JPS63104920A - Aldose reactase inhibitor - Google Patents
Aldose reactase inhibitorInfo
- Publication number
- JPS63104920A JPS63104920A JP24839086A JP24839086A JPS63104920A JP S63104920 A JPS63104920 A JP S63104920A JP 24839086 A JP24839086 A JP 24839086A JP 24839086 A JP24839086 A JP 24839086A JP S63104920 A JPS63104920 A JP S63104920A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- methanol
- water
- glucose
- active ingredient
- 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.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 3
- 150000001323 aldoses Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 9
- 239000008103 glucose Substances 0.000 claims abstract description 9
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 2
- 239000003288 aldose reductase inhibitor Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 21
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 238000004440 column chromatography Methods 0.000 abstract description 9
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 abstract description 7
- 241000202807 Glycyrrhiza Species 0.000 abstract description 6
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 abstract description 6
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 abstract description 6
- 229940010454 licorice Drugs 0.000 abstract description 6
- 229920005654 Sephadex Polymers 0.000 abstract description 4
- 239000012507 Sephadex™ Substances 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 4
- GSZUGBAEBARHAW-UHFFFAOYSA-N sophoraflavone B Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C=2OC3=CC(O)=CC=C3C(=O)C=2)C=C1 GSZUGBAEBARHAW-UHFFFAOYSA-N 0.000 abstract description 4
- KSDSYIXRWHRPMN-UHFFFAOYSA-N 4'-O-beta-D-Galactopyranoside-6''-p-Coumaroylprunin-4',5,7-Trihydroxyflavanone Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C2OC3=CC(O)=CC(O)=C3C(=O)C2)C=C1 KSDSYIXRWHRPMN-UHFFFAOYSA-N 0.000 abstract description 3
- 208000002177 Cataract Diseases 0.000 abstract description 3
- 208000017442 Retinal disease Diseases 0.000 abstract description 3
- 206010038923 Retinopathy Diseases 0.000 abstract description 3
- 238000010828 elution Methods 0.000 abstract description 3
- 208000017169 kidney disease Diseases 0.000 abstract description 3
- DEMKZLAVQYISIA-ONJCETCRSA-N Liquiritin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)c1ccc([C@@H]2Oc3c(C(=O)C2)ccc(O)c3)cc1 DEMKZLAVQYISIA-ONJCETCRSA-N 0.000 abstract description 2
- DEMKZLAVQYISIA-UHFFFAOYSA-N Liquirtin Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C2OC3=CC(O)=CC=C3C(=O)C2)C=C1 DEMKZLAVQYISIA-UHFFFAOYSA-N 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- DEMKZLAVQYISIA-ZRWXNEIDSA-N liquiritin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C([C@H]2OC3=CC(O)=CC=C3C(=O)C2)C=C1 DEMKZLAVQYISIA-ZRWXNEIDSA-N 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 abstract description 2
- FURUXTVZLHCCNA-UHFFFAOYSA-N Liquiritigenin Natural products C1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 FURUXTVZLHCCNA-UHFFFAOYSA-N 0.000 abstract 2
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 abstract 2
- FURUXTVZLHCCNA-AWEZNQCLSA-N liquiritigenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC=C2C(=O)C1 FURUXTVZLHCCNA-AWEZNQCLSA-N 0.000 abstract 2
- KSDSYIXRWHRPMN-SFTVRKLSSA-N (2s)-5,7-dihydroxy-2-[4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]-2,3-dihydrochromen-4-one Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C([C@H]2OC3=CC(O)=CC(O)=C3C(=O)C2)C=C1 KSDSYIXRWHRPMN-SFTVRKLSSA-N 0.000 abstract 1
- FTVWIRXFELQLPI-ZDUSSCGKSA-N (S)-naringenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 FTVWIRXFELQLPI-ZDUSSCGKSA-N 0.000 abstract 1
- 206010029216 Nervousness Diseases 0.000 abstract 1
- 150000001298 alcohols Chemical class 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 229940117954 naringenin Drugs 0.000 abstract 1
- WGEYAGZBLYNDFV-UHFFFAOYSA-N naringenin Natural products C1(=O)C2=C(O)C=C(O)C=C2OC(C1)C1=CC=C(CC1)O WGEYAGZBLYNDFV-UHFFFAOYSA-N 0.000 abstract 1
- 235000007625 naringenin Nutrition 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 102000016912 Aldehyde Reductase Human genes 0.000 description 15
- 108010053754 Aldehyde reductase Proteins 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229920005862 polyol Polymers 0.000 description 6
- 150000003077 polyols Chemical class 0.000 description 6
- 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 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 210000000695 crystalline len Anatomy 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000008101 lactose Substances 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- ASHGTUMKRVIOLH-UHFFFAOYSA-L potassium;sodium;hydrogen phosphate Chemical compound [Na+].[K+].OP([O-])([O-])=O ASHGTUMKRVIOLH-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- BVRDQVRQVGRNHG-UHFFFAOYSA-N 2-morpholin-4-ylpyrimido[2,1-a]isoquinolin-4-one Chemical compound N1=C2C3=CC=CC=C3C=CN2C(=O)C=C1N1CCOCC1 BVRDQVRQVGRNHG-UHFFFAOYSA-N 0.000 description 1
- OMIHGPLIXGGMJB-UHFFFAOYSA-N 7-oxabicyclo[4.1.0]hepta-1,3,5-triene Chemical compound C1=CC=C2OC2=C1 OMIHGPLIXGGMJB-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- LQVXSNNAFNGRAH-QHCPKHFHSA-N BMS-754807 Chemical compound C([C@@]1(C)C(=O)NC=2C=NC(F)=CC=2)CCN1C(=NN1C=CC=C11)N=C1NC(=NN1)C=C1C1CC1 LQVXSNNAFNGRAH-QHCPKHFHSA-N 0.000 description 1
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 240000008917 Glycyrrhiza uralensis Species 0.000 description 1
- 235000000554 Glycyrrhiza uralensis Nutrition 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000012916 chromogenic reagent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002584 ketoses Chemical class 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- -1 nicotinamide adenine nucleotide phos phate Chemical class 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、アルドースリダクターゼ阻害作用を有し、白
内障、網膜症、神経障害、腎障等の糖尿病における各種
合併症の治療に有用なアルドースリダクターゼ阻害剤に
関するものである。Detailed Description of the Invention [Industrial Application Field] The present invention is directed to an aldose reductase which has an aldose reductase inhibitory effect and is useful for the treatment of various complications of diabetes such as cataracts, retinopathy, neuropathy, and nephropathy. It concerns inhibitors.
［従来の技術および問題点］
近年、白内障、網膜症、腎症等の糖尿病における各種合
併症の成因として、グルコースの代謝経路であるポリオ
ール経路を介した細胞内ソルビトールの蓄積が注目され
ている。ポリオール経路は、グルコース、ガラクトース
等のアルドースがソルビトール、ガラクチトール等のポ
リオールを介してフルクトース等のケトースに変換され
る代謝経路であり、免疫組織化学的手法により全身請臓
器に広く存在することが明らかになってきた。[Prior Art and Problems] In recent years, the accumulation of intracellular sorbitol via the polyol pathway, which is a glucose metabolic pathway, has attracted attention as a cause of various complications in diabetes such as cataracts, retinopathy, and nephropathy. The polyol pathway is a metabolic pathway in which aldoses such as glucose and galactose are converted to ketoses such as fructose via polyols such as sorbitol and galactitol, and immunohistochemical techniques have revealed that they are widely present in all organs throughout the body. It has become.
この経路の第１段階であるアルドース−ポリオール間の
変換を触媒する酵素をアルドースリダクターゼといい、
この酵素がポリオール経路の律速酵素と考えられている
。このアルドースリダクターゼを阻害し、ソルビトール
の産生や蓄積を低下させることが、糖尿病患者における
合併症の治療に有効であるという報告がなされている。The first step in this pathway, the enzyme that catalyzes the conversion between aldose and polyol, is called aldose reductase.
This enzyme is considered to be the rate-limiting enzyme in the polyol pathway. It has been reported that inhibiting this aldose reductase and reducing the production and accumulation of sorbitol is effective in treating complications in diabetic patients.
そこで、アルドースリダクターゼ阻害作用を有する薬剤
の開発が望まれていた。Therefore, it has been desired to develop a drug that has an aldose reductase inhibitory effect.
［問題点を解決するための手段］
本発明者等は、種々の生薬についてアルドースリダクタ
ーゼ阻害作用に関する研究を行った結果、甘草（Ｇｌｙ
ｃｙｒｒｈｉｚａ ｕｒａｌｅｎｓｉｓ ＦＩＳＩＩＥ
Ｒ。[Means for Solving the Problems] As a result of research on the aldose reductase inhibitory effect of various herbal medicines, the present inventors found that licorice (Gly
cyrrhiza uralensis FISIIE
R.
Ｇｌｙｃｙｒｒｈｉｚａ ｇｌａｂｒａ ＬＩＮＮＥ
ｖａｒ、 ｇｌａｎｄｕｌｉｆｅｒａＲＥＧＥＬ ｅｔ
ＩＩＥＲＤＥＲまたはその他の同属植物の根およびス
トロン）に強いアルドースリダクターゼ阻害作用がある
ことを見い出し、次いで、甘草の活性成分について研究
を進めた結果、一般式で表される化合物が極めて強いア
ルドースリダクターゼ阻害作用を有することを見い出し
本発明を完成させた。すなわち本発明は、一般式
［式中Ｒは、水素原子またはグルコースを示し、Ｒ゛は
水素原子または水酸基を示す。コで表される化合物（以
下、一般式の化合物と称する。）を有効成分とするアル
ドースリダクターゼ阻害剤である。Glycyrrhiza glabra LINNE
var, glanduliferaREGEL et
We discovered that the roots and stolons of IIERDER and other congenerous plants have a strong aldose reductase inhibitory effect, and as a result of conducting research on the active ingredients of licorice, we found that the compound represented by the general formula has an extremely strong aldose reductase inhibitory effect. The present invention was completed based on the discovery that the present invention has the following properties. That is, the present invention is based on the general formula [where R represents a hydrogen atom or glucose, and R'' represents a hydrogen atom or a hydroxyl group]. This is an aldose reductase inhibitor containing a compound represented by (hereinafter referred to as a compound of the general formula) as an active ingredient.
一般式の化合物には、以下に示す化合物がある。Compounds of the general formula include the compounds shown below.
これらの化合物を得るためには、例えば、次のような方
法がある。For example, the following methods can be used to obtain these compounds.
甘草を、水、アルコール類または、水とアルコール類の
混合溶媒で抽出し、抽出液から除去した残渣を、順次、
水、水−メタノール（１：、１）、メタノールを溶出溶
媒として、セファデックスＬＨ−２０等のセファデック
ス、ダイヤイオンＩＰ−２０等のポーラスポリマー等を
担体に用いたカラムクロマトグラフィーに付し、それぞ
れの画分を得る。次いで、水−メタノール（１：ｌ）溶
出部、メタノール溶出部をそれぞれ水、メタノール、エ
タノール、エーテル、アセトン、クロロホルム、ベンゼ
ン、水−酢酸−メタノール混合液から選ばれる少なくと
もひとつを溶出溶媒として、セファデックスＬＨ−２０
等のセファデックス、Ｍ（、ＩゲルＣＨＰ２０Ｐ等のポ
ーラスポリマー、セルロース、シリカゲルまたは逆相系
シリカゲル等を担体に用いたカラムクロマトグラフィー
に数回付し、薄層クロマトグラフィーで目的成分を確認
しながら分画することより得ることができる。場合によ
り、メタノール、エタノール、水等の適当な溶媒を用い
て再結晶することにより精製してもよい。Licorice is extracted with water, alcohol, or a mixed solvent of water and alcohol, and the residue removed from the extract is sequentially extracted.
Water, water-methanol (1:, 1), methanol as an elution solvent, subjected to column chromatography using Sephadex such as Sephadex LH-20, porous polymer such as Diaion IP-20, etc. as a carrier, Obtain each fraction. Next, the water-methanol (1:l) eluted portion and the methanol eluted portion were treated with Sephasics using at least one selected from water, methanol, ethanol, ether, acetone, chloroform, benzene, and a water-acetic acid-methanol mixture as an elution solvent. Dex LH-20
Column chromatography using Sephadex, M(, I gel CHP20P, etc.), cellulose, silica gel, or reversed-phase silica gel as a carrier was performed several times, and the target components were confirmed using thin layer chromatography. It can be obtained by fractionation. Optionally, it may be purified by recrystallization using an appropriate solvent such as methanol, ethanol, or water.
一般式の化合物の製造の具体例を示すと次の如くである
。A specific example of the production of the compound of the general formula is as follows.
具体例１
甘草１．４に９を１０＆の水で抽出し、抽出液より水を
除去して、水工キス４００ｇを得た。この水工キスを再
び、水ＩＱに溶解した後、セファデックスＬＨ−２０（
ファルマシア製）のカラムクロマトグラフィーに付し、
順次、水、水−メタノール（１：１）、メタノールで溶
出する。水−メタノール（ＩＩＩ）溶出部を減圧上濃縮
して析出する白色粉末を水−エタノールから結晶化させ
ることにより、Ｒｆ値０．３０［薄層プレート：キーゼ
ルゲル６０Ｆｚｓい展開溶媒：クロロホルム−メタノー
ル（３：ｌ）、発色試薬：１０％硫酸（橙色）］の無無
色針状晶を得た。この化合物は標品のリクイリチンと混
融試験、赤外吸収スペクトルで一致した。Specific Example 1 Licorice 1.4 to 9 was extracted with 10&ml of water, and the water was removed from the extract to obtain 400 g of Suiko Kiss. After dissolving this Suiko Kiss again in Water IQ, Sephadex LH-20 (
Subjected to column chromatography (manufactured by Pharmacia),
Elute sequentially with water, water-methanol (1:1), and methanol. By concentrating the water-methanol (III) eluate under reduced pressure and crystallizing the precipitated white powder from water-ethanol, an Rf value of 0.30 [thin layer plate: Kieselgel 60Fzs], developing solvent: chloroform-methanol (3 :l), coloring reagent: 10% sulfuric acid (orange color)] was obtained. This compound matched the standard liquiritin in the mixing test and infrared absorption spectrum.
具体例２
具体例１のセファデックスＬＨ−２０のカラムクロマト
グラフィーで得たメタノール溶出部を、再びセファデッ
クスＬ１１−２０に付し、水−メタノール（１：０）か
ら（０：１）まで濃度勾配をかけて溶出し、水−メタノ
ール（４：６）で溶出する両分を水−エタノールから結
晶化させることよりＲｆ値０．４５［薄層プレート：キ
ーゲルゲル６０Ｆ０い展開溶媒：ベンゼン−エーテル（
１：１）、発色試薬：１０％硫酸（橙色）コの無色針状
結晶を得た。この化合物の理化学的性質は文献［Ｃ４ａ
ｎ Ｈｕｌｌｅ。Specific Example 2 The methanol eluate obtained by column chromatography on Sephadex LH-20 in Specific Example 1 was again subjected to Sephadex L11-20 to increase the concentration from water-methanol (1:0) to (0:1). By applying a gradient elution and crystallizing both eluted fractions from water-ethanol (4:6), the Rf value was 0.45 [thin layer plate: Kiegelgel 60F0].Developing solvent: benzene-ether (
Colorless needle-shaped crystals of 1:1), coloring reagent: 10% sulfuric acid (orange) were obtained. The physicochemical properties of this compound are described in the literature [C4a
n Hulle.
Ｐ、Ｂｒａｅｃｋｍａｎ、ＭＪａｎｄｅｗａｌｌｅ、Ｐ
ｌａｎｔａ Ｍｅｄ、、２０，２７８（１９７１）］記
載の“リクイリチゲニンの性質と一致した。Braeckman, P., Jandewalle, P.
lanta Med, 20, 278 (1971)].
具体例３
具体例２のＭＣＩゲルＣ１１Ｐ２０Ｐカラムクロマトグ
ラフィーで水−メタノール（４：６）で溶出する両分を
、逆相系シリカゲルであるフジゲル（ＯＤＳＧ ａ型、
水戸化学技術研究新製）のカラムクロマトグラフィーに
付し、水−メタノール（１：ｌ）で溶出する両分を得た
。この画分を減圧上濃縮して析出する結晶を、水−メタ
ノールから再結晶させることによりＲｆ値０．４０［薄
層プレート：キーゲルゲル６０ Ｆ ２５い展開溶媒：
クロロホルム−メタノール（３：１）、発色試薬：１０
％硫酸（黄色）］の無無色針状晶を得た。この化合物の
理化学的性質は文献［呂永鎮、王玉蘭、楼朱雄、祖景余
、粱貨清２周卓倫、朽学学報、＋８．＋９９（１９８３
）］記載のケロスボンデインの性質と一致した。Specific Example 3 Both fractions eluted with water-methanol (4:6) in the MCI Gel C11P20P column chromatography of Specific Example 2 were treated with Fujigel (ODSG a type,
The mixture was subjected to column chromatography (Mito Kagaku Gijutsu Kenkyushin) to obtain both fractions, which were eluted with water-methanol (1:l). This fraction was concentrated under reduced pressure and the precipitated crystals were recrystallized from water-methanol to obtain an Rf value of 0.40 [thin layer plate: Kiegelgel 60 F25 developing solvent:
Chloroform-methanol (3:1), color reagent: 10
% sulfuric acid (yellow)] was obtained. The physical and chemical properties of this compound are described in the literature [Lu Yongzhen, Wang Yulan, Lou Zhuoxiong, Zu Jingyu, Lianguanqing 2 Zhou Zhuolun, Kuxuexuepo, +8. +99 (1983
)] was consistent with the properties of kerosbondein.
具体例４
具体例１のセファデックスＬＨ−２０カラムクロマトグ
ラフィーで水−メタノール（３ニア）で溶出する画分を
、次いでＭＣＩゲルＣＨＰ２０Ｐのカラムクロマトグラ
フィーに付し、水−メタノールで５度勾配をかけて溶出
し、水−メタノール（３ニア）で溶出する両分を得た。Specific Example 4 The fraction eluted with water-methanol (3N) in Sephadex LH-20 column chromatography in Specific Example 1 was then subjected to MCI gel CHP20P column chromatography, and a 5-degree gradient was applied with water-methanol. Both fractions were obtained, eluting with water-methanol (3N).
これをセルロース（アビセル、脂化成製）カラムクロマ
トグラフィーに付し、２％酢酸−メタノール（４：１）
で溶出した。最初の１１２で溶出する両分を減圧下で濃
縮し、析出した結晶を水−メタノールで再結晶すること
によりＲｆ値０．５０［薄層プレート：キーゲルゲル６
０Ｆ２５＜、展開溶媒：ベンゼン−アセトン（２：１）
、発色試薬。This was subjected to cellulose (Avicel, manufactured by Fukaisei) column chromatography, and 2% acetic acid-methanol (4:1) was used.
It was eluted. Both fractions eluted with the first 112 were concentrated under reduced pressure, and the precipitated crystals were recrystallized with water-methanol to obtain an Rf value of 0.50 [thin layer plate: Kiegelgel 6].
0F25<, developing solvent: benzene-acetone (2:1)
, chromogenic reagent.
１０％硫酸（黄色）コの無色針状結晶を得た。この化合
物の理化学的性質は文献［呂永鎮、王玉蘭。Colorless needle-shaped crystals of 10% sulfuric acid (yellow) were obtained. The physical and chemical properties of this compound are described in the literature [Lu Yongzhen, Wang Yulan.
楼朱雄、祖景、余、梁貨清２周卓倫、杓学学報。Lou Zhu Xiong, Zu Jing, Yu, Liang Kuanqing, 2 Zhou Zhuolun, and Ping Xuebao.
ＬＬ、１９９（１９８３）］記載のナリンゲンと一致し
た。LL, 199 (1983)].
次に、一般式の化合物がアルドースリダクターゼ阻害作
用を有することを実験例を挙げて説明する。Next, the fact that the compound of the general formula has an aldose reductase inhibitory effect will be explained with reference to experimental examples.
実験例１
くアルドースリダクターゼ活性の測定〉−２０℃にて保
存した。Experimental Example 1 Measurement of aldose reductase activity> Stored at -20°C.
水晶体は０．５ｍＭフェニルメチルスルホニルフロリド
を含む１３５ｍＭナトリウム−カリウム−リン酸緩衝液
（ｐＨ７，０）にてホモジナイズして、３０、ＯＯＯｒ
ｐｍで３０分間遠心した。その上清をアルドースリダク
ターゼ活性測定の検体とした。The crystalline lens was homogenized in 135mM sodium-potassium-phosphate buffer (pH 7.0) containing 0.5mM phenylmethylsulfonyl fluoride.
Centrifuged at pm for 30 minutes. The supernatant was used as a sample for aldose reductase activity measurement.
また、以上の操作はすべて４℃で行い、検体は０℃で保
存した。Furthermore, all of the above operations were performed at 4°C, and the specimens were stored at 0°C.
アルドースリダクターゼ活性の測定はデュフラン（Ｄｕ
ｆｒａｎｅ）らの方法［Ｂｉｏｃｈｅａ＋１ｃａｌ Ｍ
ｅｄｉｃｉｎｅ。Aldose reductase activity was measured using Dufuran (Dufuran).
frane) et al. [Biochea+1cal M
edicine.
ＬＬ、９９−１０５（１９８４）参照］により行った。LL, 99-105 (1984)].
すなわち、１００ｍＭ硫酸リチウム、０．０３ｍＭＮ
Ａ Ｄ Ｐ １１ （還元型ｎｉｃｏｔｉｎａｍｉｄｅ
ａｄｅｎｉｎｅｄｉｎｕｃｌｅｏｔｉｄｅ ｐｈｏｓ
ｐｈａｔｅ）、および基質として０．１ｍＭＤＬ−グリ
セルアルデヒドまたは２０ｍＭグルコースを含むように
調製した１３５ｍＭナトリウム−カリウム−リン酸緩衝
液（ｐ［！７．０ ）８００成に、上記の検体１００ｄ
および上記具体例１〜４で得た化合物をそれぞれエタノ
ールに１×１０−１１！９／ｄの終濃度となるように溶
解させた薬物溶解液１００度をそれぞれ加え、３０℃に
て３０分間反応させた。次に、０．５Ｎ塩酸０．３７７
を加えて反応を停止させ、１０ｍＭイミダゾールを含む
６Ｎ水酸化ナトリウム１ ｄを添加することにより、前
記の反応によって生じたＮＡＤＰ（酸化型ｎｉｃｏｔｉ
ｎａｍｉｄｅ ａｄｅｎｉｎｅ ｄｉｎｕｃｌｅｏｔｉ
ｄｅ ｐｈｏｓｐｈａｔｅ）を蛍光物質に変換して、６
０分後にその蛍光強度を測定した。蛍光強度は、室温で
分光光度計ＲＦ−５１０（株式会社島津製作所製）を用
いて励起波長３６０ ｎｍ、蛍光波長４６０ｎｍの条件
で測定した。i.e. 100mM lithium sulfate, 0.03mMN
ADP 11 (reduced nicotinamide
adenine nucleotide phos
phate), and 135 mM sodium-potassium-phosphate buffer (p[!7.0) prepared to contain 0.1 mM DL-glyceraldehyde or 20 mM glucose as a substrate.
A 100 degree drug solution prepared by dissolving each of the compounds obtained in Specific Examples 1 to 4 above in ethanol to a final concentration of 1 x 10-11!9/d was added to each, and reacted at 30°C for 30 minutes. I let it happen. Next, 0.5N hydrochloric acid 0.377
was added to stop the reaction, and 1 d of 6N sodium hydroxide containing 10 mM imidazole was added to remove NADP (oxidized nicoti) produced by the above reaction.
namide adenine dinucleoti
de phosphate) into a fluorescent substance, and 6
The fluorescence intensity was measured 0 minutes later. The fluorescence intensity was measured at room temperature using a spectrophotometer RF-510 (manufactured by Shimadzu Corporation) under conditions of an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm.
また、薬物溶解液を加えるかわりにエタノールを加える
以外は上記と同様にして反応させて測定した蛍光強度を
コントロール値とした。Further, the fluorescence intensity measured by reacting in the same manner as above except that ethanol was added instead of adding the drug solution was used as a control value.
アルドースリダクターゼはＮＡＤＰＨを補酵素として、
ＤＬ−グリセルアルデヒドあるいはグルコースをポリオ
ールに変換する酵素であり、この反応に伴ってＮＡＤＰ
ＨはＮＡＤＰに変化する。従ってＮＡＤＰが少なければ
、アルドースリダクターゼが阻害されていることになる
。Aldose reductase uses NADPH as a coenzyme,
DL-An enzyme that converts glyceraldehyde or glucose into polyol, and along with this reaction, NADP
H changes to NADP. Therefore, if NADP is low, aldose reductase is inhibited.
その結果を、阻害度（％）および５０％阻害濃度（ｌＣ
５ｏ）として、第１表に示す。The results are expressed as the degree of inhibition (%) and the 50% inhibitory concentration (lC
5o) shown in Table 1.
第 １ 表
ラットレンズのアルドースリダクターゼ以上の結果から
、一般式の化合物はアルドースリダクターゼの活性を阻
害することが認められ、糖尿病の合併症の予防または治
療に有効であることが期待される。Table 1 Rat Lens Aldose Reductase From the above results, it was confirmed that the compound of the general formula inhibits the activity of aldose reductase, and is expected to be effective in preventing or treating diabetic complications.
次に具体例１〜４で得た化合物の経口投与での急性毒性
試験をｄｄＹ系マウスおよびウィスター（ｌｌｉｓｔａ
ｒ）系ラットを用いて行ったところ、具体例１〜４で得
た化合物は１ｇ１ｋｇの経口投与で死亡例はなかった。Next, acute toxicity tests were conducted on oral administration of the compounds obtained in Examples 1 to 4 using ddY mice and Wistar (llista) mice.
When experiments were conducted using rats of the r) type, there were no deaths when the compounds obtained in Specific Examples 1 to 4 were orally administered at a dose of 1 g/kg.
このように、一般式の化合物は極めて毒性が低く、安全
性の高いものである。As described above, the compound of the general formula has extremely low toxicity and high safety.
本発明における実験データおよび急性毒性試験の結果か
ら考えて、一般式の化合物の有効投与量は患者の年令、
体重、疾患の程度によっても異なるが、通常成人で一般
式の化合物重量として１日ｆｆ１１２０〜６００ Ｑを
症状に合わせて１日３回程度に分けての服用が適当と認
められる。Considering the experimental data and the results of acute toxicity tests in the present invention, the effective dosage of the compound of the general formula is based on the patient's age,
Although it varies depending on the body weight and severity of the disease, it is generally considered appropriate for adults to take the general formula compound in doses of 1120 to 600 Q per day, divided into three doses per day depending on the symptoms.
次に用例を示して具体的に説明するが、本発明はこれに
より制限されるものではない。Next, the present invention will be specifically explained using an example, but the present invention is not limited thereto.
用例１
上記の具体例１で得た化合物１００ｇを無水ケイ酸２０
ｇと混合し、これにトウモロコシデンプン７５ｇを加え
、さらに混合した。この混合物に１０％ハイドロキシプ
ロピルセルロース・エタノール溶液を１００−加え、常
法通りねつ和し、押し出し、乾燥し、篩別することによ
り２０〜５０メツシユの粒子の顆粒剤を得た。Example 1 100g of the compound obtained in Example 1 above was mixed with 20g of silicic anhydride.
75 g of corn starch was added thereto and further mixed. A 10% ethanol solution of 10% hydroxypropyl cellulose was added to this mixture, and the mixture was wetted in a conventional manner, extruded, dried and sieved to obtain granules of 20 to 50 mesh particles.
この顆粒剤は、症状に合わせて１目量８０〜４００１４
９ （具体例１で得た化合物の重量として４０〜２００
ｘｗに相当）として１日３回服用する。This granule has a dosage of 80 to 40,014 depending on the symptoms.
9 (40 to 200 as the weight of the compound obtained in Specific Example 1)
xw) 3 times a day.
用例２
具体例２で得た化合物４０ｇを無水ケイ酸２０ｇと混合
し、これに微結晶セルロースＩＯｆ、ステアリン酸マグ
ネシウム、乳糖５０ｇを加えて混合し、この混合物を単
発式打錠機にて打錠して径７ｍｍ、重量１２０１９の錠
剤を製造した。Example 2 40 g of the compound obtained in Example 2 was mixed with 20 g of silicic anhydride, 50 g of microcrystalline cellulose IOf, magnesium stearate, and lactose were added and mixed, and the mixture was compressed into tablets using a single-shot tablet machine. Tablets with a diameter of 7 mm and a weight of 12,019 were produced.
本錠剤１錠は、具体例２で得た化合物４０ｍ９を含有す
る。本錠剤は、１回１〜５錠、１日３回服用する。One tablet of the present invention contains 40m9 of the compound obtained in Specific Example 2. This tablet is taken 1 to 5 tablets at a time, three times a day.
用例３
具体例３で得た化合物４０１！９を乳糖１００１！ｒ９
と混合し、Ｎｏ、 Ｏのゼラチンカプセルに充填してカ
プセル剤を得た。Example 3 Compound 401!9 obtained in Example 3 was converted into lactose 1001! r9
and filled into gelatin capsules No. and O to obtain capsules.
本カプセル剤は、症状に合わせて１回１〜５カプセルを
１日３回服用する。This capsule preparation is taken 1 to 5 capsules at a time, three times a day, depending on the symptoms.
用例４
具体例４で得た化合物１００ｇを無水ケイ酸２０ｇと混
合し、これにトウモロコシデンブン７５ｇを加え、さら
に混合した。この混合物に１０％ハイドロキシプロピル
セルロース・エタノール溶液を１００１ｄ加え、常法通
りねつ和し、押し出し、乾燥し、篩別することにより２
０〜′５０メツシユの粒子の顆粒剤を得た。Example 4 100 g of the compound obtained in Example 4 was mixed with 20 g of silicic anhydride, and 75 g of corn starch was added thereto and further mixed. To this mixture, 1001 d of 10% hydroxypropylcellulose ethanol solution was added, and the mixture was stirred in a conventional manner, extruded, dried, and sieved.
Granules with particles of 0 to '50 mesh were obtained.
この顆粒剤は、症状に合わせて１目量８０〜４００ ｔ
ｔｔｇ（具体例４で得た化合物の重量として４０〜２０
０■に相当）として１日３回服用する。This granule has a dosage of 80 to 400 tons depending on the symptoms.
ttg (40 to 20 as the weight of the compound obtained in Specific Example 4)
(equivalent to 0■) and should be taken three times a day.
Claims (1)
水素原子または水酸基を示す。］ で表される化合物を有効成分とするアルドースリダクタ
ーゼ阻害剤。[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents a hydrogen atom or glucose, and R' represents a hydrogen atom or a hydroxyl group. ] An aldose reductase inhibitor containing a compound represented by the following as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24839086A JPS63104920A (en) | 1986-10-21 | 1986-10-21 | Aldose reactase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24839086A JPS63104920A (en) | 1986-10-21 | 1986-10-21 | Aldose reactase inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63104920A true JPS63104920A (en) | 1988-05-10 |
Family
ID=17177393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24839086A Pending JPS63104920A (en) | 1986-10-21 | 1986-10-21 | Aldose reactase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63104920A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0270690A1 (en) * | 1986-06-21 | 1988-06-15 | Dainippon Ink And Chemicals, Inc. | Drug for treatment and prophylaxis of kidney and liver diseases |
| EP0516860A1 (en) * | 1990-11-30 | 1992-12-09 | TSUMURA & CO. | Chromone derivative and aldose reductase inhibitor containing the same as active ingredient |
| WO1998016221A1 (en) * | 1996-10-14 | 1998-04-23 | Korea Institute Of Science And Technology | NARINGIN AND NARINGENIN AS 3-HYDROXY-3-METHYLGLUTARYL CoA(HMG-CoA) REDUCTASE INHIBITOR |
| WO1999021548A1 (en) * | 1997-10-28 | 1999-05-06 | Korea Institute Of Science And Technology | Naringin and naringenin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive or treating agent for hepatic diseases |
| WO2000015174A3 (en) * | 1998-09-15 | 2000-07-13 | Korea Inst Sci & Tech | Bioflavonoid as blood glucose level lowering agent |
| KR100592482B1 (en) | 2004-07-19 | 2006-06-26 | 경북대학교 산학협력단 | Methods for increasing liquiritigenin content in a licorice and its extracts and the method for the isolation and extraction of liquiritigenin from them |
-
1986
- 1986-10-21 JP JP24839086A patent/JPS63104920A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0270690A1 (en) * | 1986-06-21 | 1988-06-15 | Dainippon Ink And Chemicals, Inc. | Drug for treatment and prophylaxis of kidney and liver diseases |
| EP0516860A1 (en) * | 1990-11-30 | 1992-12-09 | TSUMURA & CO. | Chromone derivative and aldose reductase inhibitor containing the same as active ingredient |
| US5455267A (en) * | 1990-11-30 | 1995-10-03 | Tsumura & Co. | Chromone derivative, and aldose reductase inhibitor comprising said compound as active component |
| US5627204A (en) * | 1990-11-30 | 1997-05-06 | Tsumura & Company | Chromone derivative, and aldose reductase inhibitor comprising said compound as active component |
| US5675023A (en) * | 1990-11-30 | 1997-10-07 | Tsumura & Co. | Chromone derivative, and aldose reductase inhibitor comprising said compound as active component |
| WO1998016221A1 (en) * | 1996-10-14 | 1998-04-23 | Korea Institute Of Science And Technology | NARINGIN AND NARINGENIN AS 3-HYDROXY-3-METHYLGLUTARYL CoA(HMG-CoA) REDUCTASE INHIBITOR |
| CN1106840C (en) * | 1996-10-14 | 2003-04-30 | 韩国科学技术研究院 | Naringin and naringenin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor |
| WO1999021548A1 (en) * | 1997-10-28 | 1999-05-06 | Korea Institute Of Science And Technology | Naringin and naringenin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive or treating agent for hepatic diseases |
| WO2000015174A3 (en) * | 1998-09-15 | 2000-07-13 | Korea Inst Sci & Tech | Bioflavonoid as blood glucose level lowering agent |
| KR100592482B1 (en) | 2004-07-19 | 2006-06-26 | 경북대학교 산학협력단 | Methods for increasing liquiritigenin content in a licorice and its extracts and the method for the isolation and extraction of liquiritigenin from them |
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