description 7
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 206010007749 Cataract diabetic Diseases 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- AHMIDUVKSGCHAU-UHFFFAOYSA-N Dopaquinone Natural products OC(=O)C(N)CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-UHFFFAOYSA-N 0.000 description 4
- AHMIDUVKSGCHAU-LURJTMIESA-N L-dopaquinone Chemical compound [O-]C(=O)[C@@H]([NH3+])CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-LURJTMIESA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 201000007025 diabetic cataract Diseases 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 150000001323 aldoses Chemical class 0.000 description 3
- 239000005515 coenzyme Substances 0.000 description 3
- -1 lipid peroxide Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 201000008525 senile cataract Diseases 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920000818 Catalin Polymers 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- OKPNYGAWTYOBFZ-UHFFFAOYSA-N Pirenoxine Chemical compound C12=NC3=CC=CC=C3OC2=CC(=O)C2=C1C(=O)C=C(C(=O)O)N2 OKPNYGAWTYOBFZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- RAPRJRLALQKSHB-UHFFFAOYSA-N benzoquinoneacetic acid Chemical compound OC(=O)CC1=CC(=O)C=CC1=O RAPRJRLALQKSHB-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- XFQYJNINHLZMIU-UHFFFAOYSA-N cataline Natural products CN1CC(O)C2=CC(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(OC)=C1 XFQYJNINHLZMIU-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000003885 eye ointment Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- QAXXQMIHMLTJQI-UHFFFAOYSA-N hexacosanal Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC=O QAXXQMIHMLTJQI-UHFFFAOYSA-N 0.000 description 2
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 125000004151 quinonyl group Chemical group 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- RPHLQSHHTJORHI-UHFFFAOYSA-N Adrenochrome Chemical compound O=C1C(=O)C=C2N(C)CC(O)C2=C1 RPHLQSHHTJORHI-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 208000022877 amino acid metabolic disease Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 150000002211 flavins Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- NFIYTPYOYDDLGO-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].OP(O)(O)=O NFIYTPYOYDDLGO-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、ピロロキノリンキノン又はその誘導体を有効
成分とする抗白内障剤に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an anti-cataract agent containing pyrroloquinoline quinone or a derivative thereof as an active ingredient.
（従来の技術）
白内障は老人性白内障と糖尿病性白内障の２つに大きく
分けることができる。(Prior Art) Cataracts can be broadly divided into two types: senile cataracts and diabetic cataracts.
老人性白内障は加齢、老化によるものであることには異
論はでないが、その原因については種々の説が提唱され
ており、水晶体膜機能障害、アミノ酸代謝障害、過酸化
脂質生成、糖代紺異常、酸化障害、紫外線障害、免疫機
能低下などが複雑に組み合わさりながら進行していくと
考えられている。There is no dispute that senile cataracts are caused by aging, but various theories have been proposed regarding its causes, including lens membrane dysfunction, amino acid metabolic disorders, lipid peroxide production, and sugar levels. It is thought that the disease progresses through a complex combination of abnormalities, oxidative damage, UV damage, and decreased immune function.
一般に、有核アミノ酸（チロシン、トリプトファン）の
代謝異常で生じるキノイド物ｆｆ（ベンゾキノン酢酸、
アドレノクロム、アドレナリンキノン、キノンイミンカ
ルボン酸等）によって水晶体の水溶性タン白が変性し不
溶化することにより白内障になるというキノイド学説が
有力である。In general, quinoids ff (benzoquinone acetic acid, benzoquinone acetic acid,
The quinoid theory holds that cataracts result from the denaturation and insolubility of water-soluble proteins in the crystalline lens by adrenochrome, adrenaline quinone, quinone imine carboxylic acid, etc.).
この説に基づいてキノイド物質と競合的に水晶体のタン
白に結合し、タン白の不溶化を阻止する薬物が開発され
（カタリン・、ファコリジン・）。Based on this theory, drugs have been developed that bind to protein in the crystalline lens competitively with quinoid substances and prevent protein insolubilization (catalin, phacolidin).
長年にわたり実用に供されている。It has been in practical use for many years.
また有核アミノ酸のうちチロシンは
チロシン→ドーパ→ドーパキノン
という系でも代謝され、ドーパキノンが白内障をひきお
こすことが知られている。ドーパからドーパキノンへは
チロシナーゼが関与しており、チロシナーゼの活性を阻
害することによりドーパキノンの生成は抑制することが
できる。チロシナーゼの活性は紫外線により増大するが
、これと紫外線障害による白内障の発生とを合わせ考え
ると、チロシナーゼ活性阻害による白内障の予防および
進行阻止の効果は大きい。Among nucleated amino acids, tyrosine is also metabolized in the system tyrosine → dopa → dopaquinone, and dopaquinone is known to cause cataracts. Tyrosinase is involved in the conversion from dopa to dopaquinone, and the production of dopaquinone can be suppressed by inhibiting the activity of tyrosinase. The activity of tyrosinase is increased by ultraviolet rays, and when this is considered together with the occurrence of cataracts due to damage caused by ultraviolet rays, inhibition of tyrosinase activity is highly effective in preventing and inhibiting the progression of cataracts.
更に糖尿病性白内障はグルコースの直接の障害あるいは
糖尿病による異常代謝物質、たとえばキノイド物質が原
因とされてきたが、現在では更に細胞内に蓄積された糖
アルコールのソルビトールが原因であるというポリオー
ル説も支持されつつある。Furthermore, diabetic cataracts have been thought to be caused by direct impairment of glucose or abnormal metabolic substances caused by diabetes, such as quinoid substances, but now there is also support for the polyol theory that the cause is the sugar alcohol sorbitol accumulated in cells. It is being done.
この説によると糖尿病患者ではアルドース還元酵素（Ａ
ｌｄｏｓｅ Ｒｅｄｕｃｔ、ａｓｅ ： ＡＲ）が増加
するため、グルコースがソルビトールへと還元され、１
■胞内にソルビトールが蓄積される。ついで電解質の移
動が始まり、水晶体の構成タン白の凝集がおこり不溶性
のタン白が増加し水晶体が混濁してくるといわれている
。According to this theory, in diabetic patients, aldose reductase (A
ldose Reduct, ase: AR) increases, glucose is reduced to sorbitol, and 1
■Sorbitol accumulates within the cells. It is said that electrolyte movement then begins, and the constituent proteins of the crystalline lens coagulate, resulting in an increase in insoluble proteins and the clouding of the crystalline lens.
従って、アルドース還元酵素（ＡＲ）を阻害することし
こより白内障の予防および進行阻止が可能であり、種々
のアルドース還元酵素阻害剤（ＡｌｄｏｓｅＲｅｄｕｃ
ｔａｓｅ Ｉｎｈｉｂｉｔｏｒｓ ： ＡＲＩ）が研究
開発されているが、いまだに実用に供されているものは
ない。Therefore, it is possible to prevent cataract and inhibit its progression by inhibiting aldose reductase (AR), and various aldose reductase inhibitors (AR)
tase inhibitors (ARI) have been researched and developed, but none have been put to practical use yet.
本発明の抗白内障剤は、このような白内障の予防乃至は
治療に提供されるもので、医学界に貢献するところ大な
るものである。The anti-cataract agent of the present invention is provided for the prevention or treatment of such cataracts, and will greatly contribute to the medical world.
（発明が解決しようとする問題点）
このように白内障の原因として各々有力な説があげられ
ているが、いずれも確定したものではなく、また単独の
原因を限定できるものではない。(Problems to be Solved by the Invention) As described above, various theories have been proposed as the cause of cataracts, but none of them are definitive, and it is not possible to limit a single cause.
事実、糖尿病性白内障でもＡＲ活性が低下する場合もあ
るし、キノイド説しこ基づくカタリン・やファコリジン
・にもＡＲの抑制効果があることも知られでいる。In fact, AR activity may be reduced in diabetic cataracts, and it is also known that catalin and phacolidin, which are based on the quinoid theory, have an AR suppressing effect.
さらに糖尿病性白内障患者の加齢による老人性白内障の
併発もさけられない現実である。Furthermore, it is an unavoidable reality that diabetic cataract patients develop senile cataract as they age.
一方、オゾン層の破壊による地表への紫外線到達量の増
大により、紫外線障害による白内障の危険も高まってい
る。On the other hand, as the amount of ultraviolet radiation reaching the earth's surface increases due to the destruction of the ozone layer, the risk of cataracts due to ultraviolet damage is also increasing.
（問題点を解決するための手段）
以上のような現状をふまえ、本発明者らはアルドース還
元酵素阻害能とチロシナーゼ活性阻害能の両方を有し、
さらにキノイド物質と競合する物質こそが理想的な抗白
内障剤になると考え、種々の化合物についてスクリーニ
ングを行い、また安全性のチエツク、製剤化した場合の
安定性などにも検討を加えた結果、式［Ｉ］で示される
ピロロキノリンキノン（Ｐｙｒｒｏｌｏｑｕｉｎｏｌｉ
ｎｅ ｑｕｉｎｏｎｅ ：以下、ＰＱＱと略す）および
その誘導体が全ての条件を満たすことをみいだし本発明
を完成した。(Means for Solving the Problems) Based on the above-mentioned current situation, the present inventors have developed a method that has both aldose reductase inhibitory ability and tyrosinase activity inhibitory ability,
Furthermore, we believed that a substance that competes with quinoid substances would be the ideal anti-cataract agent, so we screened various compounds, and also examined safety and stability when formulated, and found that the formula Pyrroloquinoline quinone (Pyrroloquinoli) represented by [I]
The present invention was completed by discovering that ne quinone (hereinafter abbreviated as PQQ) and its derivatives satisfy all the conditions.
一般に、ＰＱＱは従来の酸化−還元の補酵素ＮＡＤ（Ｐ
）やフラビン類とは異なり全く新しい補酵素であり、最
初Ａｃ１ｎｅｔｏｂａｃｔｅｒ属のグルコース脱水素酵
素の補酵素として発見されたものである。In general, PQQ is the traditional oxidation-reduction coenzyme NAD (P
) and flavins, it is a completely new coenzyme and was first discovered as a coenzyme of glucose dehydrogenase in the genus Ac1netobacter.
そして、ＰＱＱは生体内でアルコール、アルデヒド、グ
ルコースおよびアミン類の酸化反応に関与しており、あ
る種の微生物の生育促進物質としても働くことが知られ
ている。PQQ is involved in the oxidation reactions of alcohols, aldehydes, glucose, and amines in vivo, and is also known to act as a growth-promoting substance for certain microorganisms.
また、ＰＱＱは哺乳動物の血液中にも含まれておリ、ビ
タミン様の生理活性が期待されているが。PQQ is also contained in the blood of mammals, and is expected to have vitamin-like physiological activity.
生体系における役割の詳細はまだ不明である。しかし、
ＰＱＱは生体成分であり、安定且つ毒性のない物質と
いうことができる。The details of its role in biological systems are still unclear. but,
PQQ is a biological component and can be said to be a stable and non-toxic substance.
ＰＱＱにはキノン体である酸化型のいわゆるＰＱＱとキ
ノール体である還元型ＰＱＱが存在する。キノン体は酸
化剤として働いて自身はキノール体へと還元される。ま
たキノール体は適当な酸化剤があれば再びキノン体とな
る。PQQ exists in the oxidized form, which is a quinone form, so-called PQQ, and the reduced form, PQQ, which is a quinol form. The quinone body acts as an oxidizing agent and is itself reduced to the quinol body. In addition, the quinol form becomes the quinone form again if an appropriate oxidizing agent is present.
原料としてのＰＱＱは大腸菌等の微生物による発酵生産
か、有機化学的に合成によって得られ、市原もされてい
るので、供給の面で問題はない。PQQ as a raw material is obtained by fermentation production using microorganisms such as Escherichia coli or by organic chemical synthesis, and is also available in Ichihara, so there is no problem in terms of supply.
本発明に係る抗白内障剤は点眼剤、眼軟膏等による眼粘
膜への直接投与、あるいは注射剤、内服剤としての投与
等、任意の投与形態で投与可能である。また、ビタミン
Ｃ，グルタチオン、ビタミンＥ等との併用も可能である
。The anti-cataract agent according to the present invention can be administered in any desired dosage form, such as direct administration to the ocular mucosa using eye drops, eye ointment, etc., or administration as an injection or internal medicine. Further, it can also be used in combination with vitamin C, glutathione, vitamin E, etc.
本発明の有効成分を製剤化するには常法に従い。The active ingredient of the present invention can be formulated according to conventional methods.
界面活性剤、賦形剤１着色着香料、保存料、緩衝剤、
１ｌｌｌ濁剤１等張剤その他佐薬を適宜使用する。Surfactant, excipient 1 coloring and flavoring agent, preservative, buffering agent,
Use a clouding agent, an isotonic agent, and other adjuvants as appropriate.
（発明の効果）
本発明においては、 ＰＱＱによってチロシナーゼ活性
を阻害し、チロシナーゼが何らかの形で関与するタン白
の不溶化を防止し、白内障を予防乃至は進行停止するも
のである。(Effects of the Invention) In the present invention, PQQ inhibits tyrosinase activity, prevents protein insolubilization in which tyrosinase is involved in some way, and prevents or halts the progression of cataract.
次に本発明の試験例及び実施例を示す。Next, test examples and examples of the present invention will be shown.
試験例１
０．１％のし一チロシンと０．００２％の硫酸銅を含有
する０、 ＩＮリン酸緩衝液（ｐＨ？、０．） １．９
ｍ Ｑをとり、それに緩衝液に溶解した各種濃度のＰＱ
Ｑを１．０ｍｇ加える。次いでチロシナーゼ（ｓｉｇｍ
ａ社製）５ｍｇを緩衝液５ｍ＋２に溶解した酵素液をＯ
，１ｍｇ加える０反応液を３７℃で６０分間インキュベ
イトした後、８５℃に５分間保持して反応を停止し、５
８０ｎ＋＊及び６４０止ｍの吸光度を測定し、以下の式
により阻害率を求めた。Test Example 1 0.IN phosphate buffer containing 0.1% tyrosine and 0.002% copper sulfate (pH?, 0.) 1.9
Take mQ and add PQ of various concentrations dissolved in a buffer solution.
Add 1.0 mg of Q. Then tyrosinase (sigm
The enzyme solution prepared by dissolving 5mg of the enzyme solution (manufactured by company A) in 5m+2 buffer solution was
, 1 mg of the 0 reaction solution was incubated at 37°C for 60 minutes, and then held at 85°C for 5 minutes to stop the reaction.
The absorbance at 80n+* and 640m was measured, and the inhibition rate was calculated using the following formula.
結果を表１に示す。The results are shown in Table 1.
表Ｉ ＰＱＱのチロシナーゼ活性阻害率この測定法は
１反応溶液中にＣｕイオンを添加し。Table I Tyrosinase activity inhibition rate of PQQ This measurement method involves adding Cu ions to the reaction solution.
黒色メラニンの生成を直接測定する方法である。This method directly measures the production of black melanin.
５８０止ｍに於ける測定では１０−３Ｍで約６０％のチ
ロシナーゼ阻害効果が見られ、５０％阻害濃度ＩＣ，。Measurements at 580 m showed a tyrosinase inhibitory effect of about 60% at 10-3M, with a 50% inhibitory concentration IC.
は７ ｘ １０−’Ｍであった。一方、６４０止での測
定に於いてもほぼ同様の結果が得られＩＣ，。は８ Ｘ
１０−’Ｍであった・
以上のように、 ＰＱＱは、強力なチロシナーゼ活性阻
害作用を有することが判明した６
試験例２ ＰＱＱのＡｌｄｏｓｅ ｒｅｄｕｃｔａｓ
ｅ阻害作用ニワトリヒナの水晶体のホモジネートを用い
。was 7 x 10-'M. On the other hand, almost the same results were obtained when measuring at 640°C. is 8
As described above, PQQ was found to have a strong tyrosinase activity inhibitory effect.6 Test Example 2 Aldose reductas of PQQ
e Inhibitory effect using chick lens homogenate.
Ｋｉｎｏｓｈｉｔａ らの方法（Ｋｉｎｏｓｈｊ、ｔａ
、 Ｊ、Ｈ，ｅｔ ａｌ。The method of Kinoshita et al.
, J.H., et al.
Ｍｅｔａｂｏｌｉｓｍ、 ２８： ４６２−４６９．１
９７９）によってＡｌｄｏｓｅｒｅｄｕｃｔａｓｅ活性
を測定した。Metabolism, 28: 462-469.1
Aldose reductase activity was measured by 979).
すなわち、水晶体ホモジネート、ＬｉＳＯ４゜ＮＡＤＰ
Ｈ□、阻害剤を加えた反応液に基質であるｄＱ−ｇｌｙ
ｃｅｒａｌｄｅｈｙｄｅを加えることにより反応を開始
し、ＮＡＤＰＨ，の３４０ｍｍにおける吸光度（ＯＤ）
の５分間減少により酵素活性性を測定した。ブランクの
ＯＤは基質無添加時のものとした。Ａｌｄｏｓｅ ｒｅ
ｄｕｃｔａｓｅ反応の阻害剤による阻害率を次式より求
めた。Namely, lens homogenate, LiSO4°NADP
H□, the substrate dQ-gly was added to the reaction solution containing the inhibitor.
The reaction was started by adding ceraldehyde, and the optical density (OD) at 340 mm of NADPH was measured.
Enzyme activity was measured by the 5 minute decrease in . The OD of the blank was taken as the value when no substrate was added. Aldose re
The inhibition rate of the ductase reaction by the inhibitor was determined from the following formula.
阻害剤添加時の ブランクの 結果を表２に示す。Blank when adding inhibitor The results are shown in Table 2.
表２ ＰＱＱのＡｌｄｏｓｅ ｒｅｄｕｃｔａｓｅ阻
害作用表２に示したようにＰＱＱは５ Ｘ １０−’河
という濃度でＡｌｄｏｓｅ ｒｅｄｕｃｔａｓａ活性を
５０％阻止し、１０−’Ｍでは１００％阻害を示してい
る。以上のようにＰＱＱには強力なＡｌｄｏｓｅ ｒｅ
ｄｕｃｔａｓｅ阻害作用のあることが判明した。Table 2 Aldose reductase inhibitory effect of PQQ As shown in Table 2, PQQ inhibited Aldose reductase activity by 50% at a concentration of 5 x 10-'M, and showed 100% inhibition at 10-'M. As mentioned above, PQQ has a powerful Aldose re
It was found that it has a ductase inhibitory effect.
実施例１
１、 ＰＱＱ Ｏ，２ｇ２
、リン酸二水素ナトリウム ０．４ｇ３、リン酸−
水素ナトリウム ０．４７ ｇ４、塩化ナトリウム
０．１５ｇ５、ハラオキシ安息香酸メチ
ル ０．０２６ ｇ６、パラオキシ安息香酸プロピル
０．０１４ ｇｌ、滅菌精製水 全量Ｌｏ
ｏｍ （１上記１〜６を７に完全に溶解し、無菌濾過し
て点眼剤を製する。Example 1 1, PQQ O,2g2
, sodium dihydrogen phosphate 0.4g3, phosphoric acid-
Sodium hydrogen 0.47 g4, sodium chloride 0.15 g5, methyl halaoxybenzoate 0.026 g6, propyl paraoxybenzoate 0.014 gl, sterile purified water Total amount Lo
om (1) Completely dissolve the above 1 to 6 in 7 and sterile filter to prepare eye drops.
実施例２
１、 ＰＱＱ ０−１ｇ２
、精製水 ５ｇ３、防腐剤
適量４、マグロコール４００
５Ｇ、９ ｇ５、マグロコール４０００
３８ ｇｌを２に溶解し、これをあらかじめ
加熱溶解しておいた３、４．５の混合物の中へ添加し、
攪拌冷却し、眼軟膏製剤とする。Example 2 1, PQQ 0-1g2
, purified water 5g3, preservative
Appropriate amount 4, tuna call 400
5G, 9 g5, tuna call 4000
Dissolve 38 g in 2, add this to the mixture of 3 and 4.5 that has been heated and dissolved in advance,
Stir and cool to make an eye ointment formulation.
実施例３
１、 ＰＱＱ ２０ｇ２、
乳糖 ’Ｊｏｇ３、トウモロ
コシ澱粉 ２９ｇ４、ステアリン酸マグネ
シウム １ｇ１、２および１７ｇのトウモロコシ澱
粉を混和し、７ｇのトウモロコシ澱粉から作ったペース
トとともに顆粒化する。この顆粒に５ｇのトウモロコシ
澱粉と４を加え混合物を圧縮錠剤機で圧縮して１錠あた
り２０Ｉｎｇの１を含有する錠剤１，０００個を製造す
る。Example 3 1, PQQ 20g2,
Lactose 'Jog3, corn starch 29g4, magnesium stearate 1g1, 2 and 17g corn starch are blended and granulated with a paste made from 7g corn starch. 5 g of corn starch and 4 are added to the granules and the mixture is compressed in a tablet compression machine to produce 1,000 tablets containing 20 Ing of 1 per tablet.
実施例４
１、ＰＱＱ ５ｇ２、塩化
ナトリウム ９ｇ３、クロロブタノール
５ｇ４、炭酸水素ナトリウム
１ｇ全成分を蒸留水１．０００ｍ Ｑに溶解し、アン
プルに１ｍ１２ずつ分注し、注射剤１ 、０００本を＋
Ｍ造する。Example 4 1, PQQ 5g2, sodium chloride 9g3, chlorobutanol 5g4, sodium hydrogen carbonate
Dissolve 1 g of all ingredients in 1.000 m Q of distilled water, dispense 1 m12 into ampoules, and prepare 1,000 injections.
Make M.
代理人 弁理士 戸 １）親 男 手続補正書 昭和６１年 ９月２６日Agent Patent Attorney 1) Parent Male Procedural amendment September 26, 1986
Claims (1)
導体を有効成分とする抗白内障剤。 ▲数式、化学式、表等があります▼〔 I 〕 ［式中Ｒ＿１、Ｒ＿２、Ｒ＿３は同一でも異ってもよく
、水素、アルキル基、アルカリ金属又は１／２アルカリ
土類金属を表わす。］[Scope of Claims] An anti-cataract agent containing a pyrroloquinoline quinone represented by formula [I] or a derivative thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R_1, R_2, and R_3 may be the same or different and represent hydrogen, an alkyl group, an alkali metal, or a 1/2 alkaline earth metal. ]
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61184127A JPH085791B2 (en) | 1986-08-07 | 1986-08-07 | Anti-cataract agent |
| CA000543814A CA1302275C (en) | 1986-08-07 | 1987-08-05 | Enzyme inhibitor |
| EP19870111397 EP0262345A3 (en) | 1986-08-07 | 1987-08-06 | Pyrroloquinoline quinones as enzyme inhibitors |
| US07/299,024 US4898870A (en) | 1986-08-07 | 1989-01-19 | Pyrroloquinoline quinone compounds useful as an enzyme inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61184127A JPH085791B2 (en) | 1986-08-07 | 1986-08-07 | Anti-cataract agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6341421A true JPS6341421A (en) | 1988-02-22 |
| JPH085791B2 JPH085791B2 (en) | 1996-01-24 |
Family
ID=16147850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61184127A Expired - Lifetime JPH085791B2 (en) | 1986-08-07 | 1986-08-07 | Anti-cataract agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH085791B2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6348215A (en) * | 1986-08-14 | 1988-02-29 | Sogo Yatsukou Kk | Remedy for diabetic complication |
| EP0429333A1 (en) | 1989-11-13 | 1991-05-29 | Mitsubishi Gas Chemical Company, Inc. | Process for producing oxazopyrroloquinolines, novel oxazopyrroloquinolines, and use of oxazopyrroloquinolines |
| WO1995030420A1 (en) * | 1994-05-06 | 1995-11-16 | Alcon Laboratories, Inc. | Use of vitamin e tocopheryl derivatives in ophthalmic compositions |
| WO2008035686A1 (en) * | 2006-09-19 | 2008-03-27 | Kyowa Hakko Bio Co., Ltd. | Agent for improving insulin resistance |
| JP2010047533A (en) * | 2008-08-22 | 2010-03-04 | Mitsubishi Gas Chemical Co Inc | Spinal injury-improving agent |
| JP2013237644A (en) * | 2012-05-16 | 2013-11-28 | Mitsubishi Gas Chemical Co Inc | Cell activating carbonated water |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008029907A1 (en) | 2006-09-08 | 2008-03-13 | Kyowa Hakko Bio Co., Ltd. | Hypertension-ameliorating agent |
-
1986
- 1986-08-07 JP JP61184127A patent/JPH085791B2/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6348215A (en) * | 1986-08-14 | 1988-02-29 | Sogo Yatsukou Kk | Remedy for diabetic complication |
| EP0429333A1 (en) | 1989-11-13 | 1991-05-29 | Mitsubishi Gas Chemical Company, Inc. | Process for producing oxazopyrroloquinolines, novel oxazopyrroloquinolines, and use of oxazopyrroloquinolines |
| WO1995030420A1 (en) * | 1994-05-06 | 1995-11-16 | Alcon Laboratories, Inc. | Use of vitamin e tocopheryl derivatives in ophthalmic compositions |
| WO2008035686A1 (en) * | 2006-09-19 | 2008-03-27 | Kyowa Hakko Bio Co., Ltd. | Agent for improving insulin resistance |
| US8097635B2 (en) | 2006-09-19 | 2012-01-17 | Kyowa Hakko Bio Co., Ltd. | Insulin resistance improving agent |
| JP2010047533A (en) * | 2008-08-22 | 2010-03-04 | Mitsubishi Gas Chemical Co Inc | Spinal injury-improving agent |
| JP2013237644A (en) * | 2012-05-16 | 2013-11-28 | Mitsubishi Gas Chemical Co Inc | Cell activating carbonated water |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH085791B2 (en) | 1996-01-24 |
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