JPH0577651B2 - - Google Patents
Info
- Publication number
- JPH0577651B2 JPH0577651B2 JP1025273A JP2527389A JPH0577651B2 JP H0577651 B2 JPH0577651 B2 JP H0577651B2 JP 1025273 A JP1025273 A JP 1025273A JP 2527389 A JP2527389 A JP 2527389A JP H0577651 B2 JPH0577651 B2 JP H0577651B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- diuretic
- active ingredient
- alkyl group
- dichloro
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 29
- 239000002934 diuretic Substances 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 230000001882 diuretic effect Effects 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 13
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims description 13
- 229940116269 uric acid Drugs 0.000 claims description 13
- -1 1-ethoxymethyl-5-pyrazolyl Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 230000029142 excretion Effects 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- 206010030113 Oedema Diseases 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 239000003792 electrolyte Substances 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 3
- 201000001431 Hyperuricemia Diseases 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 201000006334 interstitial nephritis Diseases 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 208000002151 Pleural effusion Diseases 0.000 claims description 2
- 206010037423 Pulmonary oedema Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000002440 hepatic effect Effects 0.000 claims description 2
- 230000001926 lymphatic effect Effects 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 208000005333 pulmonary edema Diseases 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 claims 1
- 230000003449 preventive effect Effects 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 19
- 239000013078 crystal Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940030606 diuretics Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LJVRMCLEIXLBIM-UHFFFAOYSA-N (2,3-dichloro-4-hydroxyphenyl)-[2-(ethoxymethyl)pyrazol-3-yl]methanone Chemical compound CCOCN1N=CC=C1C(=O)C1=CC=C(O)C(Cl)=C1Cl LJVRMCLEIXLBIM-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- NBFHHTCEVGJOHQ-UHFFFAOYSA-N 2-[2,3-dichloro-4-[2-(ethoxymethyl)pyrazole-3-carbonyl]phenoxy]acetic acid Chemical compound CCOCN1N=CC=C1C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl NBFHHTCEVGJOHQ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 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
- 241000700159 Rattus Species 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 2
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 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
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- ZXALCVLBUDYEFN-UHFFFAOYSA-N 2-[2,3-dichloro-4-(2-ethylpyrazole-3-carbonyl)phenoxy]acetic acid Chemical compound CCN1N=CC=C1C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl ZXALCVLBUDYEFN-UHFFFAOYSA-N 0.000 description 1
- YQSOFVBDCUBYTJ-UHFFFAOYSA-N 2-[2,3-dichloro-4-(2-propan-2-ylpyrazole-3-carbonyl)phenoxy]acetic acid Chemical compound CC(C)N1N=CC=C1C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl YQSOFVBDCUBYTJ-UHFFFAOYSA-N 0.000 description 1
- ZIQRFENGMGWBGJ-UHFFFAOYSA-N 2-[2,3-dichloro-4-[2-(methoxymethyl)pyrazole-3-carbonyl]phenoxy]acetic acid Chemical compound COCN1N=CC=C1C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl ZIQRFENGMGWBGJ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-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
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 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 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- CAXRIKJTCHLXAD-UHFFFAOYSA-N ethyl 2-[2,3-dichloro-4-[2-(ethoxymethyl)pyrazole-3-carbonyl]phenoxy]acetate Chemical compound CCOCN1N=CC=C1C(=O)C1=CC=C(OCC(=O)OCC)C(Cl)=C1Cl CAXRIKJTCHLXAD-UHFFFAOYSA-N 0.000 description 1
- MGZFVSUXQXCEHM-UHFFFAOYSA-N ethyl 2-phenoxyacetate Chemical compound CCOC(=O)COC1=CC=CC=C1 MGZFVSUXQXCEHM-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
（産業上の利用分野）
本発明は新規利尿剤に関する。
（従来技術）
利尿剤は主として腎尿細管に作用し、水分や電
解質の再吸収を抑制し、それらの***を促進させ
る薬剤である。このような利尿剤としてはクロロ
サイアザイド、ヒドロクロロサイアザイドの如き
サイアザイド系利尿剤、フロセミド、エタクリン
酸の如きループ利尿剤等が知られている。しかし
ながら、従来用いられてきた利尿剤は一般に高尿
酸血症を合併しやすく、この過剰な尿酸が体内の
組織中に沈着することによつて間質性腎炎や痛風
等の疾患を招来することが少なくなかつた。その
ため水分や電解質の***を促進すると共に、尿酸
の***をも促進する利尿剤の開発が望まれてい
た。
（発明の構成及び効果）
本発明は一般式（）で示されるフエノキシ酢
酸誘導体及びその塩を有効成分とする利尿剤に関
する。
(Industrial Application Field) The present invention relates to a novel diuretic. (Prior Art) Diuretics are drugs that mainly act on the renal tubules, suppress the reabsorption of water and electrolytes, and promote their excretion. Known examples of such diuretics include thiazide diuretics such as chlorothiazide and hydrochlorothiazide, and loop diuretics such as furosemide and ethacrynic acid. However, conventionally used diuretics are generally associated with hyperuricemia, and this excess uric acid can be deposited in tissues within the body, leading to diseases such as interstitial nephritis and gout. There were quite a few. Therefore, it has been desired to develop a diuretic that not only promotes the excretion of water and electrolytes but also promotes the excretion of uric acid. (Structure and Effects of the Invention) The present invention relates to a diuretic containing a phenoxyacetic acid derivative represented by the general formula () and a salt thereof as an active ingredient.
【式】
（但し、R1は水素原子又は低級アルキル基、
R2は水素原子又は低級アルケニル基、R3は低級
アルキル基、低級アルコキシ置換低級アルキル
基、フエニル低級アルキル基又はシクロアルキル
基、Ｘはハロゲン原子、Ｚは酸素原子又はメチレ
ン基を表す。）
本発明の有効成分であるフエノキシ酢酸誘導体
又はその塩はいずれも新規化合物であるととも
に、優れた利尿作用、電解質***促進作用及び尿
酸***促進作用を有する。例えば、一夜絶食させ
たラツトに生理食塩水を経口投与し、その１時間
後に検体のカルボキシメチルセルロース懸濁液を
経口投与（投与量；100mg／Kg）して尿量及び尿
酸***量を調べたとろ、本発明の有効成分である
〔２，３−ジクロロ−４−（１−エトキシメチル−
５−ピラゾリルカルボニル）フエノキシ〕酢酸、
〔２，３−ジクロロ−４−（１−メトキシメチル−
５−ピラゾリルカルボニル）フエノキシ〕酢酸、
〔２，３−ジクロロ−４−（１−エチル−５−ピラ
ゾリルカルボニル）フエノキシ〕酢酸、〔２，３
−ジクロロ−４−（１−イソプロピル−５−ピラ
ゾリルカルボニル）フエノキシ〕酢酸等を投与し
た群は検体非投与群に比べて２倍以上の尿量増加
を示し、また〔６−アリル−２，３−ジクロロ−
４−（１−メチル−５−ピラゾリルカルボニル）
フエノキシ〕酢酸又は｛２，３−ジクロロ−４−
〔１−（１−メチル−５−ピラゾリル）ビニル〕フ
エノキシ｝酢酸等を投与した群は検体非投与群に
比べて２倍以上の尿酸***量の増加を示した。
本発明の有効成分であるフエノキシ酢酸誘導体
の具体例としては、一般式（）において、低級
アルキル基がC1-6アルキル基であり、低級アルケ
ニル基がC2-6アルケニル基であり、低級アルコキ
シ基がC1-6アルコキシ基であり、シクロアルキル
基がC3-6シクロアルキル基である化合物があげら
れ、このうち好ましい化合物は、R1が水素原子
又はC1-3アルキル基、R2が水素原子又はC3-4ア
ルケニル基、R3がC1-6アルキル基、フエニル−
C1-3アルキル基又はC1- 3アルコキシ−C1-3アルキ
ル基の化合物である。
また、より好ましい化合物は、一般式（）に
おいて、R1が水素原子又はエチル基、R2が水素
原子又はアリル基（＝２−プロペニル基）、R3が
C1-6アルキル基、ベンジル基、メトキシメチル基
又はエトキシメチル基、Ｘが塩素原子の化合物で
ある。
さらに好ましい化合物としては、一般式（）
においてR1が水素原子であり、R2が水素原子又
はアリル基であり、R3がエチル基又はエトキシ
メチル基であり、Ｘが塩素原子である化合物があ
げられる。
本発明の有効成分であるフエノキシ酢酸誘導体
（）及びその薬理的に許容しうる塩は優れた利
尿作用、電解質***促進作用及び尿酸***促進作
用を併せもつという特徴を有するため、うつ血性
心不全、種々の浮腫（例えば、肝臓性、腎炎性、
心臓性、妊娠性、リンパ性又は薬物性浮腫等）、
肺水腫、腹水症、胸膜浸出、間質性腎炎、痛風或
いは高尿酸血症の疾患の治療・予防に使用するこ
とができる。
本発明の有効成分であるフエノキシ酢酸誘導体
（）は遊離型或いはその薬理的に許容しうる塩
の形のいずれの形でも医薬として使用することが
でき、化合物（）のその薬理的に許容しうる塩
としては、例えばナトリウム塩、カリカム塩の如
きアルカリ金属塩、カシウム塩の如きアルカリ土
類金属塩、塩酸塩、臭化水素酸塩の如き鉱酸塩、
メタンスルホン酸塩、シユウ酸塩の如き有機酸塩
等を好適にあげることができる。
本発明の利尿剤は、経口的に非経口的にも投与
することができる。経口的に投与する場合には、
そのまま又は経口投与に適した賦形剤、結合剤、
崩壊剤、湿潤剤等の医薬担体と共に医薬製剤とし
て使用することができる。このような医薬担体と
しては、例えば、デン粉、ラクトース、グルコー
ス、ゼラチン、ソルビツト、トラガンド、ポリビ
ニルピロリドン、乳糖、砂糖、トウモロシデン
粉、ポリエチレングリコール、タルク、リン酸カ
リウム、ステアリン酸マグネシウム、その他通常
の賦形剤、結合剤、崩壊剤、湿潤剤等を好適に使
用することができる。また、投与剤型は錠剤、カ
プセル剤、顆粒剤、マイクロカプセル剤、坐剤の
如き固型剤であつてもよく、溶液、懸濁液、乳
液、シロツプ、エリキシル等の如き液剤であつて
もよい。一方、非経口投与で用いる場合、本発明
の利尿剤は注射剤として使用するのが好ましく、
このための溶剤としては、例えば、注射用蒸留
水、植物油、プロピレングリコール等を適宜用い
ることができる。さらには安全な溶解補助剤、緩
衝剤、安定剤等を含んでいてもよい。
本発明の有効成分である化合物（）又はその
薬理的に許容しうる塩の投与量は、投与方法、患
者の年齢、体重、状態及び疾患の種類によつても
異なるが、通常１日当たり0.3〜200mg／Kg、とり
わけ１〜100mg／Kgであるのが好ましい。
本発明の有効成分であるフエノキシ酢酸誘導体
（）は例えば、一般式[Formula] (However, R 1 is a hydrogen atom or a lower alkyl group,
R 2 represents a hydrogen atom or a lower alkenyl group, R 3 represents a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a phenyl lower alkyl group or a cycloalkyl group, X represents a halogen atom, and Z represents an oxygen atom or a methylene group. ) The phenoxyacetic acid derivatives or salts thereof, which are the active ingredients of the present invention, are all new compounds and have excellent diuretic, electrolyte excretion-promoting, and uric acid excretion-promoting effects. For example, physiological saline was orally administered to rats that had been fasted overnight, and 1 hour later, a carboxymethyl cellulose suspension was orally administered (dose: 100 mg/Kg) to examine urine volume and uric acid excretion. , [2,3-dichloro-4-(1-ethoxymethyl-
5-pyrazolylcarbonyl)phenoxy]acetic acid,
[2,3-dichloro-4-(1-methoxymethyl-
5-pyrazolylcarbonyl)phenoxy]acetic acid,
[2,3-dichloro-4-(1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid, [2,3
-dichloro-4-(1-isopropyl-5-pyrazolylcarbonyl)phenoxy]acetic acid, etc., showed an increase in urine volume more than twice that of the non-administered group, and [6-allyl-2,3 -dichloro-
4-(1-methyl-5-pyrazolylcarbonyl)
phenoxy]acetic acid or {2,3-dichloro-4-
The group administered with [1-(1-methyl-5-pyrazolyl)vinyl]phenoxy}acetic acid, etc. showed an increase in uric acid excretion more than twice that of the group to which no sample was administered. As a specific example of the phenoxyacetic acid derivative which is an active ingredient of the present invention, in the general formula (), the lower alkyl group is a C 1-6 alkyl group, the lower alkenyl group is a C 2-6 alkenyl group, and the lower alkoxy Examples include compounds in which the group is a C 1-6 alkoxy group and the cycloalkyl group is a C 3-6 cycloalkyl group. Among these, preferable compounds are those in which R 1 is a hydrogen atom or a C 1-3 alkyl group, and R 2 is a hydrogen atom or a C 3-4 alkenyl group, R 3 is a C 1-6 alkyl group, phenyl-
It is a compound of a C 1-3 alkyl group or a C 1-3 alkoxy- C 1-3 alkyl group. Further, a more preferable compound is a compound in which R 1 is a hydrogen atom or an ethyl group, R 2 is a hydrogen atom or an allyl group (=2-propenyl group), and R 3 is a
C 1-6 alkyl group, benzyl group, methoxymethyl group or ethoxymethyl group, and a compound where X is a chlorine atom. A more preferable compound is the general formula ()
Examples include compounds in which R 1 is a hydrogen atom, R 2 is a hydrogen atom or an allyl group, R 3 is an ethyl group or an ethoxymethyl group, and X is a chlorine atom. The phenoxyacetic acid derivative () and its pharmacologically acceptable salts, which are the active ingredients of the present invention, are characterized by having excellent diuretic effects, electrolyte excretion promoting effects, and uric acid excretion promoting effects. edema (e.g. hepatic, nephritic,
cardiac, gestational, lymphatic or drug-induced edema, etc.),
It can be used to treat and prevent diseases such as pulmonary edema, ascites, pleural effusion, interstitial nephritis, gout or hyperuricemia. The phenoxyacetic acid derivative (), which is the active ingredient of the present invention, can be used as a medicine in either the free form or its pharmacologically acceptable salt form, and the compound () can be used as a pharmaceutical in its pharmacologically acceptable salt form. Examples of salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, mineral salts such as hydrochlorides and hydrobromides,
Preferred examples include organic acid salts such as methanesulfonate and oxalate. The diuretic of the present invention can be administered orally or parenterally. When administered orally,
excipients, binders, suitable for neat or oral administration;
It can be used as a pharmaceutical preparation together with a pharmaceutical carrier such as a disintegrant and a wetting agent. Such pharmaceutical carriers include, for example, starch, lactose, glucose, gelatin, sorbitol, tragando, polyvinylpyrrolidone, lactose, sugar, corn flour, polyethylene glycol, talc, potassium phosphate, magnesium stearate, and other conventional excipients. Excipients, binders, disintegrants, wetting agents, etc. can be suitably used. Further, the dosage form may be a solid dosage form such as a tablet, capsule, granule, microcapsule, or suppository, or a liquid dosage form such as a solution, suspension, emulsion, syrup, or elixir. good. On the other hand, when used parenterally, the diuretic of the present invention is preferably used as an injection,
As a solvent for this purpose, for example, distilled water for injection, vegetable oil, propylene glycol, etc. can be used as appropriate. Furthermore, it may contain safe solubilizing agents, buffers, stabilizers, and the like. The dosage of the compound () or its pharmacologically acceptable salt, which is the active ingredient of the present invention, varies depending on the administration method, age, weight, condition, and type of disease of the patient, but is usually 0.3 to 0.3 per day. Preferably it is 200 mg/Kg, especially 1 to 100 mg/Kg. For example, the phenoxyacetic acid derivative () which is the active ingredient of the present invention has the general formula
【式】
（但し、R2、R3、Ｘ及びＺは前記と同一意味
を有する。）
で示されるフエノール誘導体と一般式
Ｙ−CH2COOR1 （）
（但し、Ｙはハロゲン原子を表し、R1は前記
と同一意味を有する。）
で示される酢酸化合物とを適当な溶媒中脱酸剤
（例えば、水酸化アルカリ金属等）の存在下室温
〜加熱下に反応させることにより製することがで
きる。
また、化合物（）のうちR1が水素原子であ
る化合物は、例えば一般式[Formula] (However, R 2 , R 3 , X and Z have the same meanings as above.) A phenol derivative represented by the general formula Y-CH 2 COOR 1 () (However, Y represents a halogen atom, R 1 has the same meaning as above.) It can be produced by reacting an acetic acid compound represented by (R 1 has the same meaning as above) in an appropriate solvent in the presence of a deoxidizing agent (for example, an alkali metal hydroxide, etc.) at room temperature to heating. can. In addition, compounds in which R 1 is a hydrogen atom among the compounds (), for example, have the general formula
【化】
（但し、R11は低級アルキル基を表し、R2、
R3、Ｘ及びＺは前記と同一意味を有する。）
で示されるフエノキシ酢酸エステル誘導体を適当
な溶媒中酸（例えば、塩酸）又は塩基（例えば、
水酸化アルカリ金属）で室温〜加熱下に加水分解
することによつても製することができる。
尚、原料化合物（）のうちＺが酸素原子であ
る化合物は、例えば一般式[Chemical formula] (However, R 11 represents a lower alkyl group, R 2 ,
R 3 , X and Z have the same meanings as above. ) in an appropriate solvent with an acid (e.g., hydrochloric acid) or a base (e.g.,
It can also be produced by hydrolysis with an alkali metal hydroxide) at room temperature to heating. In addition, among the raw material compounds (), compounds in which Z is an oxygen atom may have the following general formula, for example:
【式】
（但し、R4は低級アルキル基を表し、R2、R3
及びＸは前記と同一意味を有する。）
で示される化合物を常法により脱アルキル化処理
して製することができる。
また、原料化合物（）のうちＺがメチレン基
である化合物は、例えば一般式[Formula] (However, R 4 represents a lower alkyl group, R 2 , R 3
and X have the same meanings as above. ) can be produced by subjecting the compound represented by formula to dealkylation using a conventional method. In addition, among the raw material compounds (), compounds in which Z is a methylene group, for example, the general formula
【化】
（但し、R2、R3及びＸは前記と同一意味を有
する。）で示される化合物と式
（C6H5）3P＝CH2 （）
で示されるイリド化合物とを反応させることによ
つて製することができる。
更に、R2が低級アルケニル基である原料化合
物（）は、例えば一般式[Chemical formula] (However, R 2 , R 3 and X have the same meanings as above.) A compound represented by the formula (C 6 H 5 ) 3 P=CH 2 () is reacted with a ylide compound represented by the formula (C 6 H 5 ) 3 P=CH 2 (). It can be manufactured by Furthermore, the raw material compound () in which R 2 is a lower alkenyl group, for example, has the general formula
【化】
（但し、R3、Ｘ及びＺは前記と同一意味を有
する。）で示される化合物を低級アルケニルハラ
イドと反応させた後、加熱処理して製することも
できる。
実験例 １
（方法）
一夜絶食させたSD雄性ラツト（チヤールスリ
バー）を用い、体重100ｇ当たり３mlの生理食塩
水を経口投与した。生理食塩水投与１時間後に検
体（投与量：100mg／Kg）を0.25％カルボキシメ
チルセルロース−生理食塩液に懸濁して、体重
100ｇ当たり３mlの割合で経口投与し、検体非投
与群には同量の0.25％カルボキシメチルセルロー
ス−生理食塩液のみを投与した。投与直後から５
時間にわたつて尿を採取し、検体の効力は、検体
投与群の尿量及び尿酸***量と非投与群のそれと
の比（効力比）を求め、下記基準で判定した。It can also be produced by reacting a compound represented by the following formula with a lower alkenyl halide, followed by heat treatment. Experimental Example 1 (Method) 3 ml of physiological saline per 100 g of body weight was orally administered to SD male rats (Charles River) that had been fasted overnight. One hour after administration of physiological saline, the specimen (dose: 100 mg/Kg) was suspended in 0.25% carboxymethylcellulose-physiological saline, and the body weight was measured.
It was orally administered at a rate of 3 ml per 100 g, and the same amount of 0.25% carboxymethyl cellulose-physiological saline solution was administered to the non-sample administration group. 5 immediately after administration
Urine was collected over time, and the efficacy of the specimen was determined by determining the ratio (efficacy ratio) between the urine volume and uric acid excretion amount of the specimen administration group and that of the non-administration group (efficacy ratio).
【表】 （結果） 結果は下記第２表及び第３表の通りである。【table】 (result) The results are shown in Tables 2 and 3 below.
【表】【table】
【表】
実験例 ２
（方法）
ペントバルビタール麻酔下で、尿酸を静脈内持
続注入して血漿尿酸濃度を上昇させた雑種成犬
に、等モルのトリス−塩酸緩衝液を加え５％グル
コース水溶液に溶解した検体を静脈内投与（投与
量：５mg／Kg）した。投与前後に３回ずつ10分間
の採尿及び中間点での採血を行い、尿酸及びクレ
アチニンクリアランスから尿酸***率を求めた。
検体の効力は投与前後30分間の尿量及び尿酸***
率の比（効力比）を求め、いずれも下記基準で判
定した。[Table] Experimental Example 2 (Method) Under pentobarbital anesthesia, an equimolar Tris-HCl buffer was added to an adult mongrel dog whose plasma uric acid concentration had been increased by continuous intravenous infusion of uric acid to a 5% glucose aqueous solution. The dissolved specimen was administered intravenously (dose: 5 mg/Kg). Urine was collected for 10 minutes three times before and after administration, and blood was collected at the halfway point, and the uric acid excretion rate was determined from uric acid and creatinine clearance.
The efficacy of the sample was determined by calculating the ratio of urine volume and uric acid excretion rate (efficacy ratio) for 30 minutes before and after administration, and both were judged according to the following criteria.
【表】 （結果） 結果は下記第５表及び第６表の通りである。【table】 (result) The results are shown in Tables 5 and 6 below.
【表】【table】
【表】
製造例 １
２，３−ジクロロ−４−（１−エトキシメチル
−５−ピラゾリルカルボニル）フエノール1.67
ｇ、ブロモ酢酸エチル1.15ｇ及び炭酸カリウム
1.68ｇをアセトン60mlに加え、１時間還流する。
反応液をろ過し、ろ液から溶媒を留去する。残査
をベンゼンに溶解し、活性炭処理後、溶媒を留去
する。残査をイソプロピルエーテルから結晶化す
ることにより、〔２，３−ジクロロ−４−（１−エ
トキシメチル−５−ピラゾリルカルボニル）フエ
ノキシ〕酢酸エチルエステル1.89ｇを結晶として
得る。
m.p.92〜94℃
Mass（ｍ／ｅ）：400（M+）
製造例 ２
２，３−ジクロロ−４−（１−エトキシメチル
−５−ピラゾリルカルボニル）フエノール0.63
ｇ、ブロモ酢酸エチル0.58ｇ及び炭酸カリウム
1.11ｇをアセトン40mlに加え、48時間還流する。
反応液を濃縮し、残査に水を加え酢酸エチルで洗
浄した後、10％塩酸で酸性として酢酸エチルで抽
出する。抽出液を飽和食塩水で洗浄し、乾燥後、
溶媒を留去する。残査を水から結晶化し、得られ
た結晶を水、イソプロピルエーテルで順次洗浄
後、乾燥することにより〔２，３−ジクロロ−４
−（１−エトキシメチル−５−ピラゾリルカルボ
ニル）フエノキシ〕酢酸の結晶0.42ｇを得る。
m.p.148〜149℃
Mass（ｍ／ｅ）：372（M+）
本品のナトリウム・１水和物
m.p.194〜196.5℃
製造例 ３〜９
対応するフエノール誘導体とブロモ酢酸エステ
ル誘導体とを製造例１と同様に処理することによ
り下記第７表記載の化合物を得る。[Table] Production example 1 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol 1.67
g, 1.15 g of ethyl bromoacetate and potassium carbonate
Add 1.68 g to 60 ml of acetone and reflux for 1 hour.
The reaction solution is filtered, and the solvent is distilled off from the filtrate. The residue is dissolved in benzene, treated with activated carbon, and the solvent is distilled off. The residue was crystallized from isopropyl ether to obtain 1.89 g of ethyl [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetate as crystals. mp92-94℃ Mass (m/e): 400 (M + ) Production example 2 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol 0.63
g, ethyl bromoacetate 0.58 g and potassium carbonate
Add 1.11 g to 40 ml of acetone and reflux for 48 hours.
Concentrate the reaction solution, add water to the residue, wash with ethyl acetate, acidify with 10% hydrochloric acid, and extract with ethyl acetate. The extract was washed with saturated saline, dried, and then
The solvent is distilled off. The residue was crystallized from water, and the resulting crystals were sequentially washed with water and isopropyl ether and dried to form [2,3-dichloro-4
0.42 g of crystals of -(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid are obtained. mp148-149℃ Mass (m/e): 372 (M + ) Sodium monohydrate of this product mp194-196.5℃ Production Examples 3-9 The corresponding phenol derivative and bromoacetate derivative were prepared in the same manner as in Production Example 1. The compounds listed in Table 7 below are obtained.
【表】
製造例 10
６−アリル−２，３−ジクロロ−４−（１−メ
チル−５−ピラゾリルカルボニル）フエノール
1.13ｇとブロモ酢酸エチルエステル0.67ｇとを製
造例１と同様に処理して（６−アリル−２，３−
ジクロロ−４−（１−メチル−５−ピラゾリルカ
ルボニル）フエノキシ〕酢酸エチルエステルの油
状物1.44ｇを得る。
IRνLiquid nax（cm-1）：1755，1735，1665，1640，
1585，1550
Mass（ｍ／ｅ）：396（M+）
製造例 11〜13
対応するフエノール誘導体とブロモ酢酸エチル
エステルを製造例１と同様に処理することによつ
て、下記第８表記載の化合物を得る。[Table] Production example 10 6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol
1.13g and 0.67g of bromoacetic acid ethyl ester were treated in the same manner as in Production Example 1 (6-allyl-2,3-
1.44 g of an oil of dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxyacetic acid ethyl ester is obtained. IRν Liquid nax (cm -1 ): 1755, 1735, 1665, 1640,
1585, 1550 Mass (m/e): 396 (M + ) Production Examples 11-13 By treating the corresponding phenol derivative and bromoacetic acid ethyl ester in the same manner as in Production Example 1, the compounds listed in Table 8 below were prepared. get.
【表】
製造例 14
〔２，３−ジクロロ−４−（１−エトキシメチ
ル−５−ピラゾリルカルボニル）フエノキシ〕酢
酸エチルエステル0.9ｇのエタノール20ml懸濁液
に10％水酸化ナトリウム水溶液10mlを加え、室温
にて１時間攪拌する。反応液からエタノールを留
去し、10％塩酸でPH１〜２に調製し、析出晶をろ
取する。該結晶を水及びイソプロピルエーテルで
順次洗浄後、乾燥することにより、〔２，３−ジ
クロロ−４−（１−エトキシメチル−５−ピラゾ
リルカルボニル）フエノキシ酢酸0.82ｇを結晶と
して得る。
尚、本品の物理恒数は製造例２で得られた化合
物のそれと一致した。
製造例 15〜22
対応するフエノキシ酢酸エステル誘導体を製造
例14と同様に処理することにより下記第９表記載
の化合物を得る。[Table] Production example 14 Add 10 ml of 10% aqueous sodium hydroxide solution to a suspension of 0.9 g of ethyl acetate in 20 ml of [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid, Stir for 1 hour at room temperature. Ethanol is distilled off from the reaction solution, the pH is adjusted to 1-2 with 10% hydrochloric acid, and the precipitated crystals are collected by filtration. The crystals were washed successively with water and isopropyl ether and then dried to obtain 0.82 g of [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxyacetic acid] as crystals. The physical constants of this product matched those of the compound obtained in Production Example 2. Production Examples 15-22 The corresponding phenoxyacetate derivatives were treated in the same manner as in Production Example 14 to obtain the compounds listed in Table 9 below.
【表】【table】
【表】
製造例 23
〔６−アリル−２，３−ジクロロ−４−（１−
メチル−５−ピラゾリルカルボニル）フエノキ
シ〕酢酸エチルエステル1.44ｇを製造例14と同様
に処理（但し、エーテル−ヘキサンから結晶化）
することにより（６−アリル−２，３−ジクロロ
−４−（１−メチル−５−ピラゾリルカルボニル）
フエノキシ〕酢酸の結晶1.19ｇを得る。
m.p.111〜113℃
Mass（ｍ／ｅ）：368（M+）
製造例 24〜27
対応するフエノキシ酢酸エステル誘導体を製造
例14と同様に処理することにより下記第10表記載
の化合物を得る。[Table] Production example 23 [6-allyl-2,3-dichloro-4-(1-
1.44 g of methyl-5-pyrazolylcarbonyl)phenoxyacetic acid ethyl ester was treated in the same manner as in Production Example 14 (but crystallized from ether-hexane).
By (6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)
1.19 g of crystals of phenoxy]acetic acid were obtained. mp111-113°C Mass (m/e): 368 (M + ) Production Examples 24-27 The corresponding phenoxyacetate derivatives are treated in the same manner as in Production Example 14 to obtain the compounds listed in Table 10 below.
【表】
製造例 28
〔２，３−ジクロロ−４−〔１−（１−エトキシ
メチル−５−ピラゾリルカルボニル）フエノキ
シ〕酢酸エチルエステル1.03ｇのエタノール25ml
溶液に濃塩酸を加え、60〜65℃で3.5時間攪拌す
る。反応液に氷冷下飽和炭酸ナトリウム水溶液を
加えてPH８〜９とした後、酢酸エチルで抽出す
る。抽出液を飽和炭酸ナトリウム水溶液及び水で
順次洗浄し、乾燥後、溶媒を留去する。残査をシ
リカゲルカラムクロマトグラフイー（溶媒；ベン
ゼン−酢酸エチル）で精製したのち、ベンゼン−
クロロホルムから結晶化することにより〔２，３
−ジクロロ−４−（５−ピラゾリルカルボニル）
フエノキシ〕酢酸エチルエステルの結晶0.54ｇを
得る。
m.p.142〜149℃
Mass（ｍ／ｅ）：342（M+）
製造例 29
｛２，３−ジクロロ−４−〔１−（１−エトキシ
メチル−５−ピラゾリル）ビニル〕フエノキシ｝
酢酸エチルエステル1.10ｇを製造例28と同様に処
理（但し、イソプロピルエーテルから結晶化）す
ることによつて、｛２，３−ジクロロ−４−〔１−
（５−ピラゾリル）ビニル〕フエノキシ｝酢酸エ
チルエステルの結晶0.81ｇを得る。
m.p.110〜112℃
Mass（ｍ／ｅ）：340（M+）[Table] Production example 28 [2,3-dichloro-4-[1-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid ethyl ester 1.03g ethanol 25ml
Add concentrated hydrochloric acid to the solution and stir at 60-65°C for 3.5 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture under ice cooling to adjust the pH to 8 to 9, followed by extraction with ethyl acetate. The extract is washed successively with a saturated aqueous sodium carbonate solution and water, and after drying, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: benzene-ethyl acetate), and then purified with benzene-ethyl acetate.
By crystallization from chloroform [2,3
-dichloro-4-(5-pyrazolylcarbonyl)
0.54 g of crystals of phenoxy]acetic acid ethyl ester were obtained. mp142-149℃ Mass (m/e): 342 (M + ) Production example 29 {2,3-dichloro-4-[1-(1-ethoxymethyl-5-pyrazolyl)vinyl]phenoxy}
By treating 1.10 g of ethyl acetate in the same manner as in Production Example 28 (however, crystallizing from isopropyl ether), {2,3-dichloro-4-[1-
0.81 g of crystals of (5-pyrazolyl)vinyl]phenoxy}acetic acid ethyl ester were obtained. mp110~112℃ Mass (m/e): 340 (M + )
Claims (1)
R2は水素原子又は低級アルケニル基、R3は水素
原子、低級アルキル基、低級アルコキシ置換低級
アルキル基、フエニル低級アルキル基又はシクロ
アルキル基、Ｘはハロゲン原子、Ｚは酸素原子又
はメチレン基を表す。） で示されるフエノキシ酢酸誘導体又はその薬理的
に許容しうる塩を有効成分とする利尿剤。 ２ 一般式（）において、Ｘが塩素原子である
化合物又はその薬理的に許容しうる塩を有効成分
とする請求項１記載の利尿剤。 ３ 一般式（）において、R2が水素原子又は
アリル基、R3が炭素数１〜６のアルキル基、ベ
ンジル基、メトキシメチル基又はエトキシメチル
基、Ｘが塩素原子である化合物又はその薬理的に
許容しうる塩を有効成分とする請求項１記載の利
尿剤。 ４ 有効成分が｛２，３−ジクロロ−４−〔１−
（１−エトキシメチル−５−ピラゾリル）ビニル〕
フエノキシ｝酢酸又はその薬理的に許容しうる塩
である請求項１記載の利尿剤。 ５ 有効成分が〔２，３−ジクロロ−４−（１−
エチル−５−ピラゾリルカルボニル）フエノキシ
酢酸又はその薬理的に許容しうる塩である請求項
１記載の利尿剤。 ６ 有効成分が｛２，３−ジクロロ−４−〔１−
（１−メチル−５−ピラゾリル）ビニル〕フエノ
キシ｝酢酸又はその薬理的に許容しうる塩である
請求項１記載の利尿剤。 ７ 尿酸***促進剤及び／又は電解質***促進剤
である請求項１〜６記載の利尿剤。 ８ うつ血性心不全、浮腫、肺水腫、胸膜浸出、
間質性腎炎、痛風又は高尿酸血症の治療・予防剤
である請求項１〜７記載の利尿剤。 ９ 浮腫が肝臓性、腎炎性、心臓性、妊娠性、リ
ンパ性又は薬物性浮腫である請求項８記載の利尿
剤。[Claims] 1 General formula [Formula] (However, R 1 is a hydrogen atom or a lower alkyl group,
R 2 is a hydrogen atom or a lower alkenyl group, R 3 is a hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a phenyl lower alkyl group or a cycloalkyl group, X is a halogen atom, and Z is an oxygen atom or a methylene group . ) A diuretic containing a phenoxyacetic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2. The diuretic according to claim 1, wherein the active ingredient is a compound in the general formula () in which X is a chlorine atom or a pharmacologically acceptable salt thereof. 3 Compounds or their pharmacological properties in the general formula (), where R 2 is a hydrogen atom or an allyl group, R 3 is an alkyl group having 1 to 6 carbon atoms, a benzyl group, a methoxymethyl group, or an ethoxymethyl group, and X is a chlorine atom 2. The diuretic according to claim 1, wherein the active ingredient is a salt acceptable to . 4 The active ingredient is {2,3-dichloro-4-[1-
(1-ethoxymethyl-5-pyrazolyl)vinyl]
The diuretic according to claim 1, which is phenoxy}acetic acid or a pharmacologically acceptable salt thereof. 5 The active ingredient is [2,3-dichloro-4-(1-
The diuretic according to claim 1, which is ethyl-5-pyrazolylcarbonyl) phenoxyacetic acid or a pharmacologically acceptable salt thereof. 6 The active ingredient is {2,3-dichloro-4-[1-
The diuretic according to claim 1, which is (1-methyl-5-pyrazolyl)vinyl]phenoxy}acetic acid or a pharmacologically acceptable salt thereof. 7. The diuretic according to claims 1 to 6, which is a uric acid excretion promoter and/or an electrolyte excretion promoter. 8 Congestive heart failure, edema, pulmonary edema, pleural effusion,
The diuretic according to claims 1 to 7, which is a therapeutic/preventive agent for interstitial nephritis, gout, or hyperuricemia. 9. The diuretic according to claim 8, wherein the edema is hepatic, nephritic, cardiac, gestational, lymphatic, or drug-induced edema.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1025273A JPH01287023A (en) | 1988-02-10 | 1989-02-02 | Diuretic |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2967288 | 1988-02-10 | ||
| JP63-29672 | 1988-02-10 | ||
| JP1025273A JPH01287023A (en) | 1988-02-10 | 1989-02-02 | Diuretic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01287023A JPH01287023A (en) | 1989-11-17 |
| JPH0577651B2 true JPH0577651B2 (en) | 1993-10-27 |
Family
ID=12282603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1025273A Granted JPH01287023A (en) | 1988-02-10 | 1989-02-02 | Diuretic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01287023A (en) |
-
1989
- 1989-02-02 JP JP1025273A patent/JPH01287023A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01287023A (en) | 1989-11-17 |
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