JPH02191269A - 7-carboxymethoxy-4-phenylcumarin derivative, production thereof and usage thereof - Google Patents
7-carboxymethoxy-4-phenylcumarin derivative, production thereof and usage thereofInfo
- Publication number
- JPH02191269A JPH02191269A JP12353889A JP12353889A JPH02191269A JP H02191269 A JPH02191269 A JP H02191269A JP 12353889 A JP12353889 A JP 12353889A JP 12353889 A JP12353889 A JP 12353889A JP H02191269 A JPH02191269 A JP H02191269A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- carboxymethoxy
- phenylcumarin
- derivative
- compound
- 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
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- QOBLMSXUHNMBDB-UHFFFAOYSA-N 2-(2-oxo-4-phenylchromen-7-yl)oxyacetic acid Chemical class C=1C(=O)OC2=CC(OCC(=O)O)=CC=C2C=1C1=CC=CC=C1 QOBLMSXUHNMBDB-UHFFFAOYSA-N 0.000 title claims description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 4
- 239000003288 aldose reductase inhibitor Substances 0.000 claims description 4
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000006266 etherification reaction Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- -1 perfluoro Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 abstract description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 6
- 150000001323 aldoses Chemical class 0.000 abstract description 4
- IVJMJRRORVMRJJ-UHFFFAOYSA-N 7-hydroxy-4-phenylchromen-2-one Chemical class C=1C(=O)OC2=CC(O)=CC=C2C=1C1=CC=CC=C1 IVJMJRRORVMRJJ-UHFFFAOYSA-N 0.000 abstract description 3
- 208000002249 Diabetes Complications Diseases 0.000 abstract description 3
- 206010012655 Diabetic complications Diseases 0.000 abstract description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 abstract description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 3
- 238000009825 accumulation Methods 0.000 abstract description 2
- 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 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 239000000600 sorbitol Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 7
- 108010053754 Aldehyde reductase Proteins 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 238000002835 absorbance Methods 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 210000000695 crystalline len Anatomy 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- APFVFNSFBWLKPD-UHFFFAOYSA-N (3-oxo-3-phenylpropyl) acetate Chemical class CC(=O)OCCC(=O)C1=CC=CC=C1 APFVFNSFBWLKPD-UHFFFAOYSA-N 0.000 description 1
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- HXUIDZOMTRMIOE-UHFFFAOYSA-M 3-oxo-3-phenylpropionate Chemical class [O-]C(=O)CC(=O)C1=CC=CC=C1 HXUIDZOMTRMIOE-UHFFFAOYSA-M 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion 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](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- GHMLBKRAJCXXBS-UHFFFAOYSA-N Resorcinol Natural products OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- WFDZXWIXVHOCSJ-UHFFFAOYSA-N [P].[Na].[K] Chemical compound [P].[Na].[K] WFDZXWIXVHOCSJ-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 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
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003721 gunpowder Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 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
- 239000010452 phosphate Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- ASHGTUMKRVIOLH-UHFFFAOYSA-L potassium;sodium;hydrogen phosphate Chemical compound [Na+].[K+].OP([O-])([O-])=O ASHGTUMKRVIOLH-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000005757 von Pechmann cycloaddition reaction Methods 0.000 description 1
Landscapes
- Pyrane Compounds (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〕
本発明は医薬品として有用な新規７−カルボキシメトキ
シ−４−フェニルクマリン誘導体に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel 7-carboxymethoxy-4-phenylcoumarin derivative useful as a pharmaceutical.
（従来の技術〕
食生活の欧米化に伴い近年糖尿病患者が激増し、その治
療対策は急務となっている。糖尿病治療薬としては従来
よりインシュリンや血糖降下剤が広く用いられているが
、糖尿病は単なる糖代謝異状のみならず種々の合併症を
随伴する疾患であるため、前記の薬物のみでは不十分で
ある。(Conventional technology) The number of diabetic patients has increased dramatically in recent years due to the Westernization of dietary habits, and there is an urgent need for treatment.Insulin and hypoglycemic agents have been widely used as antidiabetic drugs, but Since this is a disease accompanied by not only abnormal glucose metabolism but also various complications, the above-mentioned drugs alone are not sufficient.
網膜症、山内症、神経障害、腎症等の糖尿病に於ける各
種合併症の成因として、グルコースの代謝経路であるポ
リオール経路の第一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還元酵素といい、
この酵素がポリオール経路の律速段階と考えられている
。このアルドース還元酵素を阻害し、ンルビトールの産
生や蓄積を低下させることにより、前述のごとき糖尿病
合併症の予防や治療が可能である（Ｒ，Ｇ、シュジルミ
ツシュ等二ニューイングランド・ジャーナル・オブ・メ
ディスン（Ｎｅｗ Ｅｎｇ、Ｊ、）ｌｅｄ、 ） 、
３０８巻、１１９〜１２５頁（１９８３） ： Ｊ
、 Ｈ，キノシタ等：メタボリズム（）ｆｅｔａｂｏｌ
ｉｓｍ） 、 ２８巻（１） 、 ４６２〜４６９頁
（１９７９） ）。Aldose is a cause of various complications of diabetes such as retinopathy, Yamanouchi syndrome, neuropathy, and nephropathy, and is known to cause the enzyme that catalyzes the conversion between aldose and polyol, which is the first step in the polyol pathway, which is the metabolic pathway for glucose. It is called reductase,
This enzyme is thought to be the rate-limiting step in the polyol pathway. By inhibiting this aldose reductase and reducing the production and accumulation of nrubitol, it is possible to prevent and treat the aforementioned diabetic complications (R. New Eng, J,) led, ),
Volume 308, pages 119-125 (1983): J
, H, Kinoshita et al.: Metabolism () fetabol
ism), Vol. 28(1), pp. 462-469 (1979)).
本発明者らは、種々の化合物についてアルドース還元酵
素阻害作用に関する研究を行った結果、特定の７−カル
ボキシメトキシ−４−フェニルクマリン誘導体がアルド
ース還元酵素阻害剤として有効であることを見出し本発
明に到達した。The present inventors conducted research on the aldose reductase inhibitory effects of various compounds, and found that a specific 7-carboxymethoxy-4-phenylcoumarin derivative is effective as an aldose reductase inhibitor. Reached.
本発明はすなわち式（Ｉ）
（但し、式中Ｒ） Ｒ２，Ｒ３及びＲ１−、ＲｒＲγ
Ｒ４”、 Ｒ５″は水素原子、ハロゲン原子。The present invention specifically relates to formula (I) (wherein R) R2, R3 and R1-, RrRγ
R4'' and R5'' are hydrogen atoms and halogen atoms.
低級アルキル基、低級アルコキシ基、ジ低級アルキルア
ミノ基、パーフルオロ低級アルキル基を表わす）
で示される７−カルボキシメトキシ−４−７工ニルクマ
リン誘導体及び該誘導体を有効成分として含有するアル
ドース還元酵素阻害剤であり次のようにして製造するこ
とができる。(representing a lower alkyl group, a lower alkoxy group, a di-lower alkylamino group, or a perfluoro-lower alkyl group) and an aldose reductase inhibitor containing the derivative as an active ingredient. and can be manufactured as follows.
すなわち式（ｎ） （但し、式中Ｒ１、Ｒ２，Ｒ３及びＲ１”、Ｒ２”。That is, formula (n) (However, in the formula, R1, R2, R3 and R1'', R2''.
Ｒｒ、、 Ｒ’、 Ｒ５″ハ上Ｈａ式（Ｉ ＞ ト同様
（７）意味を表わす）
で示される７−ヒドロキシ−４−フェニルクマリン誘導
体をグリコール酸エーテル化することによって得られる
。なお本明細書において「低級」なる語は、この語が付
された基の炭素原子数が６個以下、好ましくは４個以下
であることを意味する。Rr, , R', R5'' is obtained by glycolic acid etherification of a 7-hydroxy-4-phenylcoumarin derivative represented by the above formula (I > represents the same meaning as (7)). In the text, the term "lower" means that the group to which this term is attached has no more than 6 carbon atoms, preferably no more than 4 carbon atoms.
本発明化合物の原料となる式（ｎ）化合物は天然成分と
して存在することもある。例えば７−ヒドロキシ−４−
フェニルクマリンはバシラスチホサス（８ａｃｉｌｌｕ
ｓ ｔｙｐｈｏｓｕｓ ）やスタフィロフカスオーレウ
ス（Ｓｔａｐｈｙｌｏｃｏｃｕｓ ａｕｒｅｕｓ）等の
植物に含有する。またペッヒマン縮合反応（Ｐｅｃｈｍ
ａｎｎＣｏｎｄｅｎｓａｔｉｏｎ Ｒｅａｃｔｉｏｎ
）により、置換ベンゾイル酢酸エステルと、置換レゾル
シン等から合成することができる（例えば、Ｈｕｋｅｒ
ｊｅｅ、 ｅｔ、 ａｌ、 、 Ｉｎｄ−ｉａｎ、Ｊ、
Ｃｈｅｍ、、 ７．６７１．（１９６９） ）。The compound of formula (n), which is a raw material for the compound of the present invention, may exist as a natural component. For example, 7-hydroxy-4-
Phenylcoumarin is produced by Bacillus typhosus (8acillu).
S typhosus) and Staphylococcus aureus. Also, Pechmann condensation reaction (Pechman condensation reaction)
annCondensation Reaction
) can be synthesized from substituted benzoyl acetate and substituted resorcinol, etc. (for example, Huker
jee, et, al, , Indian, J.
Chem,, 7.671. (1969)).
式（Ｉｆ＞化合物をグリコール酸エーテル化して式（Ｉ
＞化合物を合成するには、通常の方法で行われる。例え
ばアセトン中、炭酸カリウムとブロム酢酸エチルを用い
て反応すると式（Ｉ）化合物のエステルが得られる。Formula (If> Compound is glycolic acid etherified to form formula (I
> Compounds can be synthesized using conventional methods. For example, reaction with potassium carbonate and ethyl bromoacetate in acetone provides the ester of the compound of formula (I).
得られた式（Ｉ＞化合物のエステルを塩基性で加水分解
し、鉱酸でｐＨ４付近に調整することにより、遊離酸す
なわち式（Ｉ）化合物となり、これを無機塩基でｌ）Ｈ
９付近に調整することにより、式（Ｉ）化合物の無機塩
となる。The resulting ester of the compound of formula (I) is hydrolyzed in a basic setting and adjusted to pH around 4 with a mineral acid, resulting in a free acid, that is, a compound of formula (I), which is then diluted with an inorganic base (l)H
By adjusting it to around 9, it becomes an inorganic salt of the compound of formula (I).
これらはいずれも公知の方法２例えば濃縮乾固その他の
方法で単離し、再結晶等で精製することができる。ここ
で用いる鉱酸としては、塩酸、硫酸、リン酸等があり、
無機塩基としては水酸化ナトリウム、水酸化カリウム、
水酸化リチウム、水酸化アンモニウム等の水酸化アルカ
リ、（１）炭酸ナトリウム、（重）炭酸カリウム、（重
）炭酸アンモニウム等の（重）炭酸アルカリがある。All of these can be isolated by known methods such as concentration to dryness or other methods, and purified by recrystallization or the like. Mineral acids used here include hydrochloric acid, sulfuric acid, phosphoric acid, etc.
Inorganic bases include sodium hydroxide, potassium hydroxide,
There are alkali hydroxides such as lithium hydroxide and ammonium hydroxide, and (1) alkali (bi) carbonates such as sodium carbonate, potassium (bi) carbonate, and ammonium (bi) carbonate.
式（Ｉ＞化合物は酸性又はアルカリ性溶液中いずれでも
かなり安定である。Compounds of formula (I>) are fairly stable in either acidic or alkaline solutions.
式（Ｉ）で示される化合物を有効成分とするアルドース
還元酵素阻害剤は、通常用いられるキャリアーを用い、
常法にしたがって錠剤、カプセル剤、注射剤、散剤、火
剤、顆粒剤、半開２点眼剤等に使用してもよい。The aldose reductase inhibitor containing the compound represented by formula (I) as an active ingredient can be prepared by using a commonly used carrier,
It may be used in tablets, capsules, injections, powders, gunpowder, granules, half-open eye drops, etc. in a conventional manner.
次に実施例を挙げて本発明の化合物、その製造法及びア
ルドース還元阻害作用を詳しく説明するが、本発明は下
記実施例に限定されるものではない。なお各実施例中に
おける生成物の融点はいずれも未補正である。Next, the compound of the present invention, its production method, and aldose reduction inhibitory effect will be explained in detail with reference to Examples, but the present invention is not limited to the following Examples. Note that the melting points of the products in each example are all uncorrected.
参考例
式 ■） 八 の ・・・ペツヒマン ４置換レゾル
シンと当モルの置換ベンゾイル酢酸エチルをエタノール
中に溶解し、水冷下、塩化水素ガスを飽和させる。室温
で１夜放置後、氷水中に流入し、析出する沈澱をか集、
水洗する。乾燥後、溶媒で再結晶する。Reference Example Formula (1) 8...Petuhimann 4-substituted resorcinol and equimolar amount of substituted benzoyl ethyl acetate are dissolved in ethanol and saturated with hydrogen chloride gas under water cooling. After leaving it at room temperature overnight, pour it into ice water and collect the precipitate.
Wash with water. After drying, recrystallize from a solvent.
このようにして得られた式（ｎ）化合物の物性値を第１
表に示す。The physical property values of the compound of formula (n) obtained in this way are
Shown in the table.
実施例
Ｌ■月ｊ皇り槌
６−ニチルー７−ヒドロキシー４−（３−イソプロピル
オキシフェニル）クマリン〔第１表式（ｎ−４２） ）
４．７ｇ（０，０１４５モル）、ブロモ酢酸エチル２
．６ｇ（０，０１１５モ／Ｌｚ） 、 ヨウ化カリウム
０．２ｇ及び無水炭酸カリウム２．０ｇをアセトン２０
０ｍ１中に加え、撹拌下、４時間加熱還流する。冷却後
、不溶物を炉別し、溶媒を留去して得られる残渣をエー
テルに溶解する。このエーテル溶液を水、５％ＮａＯＨ
水溶液、水の順に洗浄し、エーテル層を無水硫酸ナトリ
ウムで乾燥する。溶媒を留去し、得られる残渣をシリカ
ゲルカラムで処理する。クロロフォルム分画により、６
−ニチルー４−（３−イソプロピルオキシフェニル）ク
マリン−７−イルオキシ酢酸エチル４．５ｇを得る。Example L■ Tsukij Koritsuchi 6-Nichiru-7-hydroxy-4-(3-isopropyloxyphenyl)coumarin [Table 1 Formula (n-42)]
4.7 g (0,0145 mol), ethyl bromoacetate 2
．． 6 g (0,0115 mo/Lz), 0.2 g of potassium iodide and 2.0 g of anhydrous potassium carbonate in 20 g of acetone.
The mixture was added to 0 ml of water and heated under reflux for 4 hours while stirring. After cooling, the insoluble matter is separated by furnace, the solvent is distilled off, and the resulting residue is dissolved in ether. This ether solution was mixed with water and 5% NaOH.
Wash the aqueous solution and then water, and dry the ether layer over anhydrous sodium sulfate. The solvent is distilled off, and the resulting residue is treated with a silica gel column. By chloroform fractionation, 6
-4.5 g of ethyl nityl-4-(3-isopropyloxyphenyl)coumarin-7-yloxyacetate are obtained.
上記エステル４．５ｇをエタノール６０ｒｎｉと５％Ｎ
ａＯＨ水溶液２０７の混液中に加え、３０分間加熱還流
する。放冷後、不溶物を炉別し、１戸液を塩酸酸性にす
る。析出する沈澱をアセトン−ベンゼンで再結晶すると
６−ニチルー４−（３−イソプロピルオキシフェニル）
クマリン−７−イルオキシ酢酸〔第２表式（Ｉ−４２＞
）４．ＯＵが得られる。Add 4.5 g of the above ester to 60 rni of ethanol and 5% N.
It is added to a mixture of aOH aqueous solution 207 and heated under reflux for 30 minutes. After cooling, insoluble matter is separated in a furnace and the liquid is acidified with hydrochloric acid. When the precipitate is recrystallized from acetone-benzene, 6-nityl-4-(3-isopropyloxyphenyl) is obtained.
Coumarin-7-yloxyacetic acid [Table 2 Formula (I-42>
)4. OU is obtained.
また上記と同様の手法で第１表に示される式（ｎ）化合
物より第２表に示される式（Ｉ＞化合物を得た。それら
の物性値及びアルドース還元酵素阻害活性を第２表に併
記する。In addition, compounds of formula (I> shown in Table 2) were obtained from compounds of formula (n) shown in Table 1 using the same method as above. Their physical properties and aldose reductase inhibitory activity are also listed in Table 2. do.
アル゛−ス゛−，
７週齢のウィスター（Ｗｉｓｔａｒ）系雄性ラットをエ
ーテル麻酔下に犠殺し、直ちに水晶体を摘出した。水晶
体は１．０ｍＭ ２−メルカプトエタノール及び１．０
ｍＭ ＮＡＤＰ （酸化型ｎｉｃｏｔｉｎａｍｉｄｅ
ａｄｅｎ−ｉｎｅ ｄｉｎｕｃＩｅｏｔｉｄｅ ｐｈ
ｏｓｐｈａｔｅ）を含む１００ｍＭナトリウム−カリウ
ム−リンＭｍ’ｔＥ液（１）８６．８＞にてホモジナイ
ズした。ついで１２．００Ｏｒｐｍで１５分間遠心分離
し、その上清をアルドース還元酵素活性測定の検体とし
た。また以上の操作はすべて４℃で行い検体は一８０℃
で保存した。A 7-week-old male Wistar rat was sacrificed under ether anesthesia, and the crystalline lens was immediately removed. The lens contained 1.0mM 2-mercaptoethanol and 1.0mM 2-mercaptoethanol.
mM NADP (oxidized nicotinamide
aden-ine dinucIeotide ph
Homogenization was carried out in 100 mM sodium-potassium-phosphorus Mm'tE solution (1) containing (1) 86.8>. The mixture was then centrifuged at 12.00 rpm for 15 minutes, and the supernatant was used as a sample for aldose reductase activity measurement. All of the above operations were performed at 4°C, and the sample was kept at -80°C.
Saved with.
アルドース還元酵素の活性の測定はカドア（にＡＤＯ八
）らの方法（Ｂｉｏｐｈｙｓｉｃａｌ Ｃｈｅｍｉｓｔ
ｒｙ ８（１９７８） ８１−８５参照）に準じて行っ
た。すなわち補酵素として０．１ｍＭ ＮＡＤＰＨ（還
元型ｎ１ｃＯｔ ｉｎａｍｉｄｅａｄｅｎｉｎｅ ｄｉ
ｎｕｃＩｅＯｔ＋ｄｅ ｐｈｏｓｐｈａｔｅ）及び基質
として２．０ｍＭ ＤＬ−グリセルアルデヒドを含む
１００ｍＭナトリウム−カリウム−リン酸緩衝液（ｐＨ
６，２） ９７０μｍに、本発明化合物の各種濃度液
を１０μｐ添加し、ついで上記検体２０μｇを加え、２
５℃で反応を行った。対照として基質のみを欠いたもの
を用い、３４０ｎｍにおいて吸光度の減少を２００秒間
測定した。また、試料溶液を加える代りに溶媒のみを加
えて、上記と同様に反応させ測定したものをコントロー
ル値とした。吸光度の測定はＵＶ−２６０（株式会社島
津製作所！りを用いた。The activity of aldose reductase was measured by the method of Kado et al. (Biophysical Chemist).
ry 8 (1978) 81-85). That is, 0.1mM NADPH (reduced form n1cOt inamide adenine di
nucIeOt+de phosphate) and 100 mM sodium-potassium-phosphate buffer (pH
6,2) Add 10 μp of various concentration solutions of the compound of the present invention to 970 μm, then add 20 μg of the above specimen, and
The reaction was carried out at 5°C. As a control, only the substrate was lacking and the decrease in absorbance was measured at 340 nm for 200 seconds. In addition, instead of adding the sample solution, only the solvent was added, and the reaction and measurement were performed in the same manner as above, and the result was used as a control value. The absorbance was measured using UV-260 (Shimadzu Corporation).
その結果、アルドース還元酵素に対する阻害活性は第２
表に示したように１ｘｌＯ−８（Ｍ）で阻害活性（ＩＣ
５０）が認められた。As a result, the inhibitory activity against aldose reductase was
As shown in the table, the inhibitory activity (IC
50) was observed.
急且声ユ
上記各例で得られた式（Ｉ）化合物の経口投与での急性
毒性試験のｄｄｖ系マウス（体重２３〜２５ｇ）を用い
て行ったところ、２Ｍｋａの経口投与でも死亡例は認め
られなかった。When acute toxicity tests were conducted on oral administration of the compounds of formula (I) obtained in each of the above examples using DDV mice (body weight 23-25 g), no deaths were observed even after oral administration of 2 Mka. I couldn't.
以上の結果から明らかなように、本発明の７−カルボキ
シメトキシ−４−フェニルクマリン誘導体はアルドース
還元酵素阻害作用を有し、かつ安全性の高い糖尿病合併
治療薬として有用である。As is clear from the above results, the 7-carboxymethoxy-4-phenylcoumarin derivative of the present invention has an aldose reductase inhibitory effect and is useful as a highly safe drug for treating diabetic complications.
出願人 東洋ファルマー株式会社 ダイソー株式会社Applicant: Toyo Pharma Co., Ltd. Daiso Co., Ltd.
Claims (3)
Ｒ＾２＾′、Ｒ＾３＾′、Ｒ＾４＾′、Ｒ＾５＾′は水
素原子、ハロゲン原子、低級アルキル基、低級アルコキ
シ基、ジ低級アルキルアミノ基、パーフルオロ低級アル
キル基を表わす） で示される７−カルボキシメトキシ−４−フェニルクマ
リン誘導体。(1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, R^1, R^2, R^3 and R^1^',
R^2^', R^3^', R^4^', R^5^' are hydrogen atoms, halogen atoms, lower alkyl groups, lower alkoxy groups, di-lower alkylamino groups, perfluoro lower alkyl groups. A 7-carboxymethoxy-4-phenylcoumarin derivative represented by:
Ｒ＾２＾′、Ｒ＾３＾′、Ｒ＾４＾′、Ｒ＾５＾′は上
記式（ I ）と同様の意味を表わす） で示される７−ヒドロキシ−４−フェニルクマリン誘導
体をグリコール酸エーテル化することを特徴とする上記
式（ I ）で示される７−カルボキシメトキシ−４−フ
ェニルクマリン誘導体の製法。(2) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (However, in the formula, R^1, R^2, R^3 and R^1^',
R^2^', R^3^', R^4^', R^5^' represent the same meanings as in the above formula (I)) A method for producing a 7-carboxymethoxy-4-phenylcoumarin derivative represented by the above formula (I), which comprises acid etherification.
シ−４−フェニルクマリン誘導体を有効成分として含有
するアルドース還元酵素阻害剤。(3) An aldose reductase inhibitor containing a 7-carboxymethoxy-4-phenylcoumarin derivative represented by the above formula (I) as an active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26673188 | 1988-10-22 | ||
| JP63-266731 | 1988-10-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02191269A true JPH02191269A (en) | 1990-07-27 |
| JP2876129B2 JP2876129B2 (en) | 1999-03-31 |
Family
ID=17434905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12353889A Expired - Lifetime JP2876129B2 (en) | 1988-10-22 | 1989-05-17 | 7-carboxymethoxy-4-phenylcoumarin derivatives and their preparation and use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2876129B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5478059A (en) * | 1993-04-22 | 1995-12-26 | Toyota Jidosha Kabushiki Kaisha | Power steering torsion bar biased to return to neutral |
| US7259265B2 (en) * | 2003-05-15 | 2007-08-21 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarin compounds and method for preparing and using the same |
| CN106674176A (en) * | 2016-12-21 | 2017-05-17 | 西安交通大学 | 7-substituted-4-aryl coumarins compound, and preparation method and application thereof |
| CN107922369A (en) * | 2015-08-21 | 2018-04-17 | 默克专利股份有限公司 | Compound for optical activity device |
| EP3598972A1 (en) * | 2018-07-25 | 2020-01-29 | Lead Discovery Center GmbH | 4-phenyl-coumarin derivatives, processes for their preparation and uses thereof for the treatment of cancer |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3133067A1 (en) | 2015-08-21 | 2017-02-22 | Merck Patent GmbH | Compounds for optically active devices |
| EP3133066A1 (en) | 2015-08-21 | 2017-02-22 | Merck Patent GmbH | Hydrophilic compounds for optically active devices |
| EP3363793A1 (en) | 2017-02-15 | 2018-08-22 | Merck Patent GmbH | Hydrophobic compounds for optically active devices |
| EP3363786A1 (en) | 2017-02-15 | 2018-08-22 | Merck Patent GmbH | Compounds for optically active devices |
-
1989
- 1989-05-17 JP JP12353889A patent/JP2876129B2/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5478059A (en) * | 1993-04-22 | 1995-12-26 | Toyota Jidosha Kabushiki Kaisha | Power steering torsion bar biased to return to neutral |
| US7259265B2 (en) * | 2003-05-15 | 2007-08-21 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Coumarin compounds and method for preparing and using the same |
| CN107922369A (en) * | 2015-08-21 | 2018-04-17 | 默克专利股份有限公司 | Compound for optical activity device |
| CN106674176A (en) * | 2016-12-21 | 2017-05-17 | 西安交通大学 | 7-substituted-4-aryl coumarins compound, and preparation method and application thereof |
| EP3598972A1 (en) * | 2018-07-25 | 2020-01-29 | Lead Discovery Center GmbH | 4-phenyl-coumarin derivatives, processes for their preparation and uses thereof for the treatment of cancer |
| US10703735B2 (en) | 2018-07-25 | 2020-07-07 | Lead Discovery Center Gmbh | 4-phenyl-coumarin derivatives, processes for their preparation and uses thereof for the treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2876129B2 (en) | 1999-03-31 |
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