JPH03157331A - Diuretic - Google Patents
DiureticInfo
- Publication number
- JPH03157331A JPH03157331A JP20039490A JP20039490A JPH03157331A JP H03157331 A JPH03157331 A JP H03157331A JP 20039490 A JP20039490 A JP 20039490A JP 20039490 A JP20039490 A JP 20039490A JP H03157331 A JPH03157331 A JP H03157331A
- Authority
- JP
- Japan
- Prior art keywords
- group
- benzodioxole
- diuretic
- dichloro
- carboxylic acid
- 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
- 239000002934 diuretic Substances 0.000 title claims abstract description 21
- 230000001882 diuretic effect Effects 0.000 title claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 230000029142 excretion Effects 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 11
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 10
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 10
- 229940116269 uric acid Drugs 0.000 claims description 10
- 150000005528 benzodioxoles Chemical class 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 206010030113 Oedema Diseases 0.000 claims description 4
- 239000003792 electrolyte Substances 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 3
- 201000001431 Hyperuricemia Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 201000006334 interstitial nephritis Diseases 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 208000002151 Pleural effusion Diseases 0.000 claims description 2
- 206010037423 Pulmonary oedema Diseases 0.000 claims description 2
- 230000001926 lymphatic effect Effects 0.000 claims description 2
- 208000005333 pulmonary edema Diseases 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000002440 hepatic effect Effects 0.000 claims 1
- 230000003449 preventive effect Effects 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 34
- -1 acetic acid compound Chemical class 0.000 abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 13
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- BNVSFHJTDAWCHL-UHFFFAOYSA-N 4,5-dichloro-6-(2-methylpyrazole-3-carbonyl)-1,3-benzodioxole-2-carboxylic acid Chemical compound CN1N=CC=C1C(=O)C(C(=C1Cl)Cl)=CC2=C1OC(C(O)=O)O2 BNVSFHJTDAWCHL-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 23
- 238000004519 manufacturing process Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000284 extract Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 229940030606 diuretics Drugs 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QBDSGGHXJRGQDX-UHFFFAOYSA-N 5-benzoyl-6-chloro-1,3-benzodioxole-2-carboxylic acid Chemical compound C1=C2OC(C(=O)O)OC2=CC(Cl)=C1C(=O)C1=CC=CC=C1 QBDSGGHXJRGQDX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-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
- NIJGVVHCUXNSLL-UHFFFAOYSA-N Dibrom-essigsaeure-aethylester Natural products CCOC(=O)C(Br)Br NIJGVVHCUXNSLL-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- SIEILFNCEFEENQ-UHFFFAOYSA-N dibromoacetic acid Chemical compound OC(=O)C(Br)Br SIEILFNCEFEENQ-UHFFFAOYSA-N 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
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- ZGIAUZUZNFRBGN-UHFFFAOYSA-N 1,3-benzodioxole-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)OC2=C1 ZGIAUZUZNFRBGN-UHFFFAOYSA-N 0.000 description 1
- BCLCTNFGMGONNN-UHFFFAOYSA-N 1-(ethoxymethyl)pyrazole Chemical compound CCOCN1C=CC=N1 BCLCTNFGMGONNN-UHFFFAOYSA-N 0.000 description 1
- DGPDIKUBVNHSJR-UHFFFAOYSA-N 1-(methoxymethyl)pyrazole Chemical compound COCN1C=CC=N1 DGPDIKUBVNHSJR-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- VXAPPKKWUMXQHN-UHFFFAOYSA-N 4,5-dichloro-6-(2-pyridin-2-ylpyrazole-3-carbonyl)-1,3-benzodioxole-2-carboxylic acid Chemical compound ClC=1C(Cl)=C2OC(C(=O)O)OC2=CC=1C(=O)C1=CC=NN1C1=CC=CC=N1 VXAPPKKWUMXQHN-UHFFFAOYSA-N 0.000 description 1
- BWJDNEQJOYZMMC-UHFFFAOYSA-N 5-methyl-6-(pyridine-3-carbonyl)-1,3-benzodioxole-2-carboxylic acid Chemical compound CC1=CC=2OC(C(O)=O)OC=2C=C1C(=O)C1=CC=CN=C1 BWJDNEQJOYZMMC-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 239000002552 dosage form Substances 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
- QXUAFDIGXAKXMA-UHFFFAOYSA-N ethyl 4,5-dichloro-6-(2-methylpyrazole-3-carbonyl)-1,3-benzodioxole-2-carboxylate Chemical compound ClC=1C(Cl)=C2OC(C(=O)OCC)OC2=CC=1C(=O)C1=CC=NN1C QXUAFDIGXAKXMA-UHFFFAOYSA-N 0.000 description 1
- FEGKRBMKJURZIP-UHFFFAOYSA-N ethyl 4,5-dichloro-6-[2-(ethoxymethyl)pyrazole-3-carbonyl]-1,3-benzodioxole-2-carboxylate Chemical compound CCOCN1N=CC=C1C(=O)C(C(=C1Cl)Cl)=CC2=C1OC(C(=O)OCC)O2 FEGKRBMKJURZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 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
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- BWGRIFQGCYJBCE-UHFFFAOYSA-N methyl 4,5-dichloro-6-[2-(methoxymethyl)pyrazole-3-carbonyl]-1,3-benzodioxole-2-carboxylate Chemical compound COCN1N=CC=C1C(=O)C(C(=C1Cl)Cl)=CC2=C1OC(C(=O)OC)O2 BWGRIFQGCYJBCE-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GMZKPRWTJUMSGD-UHFFFAOYSA-M sodium;bromate;trihydrate Chemical compound O.O.O.[Na+].[O-]Br(=O)=O GMZKPRWTJUMSGD-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
Landscapes
- Plural Heterocyclic 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） 本発明は利尿剤に関する。[Detailed description of the invention] (Industrial application field) The present invention relates to diuretics.
（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。(Prior Art) Diuretics are drugs that mainly act on the renal tubules, suppress the reabsorption of water and electrolytes, and promote their excretion.
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っ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った。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。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 excess uric acid deposits in the tissues of the body, often leading to diseases such as interstitial nephritis and gout. Ta. 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.
一方、特開昭５７−１８３７８６号には５−ベンゾイル
−６−クロロ−１，３−ベンゾジオキソール−２−カル
ボン酸の如きベンゾジオキソール誘導体が、また特開昭
５９−８９６７６号には５−メチル−６−ニコチノイル
−１，３−ベンゾジオキソール−２−カルボン酸及び５
−ブロモ−６−ペンゾイルー１３−ベンゾジオキソール
−２−カルボン酸の如きベンゾジオキソール誘導体が開
示されており、これらベンゾジオキソール誘導体が利尿
剤として有用であることも示されている。On the other hand, benzodioxole derivatives such as 5-benzoyl-6-chloro-1,3-benzodioxole-2-carboxylic acid are disclosed in JP-A No. 57-183786, and JP-A No. 59-89676 discloses benzodioxole derivatives such as 5-benzoyl-6-chloro-1,3-benzodioxole-2-carboxylic acid. are 5-methyl-6-nicotinoyl-1,3-benzodioxole-2-carboxylic acid and 5
Benzodioxole derivatives such as -bromo-6-penzoyl-13-benzodioxole-2-carboxylic acid have been disclosed, and it has also been shown that these benzodioxole derivatives are useful as diuretics.
（発明の構成及び効果）
本発明は次の一般式（１）
（但し、Ｒ１は低級アルキル基、低級アルコキシ基置換
低級アルキル基、フェニル基又はピリジル基Ｈ２は水素
原子又はハロゲン原子、Ｒ３は水素原子又は低級アルキ
ル基を表す。）
で示されるベンゾジオキソール誘導体及びその塩を有効
成分とする利尿剤に関する。(Structure and Effects of the Invention) The present invention has the following general formula (1) (However, R1 is a lower alkyl group, a lower alkyl group substituted with a lower alkoxy group, a phenyl group or a pyridyl group, H2 is a hydrogen atom or a halogen atom, and R3 is a hydrogen atom. The present invention relates to a diuretic containing a benzodioxole derivative represented by the formula (atom or lower alkyl group) and a salt thereof as an active ingredient.
本発明の有効成分であるベンゾジオキソール誘導体（ｒ
）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
用を有するため、うっ血性心不全、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等の疾患の治療・予防に使用する
ことができる。Benzodioxole derivative (r
) or its salts are both novel compounds and have excellent diuretic, electrolyte excretion-promoting and uric acid excretion-promoting effects; pregnancy, lymphatic or drug-induced edema, etc.), pulmonary edema, ascites, pleural effusion, interstitial nephritis,
It can be used to treat and prevent diseases such as gout and hyperuricemia.
例えば、−夜絶食させたラットに生理食塩液を経口投与
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：１００■／ｋｇ）したとこ
ろ、本発明の有効成分化合物である４、５−ジクロロ−
６−（１−エチル−５−ピラゾリルカルボニル）−１，
３−ベンゾジオキソール−２−カルボン酸、４．５−ジ
クロロ−６−（１−プロピル−５−ビラプリルカルボニ
ル）−１，３−ベンゾジオキソール−２−カルボン酸等
を投与した群は、検体非投与群に比べて約３倍の尿量増
加を示すと共に、１．５倍以上の尿酸***量増加を示し
た。また、４．５−ジクロロ−６−（１−メチル−５−
ピラゾリルカルボニル）−１，３−ベンゾジオキソール
−２−カルボン酸等を投与した群は、検体非投与群に比
べて、３倍以上のＮａ***増加を示した。For example, when a physiological saline solution was orally administered to rats that had been fasted overnight, and one hour later, a carboxymethylcellulose suspension of the sample was orally administered (dose: 100 μ/kg). certain 4,5-dichloro-
6-(1-ethyl-5-pyrazolylcarbonyl)-1,
Groups administered with 3-benzodioxole-2-carboxylic acid, 4,5-dichloro-6-(1-propyl-5-bilaprylcarbonyl)-1,3-benzodioxole-2-carboxylic acid, etc. showed an approximately 3-fold increase in urine volume and a 1.5-fold or more increase in uric acid excretion compared to the non-sample-administered group. Also, 4,5-dichloro-6-(1-methyl-5-
The group to which pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid and the like were administered showed an increase in Na excretion three times or more compared to the group to which no sample was administered.
さらに、本発明の有効成分（１）は毒性も低く、例えば
、４．５−ジクロロ−６−（１−メトキシメチル−５−
ピラゾリルカルボニル）−１，３−ベンゾジオキソール
−２−カルボン酸をマウスに１０００■／ｋｇ３日間連
続経口投与しても死亡例は認められなかった。Furthermore, the active ingredient (1) of the present invention has low toxicity, for example, 4,5-dichloro-6-(1-methoxymethyl-5-
Even when 1,3-benzodioxole-2-carboxylic acid (pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid was orally administered to mice at a dose of 1000 μ/kg for 3 consecutive days, no deaths were observed.
本発明の有効成分であるベンゾジオキソール誘導体（１
）の具体例としては、−形式（１）において、Ｉｌｌが
直鎖又は分枝状アルキル（ＣＩ−６）基、アルコキシ（
ＣＩ−ａ）置換アルキル（ＣＩ−４）基、フェニル基又
はピリジル基であり、Ｒ８が水素原子又はハロゲン原子
であり、Ｒ３が水素原子又はアルキル（Ｃ３−４）基で
ある化合物があげられる。これらのうち好ましい化合物
としては、−形式（１）において、Ｒ１カリチル基、エ
チル基、ｎ−プロピル基、イソプロピル基、ローヘキシ
ル基、メトキシメチル基、エトキシメチル基、フェニル
基又は２−ピリジル基であり、Ｒ２が水素原子、塩素原
子又は臭素原子であり、Ｒ３が水素原子、メチル基又は
エチル基である化合物である。さらに好ましい化合物と
しては、−形式（１）において、Ｒ１カリチル基、エチ
ル基、ｎ−プロピル基、イソプロピル基、メトキシメチ
ル基又はエトキシメチル基であり、「が水素原子又は塩
素原子であり、Ｒ３が水素原子又はエチル基である化合
物である。さらにより好ましい化合物としては、−形式
（１）において、「カリチル基、エチル基、ｎ−プロピ
ル基又はメトキシメチル基であり、Ｒ２及びＲ３が水素
原子である化合物があげられる。Benzodioxole derivative (1
) As a specific example of -format (1), Ill is a linear or branched alkyl (CI-6) group, alkoxy (
Examples include compounds in which CI-a) is a substituted alkyl (CI-4) group, phenyl group or pyridyl group, R8 is a hydrogen atom or a halogen atom, and R3 is a hydrogen atom or an alkyl (C3-4) group. Preferred compounds among these are - in form (1), R1 calicyl group, ethyl group, n-propyl group, isopropyl group, rhohexyl group, methoxymethyl group, ethoxymethyl group, phenyl group or 2-pyridyl group. , R2 is a hydrogen atom, a chlorine atom, or a bromine atom, and R3 is a hydrogen atom, a methyl group, or an ethyl group. More preferred compounds include -format (1), where R1 is a calicyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group or ethoxymethyl group, "is a hydrogen atom or a chlorine atom, and R3 is a A compound that is a hydrogen atom or an ethyl group.An even more preferred compound is a compound in -form (1) that is a calicyl group, an ethyl group, an n-propyl group, or a methoxymethyl group, and R2 and R3 are hydrogen atoms. One example is a certain compound.
本発明の有効成分である化合物（１）は遊離の形でも又
その塩の形のいずれでも医薬用途に用いることができる
。医薬用途に用いる場合、塩は薬理的に許容しうる塩で
あるのが好ましく、このような塩としては、塩基又は酸
との塩、例えばナトリウム塩、カリウム塩の如きアルカ
リ金属塩、カル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
、シュウ酸塩の如き有機酸塩等を好適にあげることがで
きる。これら塩は例えば、化合物（りを適当な溶媒中塩
基又は酸で処理することにより容易に取得することがで
きる。Compound (1), which is the active ingredient of the present invention, can be used for pharmaceutical purposes either in its free form or in its salt form. When used for pharmaceutical purposes, the salts are preferably pharmacologically acceptable salts, such as salts with bases or acids, such as alkali metal salts such as sodium salts, potassium salts, calcium salts, etc. Suitable examples include alkaline earth metal salts such as salts of alkaline earth metals, mineral acid salts such as hydrochlorides and hydrobromides, and organic acid salts such as methanesulfonates and oxalates. These salts can be easily obtained, for example, by treating the compound with a base or acid in an appropriate solvent.
本発明の有効成分である化合物（１）またはその塩は、
経口的にも非経口的にも投与することができ、又経口も
しくは非経口投与に適した賦形剤と混合して用いること
ができる。Compound (1) or its salt, which is the active ingredient of the present invention, is
It can be administered orally or parenterally, and can be mixed with excipients suitable for oral or parenteral administration.
投与剤型としては、錠剤、散剤、カプセル剤、顆粒剤の
如き固形製剤であってもよく、また溶液、懸濁液、乳液
の如き液体製剤であってもよい。The dosage form may be a solid preparation such as a tablet, powder, capsule, or granule, or a liquid preparation such as a solution, suspension, or emulsion.
更に、非経口的に投与する場合には、例えば注射剤等と
して用いることができる。Furthermore, when administered parenterally, it can be used, for example, as an injection.
本発明のを効成分である化合物（１）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っても異なるが、通常１日当
たり０．１〜２００■／ｋｇ、とりわけ０．３〜１００
■／ｋｇであるのが好ましい。The dosage of Compound (1) 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 0.000 mg/day. 1-200■/kg, especially 0.3-100
■/kg is preferable.
本発明の有効成分である化合物（１）は、例えば、−形
式
意味を有する。）
で示される酢酸化合物とを反応させるか、或いは一般式
（但し、Ｒ１、Ｒ８及びＲ３は前記と同一意味を有する
。）で示されるベンゾジオキソール化合物を酸化するこ
とにより製することができる。Compound (1), which is an active ingredient of the present invention, has, for example, a -formal meaning. ) or by oxidizing a benzodioxole compound represented by the general formula (wherein R1, R8 and R3 have the same meanings as above). .
更に、目的化合物Ｎ）のうち−形式
（但し、９１及びＣは前記と同一意味を有する。）で示
される１、２−ベンゼンジオール化合物と一般式
％式％（）
（但し、Ｖは反応性残基を表し、Ｒ３は前記と同一（但
し、Ｒ１及びＲ２は前記と同一意味を有する。）で示さ
れるカシレボン酸化合物は、−形式（但し、Ｒ３１は低
級アルキル基を表し、Ｒ１及びＲＲは前記と同一意味を
有する。）
で示されるエステル化合物を加水分解することによって
も製することができる。Furthermore, among the target compounds N), a 1,2-benzenediol compound represented by the form - (where 91 and C have the same meanings as above) and the general formula % formula % () (where V is the reactive residue, and R3 is the same as above (however, R1 and R2 have the same meaning as above). It has the same meaning as above.) It can also be produced by hydrolyzing an ester compound represented by the following.
さらに、目的化合物（Ｈのうち一般式
（但し、Ｒ２１はハロゲン原子を表し、Ｒ１及びＲ３は
前記と同一意味を有する。）
で示される化合物は、−形式
（但し、Ｒ１・及びＲ１は前記と同一意味を有する。）
で示される化合物をハロゲン化することによっても製造
することができる。Furthermore, the target compound (H is a compound represented by the general formula (wherein, R21 represents a halogen atom, and R1 and R3 have the same meanings as above) is of the form - (however, R1 and R1 are the same as above). have the same meaning)
It can also be produced by halogenating the compound represented by.
なお、原料化合物（ＩＩ）は例えば、一般式前記と同一
意味を有する。）
で示される化合物を臭化水素酸、三臭化ホウ素、シアン
化アルカリ金属、チオール酢酸アルカリ金属等で脱アル
キル化処理することにより製することができる。In addition, the raw material compound (II) has, for example, the same meaning as the general formula above. ) can be produced by dealkylating the compound represented by the following with hydrobromic acid, boron tribromide, alkali metal cyanide, alkali metal thiol acetate, etc.
また原料化合物（ＴＶ）は−形式
（但し、Ｒ３は前記と同一意味を有する。）で示される
化合物と一般式
（但し、Ｒ１は前記と同一意味を有する。）で示される
化合物とをブチルリチウム等のアルキルアルカリ金属の
存在下反応させるか、或いは一般式
（但し、Ｒ４は低級アルキル基を表し、Ｒ１及びＲ８は
（但し、Ｒ１及びＲ１は前記と同一意味を有する。）で
示される化合物と酢酸化合物（！Ｉｔ）とを反応させる
ことにより製することができる。In addition, the raw material compound (TV) is a compound represented by the - format (however, R3 has the same meaning as above) and a compound represented by the general formula (however, R1 has the same meaning as above), butyl lithium or with a compound represented by the general formula (wherein, R4 represents a lower alkyl group, and R1 and R8 have the same meanings as above). It can be produced by reacting with an acetic acid compound (!It).
実験例（１）
（方法）
一夜絶食させたＳＤ雄性ラット（チャールスリバー）を
用い、体重１００ｇ当たり３ｄ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ｉｉ ：
１００ａ＋ｇ／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
３Ｉ１１Ｍ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時間にわたって尿を採
取し、検体の効力は、検体投与群の尿量、尿酸***量及
びＮａ***量と非投与群のそれとの比（効力比）で求め
た。Experimental Example (1) (Method) 3 d of physiological saline per 100 g of body weight was orally administered to SD male rats (Charles River) that had been fasted overnight. Sample 1 hour after administration of physiological saline (administration ii:
100a+g/kg) was suspended in 0.25% carboxymethylcellulose-physiological saline and administered orally at a rate of 3I11M per 100g body weight, and the same amount of 0.25% carboxymethylcellulose-physiological saline was administered to the non-sample administration group. was administered only. Urine was collected for 5 hours immediately after administration, and the efficacy of the specimen was determined by the ratio of the urine volume, uric acid excretion amount, and Na excretion amount of the specimen administration group to that of the non-administration group (efficacy ratio).
（結果）
結果は下記第１表、第２表及び第３表の通りで第
２
表
（注１）実験に際しては、後記各製造例で得た生成物を
供試化合物として使用した。（以下同じ）実験例（２）
（方法）
ベンドパ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人に、等モルのトリ
スヒドロキシメチルアミノメタンを加え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： ３ｎ＋
ｇ／ｋｇ） Ｌ／た。投与前後に１０分間の採尿及びそ
の中間点での採血を行った。(Results) The results are shown in Table 1, Table 2, and Table 3 below. Table 2 (Note 1) In the experiment, the products obtained in each of the production examples described below were used as test compounds. (The same applies hereafter) Experimental example (2) (Method) Under bendoparbital anesthesia, an equimolar amount of tris-hydroxymethylaminomethane was added to a mongrel adult whose plasma uric acid concentration was increased by continuous intravenous infusion of uric acid to 5% Intravenous administration of the sample dissolved in a glucose aqueous solution (dose: 3n+
g/kg) L/ta. Urine was collected for 10 minutes before and after administration, and blood was collected at the midpoint.
検体の効力は、投与前後１０分間の尿量、尿酸***率及
びＮａ***量の比（効力比）で求めた。The efficacy of the sample was determined by the ratio of urine volume, uric acid excretion rate, and Na excretion amount (efficacy ratio) for 10 minutes before and after administration.
尚、尿酸***率は尿酸の尿中***量、血漿濃度及びクレ
アチニンクリアランスから求めた。The uric acid excretion rate was determined from the urinary excretion amount, plasma concentration, and creatinine clearance.
（結果） 結果は下記第４表、第５表及び第６表の通りである。(result) The results are shown in Tables 4, 5 and 6 below.
第４表
第６表
第５表
製造例１
（１） （１−メチル−ピラゾール−５−イル）−
（２，３−ジクロロ−４，５−ジメトキシフェニル）−
メタノン６．２５ｇの４７％臭化水素酸７０＋ｗｌの混
合物を３時間還流後、減圧下に溶媒を留去する。残香を
１０％水酸化ナトリウム水に水冷上溶解し、酢酸でｐ１
１３〜４とした後酢酸エチルで抽出する。抽出液を飽和
食塩水で洗浄し、乾燥後減圧下に溶媒を留去する。残香
をイソプロピルエーテルで結晶化しろ取することにより
、（１−メチル−ピラゾール−５−イル）−（２，３−
ジクロロ−４，５−ジヒドロキシフェニル）−メタノン
４．７７ｇを得る。Table 4 Table 6 Table 5 Production Example 1 (1) (1-Methyl-pyrazol-5-yl)-
(2,3-dichloro-4,5-dimethoxyphenyl)-
A mixture of 6.25 g of methanone and 70+wl of 47% hydrobromic acid was refluxed for 3 hours, and then the solvent was distilled off under reduced pressure. Dissolve the residual aroma in 10% sodium hydroxide solution on water cooling, and add p1 with acetic acid.
13-4 and then extracted with ethyl acetate. The extract is washed with saturated brine, dried, and the solvent is distilled off under reduced pressure. (1-Methyl-pyrazol-5-yl)-(2,3-
4.77 g of dichloro-4,5-dihydroxyphenyl)-methanone are obtained.
論、ｐ、 ２０１〜２０４ ’Ｃ
（２） 本島２．０ｇのジメチルホルムアミド２２ｍ１
溶液に粉末炭酸カリウム２．１２ｇ及びジブロモ酢酸エ
チルエステル３．７ｇを加えアルゴン雰囲気下９０〜１
００°Ｃで２時間撹拌する。冷後、混合物を氷水に注入
し、酢酸エチルで抽出する、抽出液を飽和食塩水で洗浄
し、乾燥後減圧下に溶媒を留去する。残香をシリカゲル
クロマトグラフィーで精製することにより、４．５−ジ
クロロ−６−（１−メチル−５−ピラゾリルカルボニル
）−１，３−ベンゾジオキソール−２−カルボン酸エチ
ルエステル１．６４ｇを得る。Theory, p, 201-204'C (2) Main island 2.0g dimethylformamide 22ml
2.12 g of powdered potassium carbonate and 3.7 g of dibromoacetic acid ethyl ester were added to the solution, and the mixture was heated to 90 to 100 g under an argon atmosphere.
Stir at 00°C for 2 hours. After cooling, the mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. By purifying the residual aroma with silica gel chromatography, 1.64 g of 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester is obtained. .
ｍ、ｐ、 １２４〜１２６．５°Ｃ
製造例２〜９
対応原料化合物を製造例１と同様に処理することにより
、下記第４表記載の化合物を得る。m, p, 124-126.5°C Production Examples 2-9 The corresponding raw material compounds were treated in the same manner as in Production Example 1 to obtain the compounds listed in Table 4 below.
第 ４ 表
＊置換位置：１−置換ビラゾールー５−カルボニル基の
ベンゾジオキソール化合物上
の置換位置
製造例１０
（１−エチル−ピラゾール−５−イル）−（２３−ジク
ロロ−４，５−ジヒドロキシフェニル）−メタノン３．
０１ｇのジメチルホルムアミド３０ｇ＋１溶液に炭酸カ
リウム６．９ｇ及びジブロモ酢酸２．８３ｇを加え８０
°Ｃで５時間撹拌する。Table 4 * Substitution position: Substitution position of 1-substituted virazole-5-carbonyl group on benzodioxole compound Production Example 10 (1-ethyl-pyrazol-5-yl)-(23-dichloro-4,5-dihydroxy phenyl)-methanone3.
Add 6.9 g of potassium carbonate and 2.83 g of dibromoacetic acid to 30 g of dimethylformamide + 1 solution of 80
Stir at °C for 5 hours.
冷後、混合物に水を加え、次いで６Ｎ塩酸でｐＨｌとす
る。析出晶をろ取し、水及びイソプロピルエーテルで洗
浄後含水ジメチルホルムアミドから再結晶することによ
り、４．５−ジクロロ−６−（１−エチル−５−ピラゾ
リルカルボニル）−１＃３−ベンゾジオキソール−２−
カルボン酸１．３６ｇを得る。After cooling, water is added to the mixture and the pH is then brought to pH1 with 6N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and isopropyl ether, and recrystallized from aqueous dimethylformamide to give 4,5-dichloro-6-(1-ethyl-5-pyrazolylcarbonyl)-1#3-benzodioxide. Sole-2-
1.36 g of carboxylic acid are obtained.
ｍ、ｐ、 ２３３〜２３５°Ｃ（分解）本島のナトリウ
ム塩：
ｍ、ｐ、 １４０〜１５０°Ｃ
製造例１１
（１） ｌ−エトキシメチルピラゾール２．４５ｇのテ
トラヒドロフラン５０ｍ１溶液をアルゴン雰囲気下−５
０〜−６０°Ｃに冷却し、この溶液に１６Ｍｎ−ブチル
リチウム／ｎ−ヘキサン溶液１２．２■Ｉを加え同温で
４０分間撹拌する。混合物に４．５−ジクロロ−６−ホ
ルミル−１，３−ベンゾジオキソール−２−カルボン酸
・リチウム塩５．２３ｇのへキサメチルリン酸トリアミ
ド４０１溶液を一５０℃〜−６０℃で滴下し、同温で３
０分撹拌する０反応混合物に飽和塩化アンモニウム水及
びＩＮ塩酸を加えた後、酢酸エチルで抽出（この抽出液
は６−（（１−エトキシメチル−ピラゾール−５−イル
）ヒドロキシメチル〕−４゜５−ジクロロ−１，３−ベ
ンゾジオキソール−２−カルボン酸を含む）する、酢酸
エチル抽出液に過剰のジアゾメタンのエーテル溶液を加
え１０分撹拌後、水洗し、乾燥後減圧下に溶媒を留去す
る。m, p, 233-235°C (decomposed) Sodium salt of the main island: m, p, 140-150°C Production Example 11 (1) A solution of 2.45 g of l-ethoxymethylpyrazole in 50 ml of tetrahydrofuran was heated under an argon atmosphere to -5
Cool to 0 to -60°C, add 12.2 ml of 16M n-butyllithium/n-hexane solution to this solution, and stir at the same temperature for 40 minutes. A solution of 5.23 g of 4.5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylic acid lithium salt in hexamethylphosphoric acid triamide 401 was added dropwise to the mixture at -50°C to -60°C, 3 at the same temperature
After adding saturated ammonium chloride water and IN hydrochloric acid to the reaction mixture, which was stirred for 0 minutes, it was extracted with ethyl acetate. To the ethyl acetate extract (containing 5-dichloro-1,3-benzodioxole-2-carboxylic acid), add excess ethereal solution of diazomethane, stir for 10 minutes, wash with water, dry, and remove the solvent under reduced pressure. To leave.
残香をシリカゲルクロマトグラフィーで精製することに
より、６−（（１−エトキシメチル−ピラゾール−５−
イル）ヒドロキシメチル）−４，５−ジクロロ−１，３
−ベンゾジオキソール−２−カルボン酸メチルエステル
（本島はジアステレオマーの混合物である）５．９ｇ油
状物として得る。By purifying the residual aroma using silica gel chromatography, 6-((1-ethoxymethyl-pyrazole-5-
yl)hydroxymethyl)-4,5-dichloro-1,3
5.9 g of -benzodioxole-2-carboxylic acid methyl ester (mainly a mixture of diastereomers) are obtained as an oil.
ＭＳ（ｍ／ｅ）： ４０２（？ｉ” ）ＩＲ（ｌｉｑｕ
ｉｄ）： ３２５０．１７６０ｃｏ＋ −’（２） 本
島５．９ｇの塩化メチレン１５０ｍ１溶液にピリジニウ
ムジクロメート１１．０ｇを加え室温で１６時間撹拌す
る０反応混合物をシリカゲルクロマトグラフィーに付し
、目的化合物を含有するフラクションを集め、減圧下に
溶媒を留去することにより、６−（１−エトキシメチル
−５−ピラゾリルカルボニル）−４，５−ジクロロ−１
３−ベンゾジオキソール−２−カルボン酸メチルエステ
ル４．６１ｇを油状物として得る。MS(m/e): 402(?i”)IR(liqu
id): 3250.1760co+ -' (2) Add 11.0 g of pyridinium dichromate to a solution of 5.9 g of Otojima in 150 ml of methylene chloride and stir at room temperature for 16 hours. The reaction mixture was subjected to silica gel chromatography to determine whether it contained the target compound. By collecting the fractions and distilling off the solvent under reduced pressure, 6-(1-ethoxymethyl-5-pyrazolylcarbonyl)-4,5-dichloro-1
4.61 g of 3-benzodioxole-2-carboxylic acid methyl ester are obtained as an oil.
ＭＳ（ｍ／ｅ）： ４００（Ｍ” ）
ＩＲ（ｌｉｑｕｉｄ）： １７５５．１６６０ ｃ＋ａ
−’製造側１２
対応原料化合物を製造例１１− （１）と同様に処理す
ることにより、６−（（１−メトキシメチル−ピラゾー
ル−５−イル）ヒドロキシメチル〕−４，５−ジクロロ
−１，３−ベンゾジオキソール−２−カルボン酸メチル
エステル（本島はジアステレオマーの混合物である）を
得、次いで本島を製造例１１− （２）と同様に処理す
ることにより、６−（ｌ−メトキシメチル−５−ピラゾ
リルカルボニル）−４，５−ジクロロ−１，３−ベンゾ
ジオキソール−２−カルボン酸メチルエステルを得る。MS (m/e): 400 (M”) IR (liquid): 1755.1660 c+a
-'Production side 12 By treating the corresponding raw material compound in the same manner as in Production Example 11-(1), 6-((1-methoxymethyl-pyrazol-5-yl)hydroxymethyl]-4,5-dichloro-1 , 3-benzodioxole-2-carboxylic acid methyl ester (Hijima is a mixture of diastereomers) and then treated Hijima in the same manner as in Production Example 11-(2) to obtain 6-(l -methoxymethyl-5-pyrazolylcarbonyl)-4,5-dichloro-1,3-benzodioxole-2-carboxylic acid methyl ester is obtained.
ＩＲ（ｌｉｑｕｉｄ） １７５５．１６６０ ｃｍ−’
ＭＳ（ａ＋／ｅ）： ３８６（Ｍ” ）製造例１３
（１） １−エトキシメチルピラゾール２５２＋ａｇ
のテトラヒドロフラン５ｍｌ溶液を−５０〜−６０℃に
冷却後、１．６Ｍｎ−ブチルリチウム／ ｎ −ヘキサ
ン溶液１．２５＋＋＋１を滴下し、さらにヘキサメチル
リン酸トリアミド０．４ｍｌを加え同温で１時間撹拌す
る。この溶液を４，５−ジクロロ−６−ホルミル１．３
−ベンゾジオキソール−２−力ｔｔｔホ７酸エチルエス
テル５８２ｒｍｇのテトラヒドロフランｌ０Ｉｌｌ溶液
に−５０〜−６０°Ｃで加え５分間同温で撹拌する。混
合物に飽和塩化アンモニウム水溶液を加え、酢酸エチル
で抽出する。抽出液を水洗、乾燥後減圧下に溶媒を留去
する。残香をシリカゲルクロマトグラフィで精製するこ
とにより、６−（（１−エトキシメチル−ピラゾール−
５−イル）ヒドロキシメチル〕−４５〜ジクロロ−１，
３−ベンゾジオキソール−２−カルボン酸エチルエステ
ル（本島はジアステレオマーの混合物である）２４０ｍ
ｇを得る。IR (liquid) 1755.1660 cm-'
MS (a+/e): 386 (M”) Production Example 13 (1) 1-ethoxymethylpyrazole 252+ag
After cooling 5 ml of tetrahydrofuran solution to -50 to -60°C, 1.25++1 of 1.6 M n-butyllithium/n-hexane solution was added dropwise, and 0.4 ml of hexamethylphosphoric acid triamide was further added and stirred at the same temperature for 1 hour. do. This solution was mixed with 4,5-dichloro-6-formyl 1.3
-Benzodioxole-2-forcetttTo a solution of 582 rmg of 7-acid ethyl ester in 10 Ill of tetrahydrofuran was added at -50 to -60°C and stirred at the same temperature for 5 minutes. A saturated aqueous ammonium chloride solution is added to the mixture, and the mixture is extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By purifying the residual aroma using silica gel chromatography, 6-((1-ethoxymethyl-pyrazole-
5-yl)hydroxymethyl]-45-dichloro-1,
3-benzodioxole-2-carboxylic acid ethyl ester (main island is a mixture of diastereomers) 240 m
get g.
ＩＲ（ｌｉｑｕｉｄ） ３２５０．１７６０ ｃｒａ−
’ＭＳ（＋ｍ／ｅ）： ４１６（Ｍ’ ）（２） 本島
を製造例１１− （２）と同様に処理（酸化剤はピリジ
ニウムジクロメートの代わりに二酸化マンガンを使用〕
することにより、６−（１−エトキシメチル−５−ピラ
ゾリルカルボニル）−４，５−ジクロロ−１，３−ベン
ゾジオキソール−２−カルボン酸エチルエステルを得る
。IR (liquid) 3250.1760 cra-
'MS (+m/e): 416 (M') (2) The main island was treated in the same manner as in Production Example 11-(2) (manganese dioxide was used as the oxidizing agent instead of pyridinium dichromate).
By doing so, 6-(1-ethoxymethyl-5-pyrazolylcarbonyl)-4,5-dichloro-1,3-benzodioxole-2-carboxylic acid ethyl ester is obtained.
ＩＲ（ｌｉｑｕｉｄ） １７５５．１６６０ ｃｍ−’
ＭＳ（ｍ／ｅ＞＝ ４１４（Ｍ” ）
製造例１４
１−メトキシメチルピラゾール１１２ｇ、テトラヒドロ
フラン２５ｍ１，１．６Ｍｎ−ブチルリチウム／ｎ−ヘ
キサン溶液６．８８ｍ１及び４，５−ジクロロ−６−ホ
ルミル−１，３−ベンゾジオキソール−２−カルボン酸
・リチウム塩２．６９ｇのへキサメチルリン酸トリアミ
ド溶液１２ｍ１を実施例１１− （１）と同様に処理し
て、６−〔（ｌ−メトキシメチル−ピラゾール−５−イ
ル）ヒドロキシメチル）−４，５−ジクロロ−１，３−
ベンゾジオキソール−２−カルボン酸含有酢酸エチル溶
液を得る。この酢酸エチル液を水洗、乾燥後減圧下に溶
媒を留去する。残香（粗製の６−〔（１−メトキシメチ
ル−ピラゾール−５−イル）ヒドロキシメチル）−４，
５−ジクロロ−１，３−べ４ンゾジオキソールー２−カ
ルボン酸）を塩化メチレン１００ｍ１に溶解し、この溶
液にピリジニウムジクロメート１０ｇを加え室温で１７
時間撹拌する。不溶物をろ別し、塩化メチレンで洗浄す
る。ろ液及び洗液を合わせ、減圧下に溶媒を留去する。IR (liquid) 1755.1660 cm-'
MS (m/e>=414 (M”) Production Example 14 112 g of 1-methoxymethylpyrazole, 25 ml of tetrahydrofuran, 6.88 ml of 1.6 M n-butyllithium/n-hexane solution and 4,5-dichloro-6-formyl- 12 ml of a solution of 2.69 g of 1,3-benzodioxole-2-carboxylic acid lithium salt in hexamethylphosphoric acid triamide was treated in the same manner as in Example 11-(1) to obtain 6-[(l-methoxymethyl- pyrazol-5-yl)hydroxymethyl)-4,5-dichloro-1,3-
An ethyl acetate solution containing benzodioxole-2-carboxylic acid is obtained. After washing this ethyl acetate solution with water and drying, the solvent was distilled off under reduced pressure. Residue (crude 6-[(1-methoxymethyl-pyrazol-5-yl)hydroxymethyl)-4,
5-dichloro-1,3-benzodioxole-2-carboxylic acid) was dissolved in 100 ml of methylene chloride, and 10 g of pyridinium dichromate was added to this solution, and the mixture was heated to 17 ml at room temperature.
Stir for an hour. Insoluble matter is filtered off and washed with methylene chloride. The filtrate and washing liquid are combined and the solvent is distilled off under reduced pressure.
残香に酢酸エチルを加え、不溶物をろ別する。ろ液を水
洗、乾燥後溶媒を減圧下に留去する、残香を酢酸エチル
とｎ−ヘキサンから再結晶することにより、６−（ｌ−
メトキシメチル−５−ビラプリルカルボニル）−４，５
−ジクロロ−１３−ベンゾジオキソール−２−カルボン
酸１゜５７ｇを得る。 ｍ、ｐ、 １６８〜１７０°Ｃ
製造例１５
６−（１−メチル−５−ピラゾリルカルボニル）−４，
５−ジクロロ−１，３−ベンゾジオキソール−２−カル
ボン酸エチルエステル２．０ｇの酢酸２０ｍ１溶液に臭
素酸ナトリウム・３水和物１５３ｇの水５ｍｌ溶液を室
温で滴下し、室温で１５時間撹拌する。混合物を減圧下
に濃縮して酢酸を留去する。残香を飽和炭酸水素す）
リウム水で中和し、酢酸エチルで抽出する。抽出液を水
洗、乾燥後減圧下に溶媒を留去する。残香をシリカゲル
クロマトグラフィーで精製することにより、６−（１−
メチル−４−ブロモ−５−ピラゾリルカルボニル）−４
，５−ジクロロ−１，３−ベンゾジオキソール−２−カ
ルボン酸エチルエステル１０ｇを油状物として得る。Add ethyl acetate to the residual aroma and filter out insoluble matter. After washing the filtrate with water and drying, the solvent was distilled off under reduced pressure. The residual aroma was recrystallized from ethyl acetate and n-hexane to obtain 6-(l-
methoxymethyl-5-bilaprylcarbonyl)-4,5
1.57 g of -dichloro-13-benzodioxole-2-carboxylic acid is obtained. m, p, 168-170°C
Production Example 15 6-(1-methyl-5-pyrazolylcarbonyl)-4,
A solution of 153 g of sodium bromate trihydrate in 5 ml of water was added dropwise to a solution of 2.0 g of 5-dichloro-1,3-benzodioxole-2-carboxylic acid ethyl ester in 20 ml of acetic acid at room temperature, and the mixture was stirred at room temperature for 15 hours. Stir. The mixture is concentrated under reduced pressure to remove acetic acid. Saturated hydrogen carbonate to remove residual aroma)
Neutralize with sodium chloride water and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By purifying the residual aroma using silica gel chromatography, 6-(1-
Methyl-4-bromo-5-pyrazolylcarbonyl)-4
, 10 g of 5-dichloro-1,3-benzodioxole-2-carboxylic acid ethyl ester are obtained as an oil.
ＩＲ（ｌｉｑｕｉｄ）： １７６０．１６６０ ｃｍ
−’ＭＳ（ｓ＋／ｅ）： ４４８（Ｍ” ）製造例１６
４．５−ジクロロ−６−（ｌ−メチル−５−ピラゾリル
カルボニル）−１，３−ベンゾジオキソール−２−カル
ボン酸エチルエステル１．８６ｇのエタノール３５ａｉ
１懸濁液に水酸化ナトリウム０．３６ｇの水１５ｏ＋１
溶液を加え室温で３０分間撹拌する。混合物を減圧下に
濃縮してエタノールを留去し、残香を水冷下１０％塩酸
でｐＨ１とする。IR (liquid): 1760.1660 cm
-'MS (s+/e): 448 (M") Production Example 16 Ethyl 4.5-dichloro-6-(l-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate ester 1.86g ethanol 35ai
1 suspension of 0.36g of sodium hydroxide and 15o+1 of water
Add the solution and stir at room temperature for 30 minutes. The mixture is concentrated under reduced pressure to remove ethanol, and the residual aroma is adjusted to pH 1 with 10% hydrochloric acid while cooling with water.
析出晶をろ取し、水及びイソプロピルエーテルで洗浄後
乾燥することにより、４．５−ジクロロー６−（ｌ−メ
チル−５−ピラゾリルカルボニル）Ｌ、 ３−ベンゾ
ジオキソール−２−カルボン酸１．６６ｇを得る。The precipitated crystals were collected by filtration, washed with water and isopropyl ether, and dried to obtain 4,5-dichloro6-(l-methyl-5-pyrazolylcarbonyl)L, 3-benzodioxole-2-carboxylic acid 1. Obtain .66 g.
鵬、ｐ、 ２５１．５〜２５２°Ｃ（分解）製造例１７
〜２４
対応原料化合物を実施例１６と同様に処理することによ
り、下記第５表記載化合物を得る。Peng, p. 251.5-252°C (decomposition) Production Example 17
~24 The corresponding starting compounds were treated in the same manner as in Example 16 to obtain the compounds listed in Table 5 below.
第 ５ 表
＊置換位置：１−置換ビラゾールー５−カルボニル基の
ベンゾジオキソール化合物上
の置換位置
製造例２５
４．５−ジクロロ−６二〔ｌ−（ピリジン−２−４ル）
−５−ピラゾリルカルボニル）−１，３−ベンゾジオキ
ソール−２−カルボン酸エチルエステル１．５．をテト
ラヒドロフラン１８鵬Ｉ及び水２ｍｌとの混液に溶解し
、水酸化リチウム・１水和物１７７＋ｓｇを加え１時間
撹拌する。混合物を減圧下に濃縮してテトラヒドロフラ
ンを留去する。Table 5 *Substitution position: Substitution position of 1-substituted virazole-5-carbonyl group on benzodioxole compound Production Example 25 4.5-dichloro-62[l-(pyridine-2-4l)
-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester 1.5. was dissolved in a mixture of 18 Peng I of tetrahydrofuran and 2 ml of water, 177+sg of lithium hydroxide monohydrate was added, and the mixture was stirred for 1 hour. The mixture is concentrated under reduced pressure to remove tetrahydrofuran.
残香に水及びＩＮ塩酸を加え、酢酸エチルで抽出する。Add water and IN hydrochloric acid to the residual aroma, and extract with ethyl acetate.
抽出液を飽和食塩水で洗浄し、乾燥後減圧下に溶媒を留
去する。残香を酢酸エチルとｎ−ヘキサンとの混液で結
晶化しろ取することにより、４．５−ジクロロ−６−（
１−（ピリジン−２−イル）−５−ピラゾリルカルボニ
ル）−１，３−ベンゾジオキソール−２−カルボン酸１
．３５ｇを得る。The extract is washed with saturated brine, dried, and the solvent is distilled off under reduced pressure. By crystallizing the residual aroma with a mixture of ethyl acetate and n-hexane and collecting it by filtration, 4,5-dichloro-6-(
1-(pyridin-2-yl)-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid 1
．． Obtain 35g.
ａ＋、ｐ、 ２１１〜２１４°Ｃ（分解）製造例２６〜
２８
対応原料化合物を製造例２５と同様に処理することによ
り、下記第６表記載の化合物を得る。a+, p, 211-214°C (decomposition) Production Example 26-
28 By treating the corresponding raw material compounds in the same manner as in Production Example 25, the compounds listed in Table 6 below are obtained.
第 ６ 表 ２２Table 6 22
Claims (1)
換低級アルキル基、フェニル基又はピリジル基、Ｒ＾２
は水素原子又はハロゲン原子、Ｒ＾３は水素原子又は低
級アルキル基を表す。） で示されるベンゾジオキソール誘導体又はその塩を有効
成分とする利尿剤。 ２、Ｒ＾１が直鎖又は分枝状アルキル（Ｃ＿１＿−＿４
）基、アルコキシ（Ｃ＿１＿−＿４）置換アルキル（Ｃ
＿１＿−＿４）基、フェニル基又はピリジル基であり、
Ｒ＾２が水素原子又はハロゲン原子であり、Ｒ＾３が水
素原子又はアルキル（Ｃ＿１＿−＿４）基である請求項
１記載の利尿剤。 ３、Ｒ＾１が直鎖又は分枝状アルキル（Ｃ＿１＿−＿６
）基、アルコキシ（Ｃ＿１＿−＿４）置換アルキル（Ｃ
＿１＿−＿４）基であり、Ｒ＾２が水素原子又はハロゲ
ン原子であり、Ｒ＾３が水素原子又はアルキル（Ｃ＿１
＿−＿４）基である請求項１記載の利尿剤。 ４、Ｒ＾１カリチル基、エチル基、プロピル基、イソプ
ロピル基又はメトキシメチル基であり、Ｒ＾２及びＲ＾
３が水素原子である請求項３記載の利尿剤。 ５、４，５−ジクロロ−６−（１−メチル−５−ピラゾ
リルカルボニル）−１，３−ベンゾジオキソール−２−
カルボン酸又はその塩を有効成分とする利尿剤。 ６、４，５−ジクロロ−６−（１−エチル−５−ピラゾ
リルカルボニル）−１，３−ベンゾジオキソール−２−
カルボン酸又はその塩を有効成分とする利尿剤。 ７、４，５−ジクロロ−６−（１−プロピル−５−ピラ
ゾリルカルボニル）−１，３−ベンゾジオキソール−２
−カルボン酸又はその塩を有効成分とする利尿剤。 ８、４，５−ジクロロ−６−（１−イソプロピル−５−
ピラゾリルカルボニル）−１，３−ベンゾジオキソール
−２−カルボン酸又はその塩を有効成分とする利尿剤。 ９、尿酸***促進剤及び／又は電解質***促進剤である
請求項１〜８記載の利尿剤。 １０、うっ血性心不全、浮腫、肺水腫、胸膜侵出、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１〜９記載の利尿剤。 １１、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１０記載の利尿剤。[Claims] 1. General formula▲ Numerical formula, chemical formula, table, etc.▼ (However, R^1 is a lower alkyl group, a lower alkyl group substituted with a lower alkoxy group, a phenyl group or a pyridyl group, R^2
represents a hydrogen atom or a halogen atom, and R^3 represents a hydrogen atom or a lower alkyl group. ) A diuretic containing a benzodioxole derivative or a salt thereof as an active ingredient. 2, R^1 is a straight chain or branched alkyl (C_1_-_4
) group, alkoxy (C_1_-_4) substituted alkyl (C
_1_-_4) group, phenyl group or pyridyl group,
The diuretic according to claim 1, wherein R^2 is a hydrogen atom or a halogen atom, and R^3 is a hydrogen atom or an alkyl (C_1_-_4) group. 3, R^1 is a straight chain or branched alkyl (C_1_-_6
) group, alkoxy (C_1_-_4) substituted alkyl (C
_1_-_4) group, R^2 is a hydrogen atom or a halogen atom, and R^3 is a hydrogen atom or an alkyl (C_1
The diuretic according to claim 1, which is _-_4) group. 4, R^1 is a calicyl group, ethyl group, propyl group, isopropyl group or methoxymethyl group, R^2 and R^
The diuretic according to claim 3, wherein 3 is a hydrogen atom. 5,4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-
A diuretic containing carboxylic acid or its salt as an active ingredient. 6,4,5-dichloro-6-(1-ethyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-
A diuretic containing carboxylic acid or its salt as an active ingredient. 7,4,5-dichloro-6-(1-propyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2
- A diuretic containing a carboxylic acid or its salt as an active ingredient. 8,4,5-dichloro-6-(1-isopropyl-5-
A diuretic containing as an active ingredient pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid or a salt thereof. 9. The diuretic according to claims 1 to 8, which is a uric acid excretion promoter and/or an electrolyte excretion promoter. 10. The diuretic according to claims 1 to 9, which is a therapeutic or preventive agent for congestive heart failure, edema, pulmonary edema, pleural effusion, interstitial nephritis, gout or hyperuricemia. 11. The diuretic according to claim 10, wherein the edema is hepatic, nephritic, cardiac, gestational, lymphatic or drug-induced edema.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20211089 | 1989-08-03 | ||
| JP1-202110 | 1989-08-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03157331A true JPH03157331A (en) | 1991-07-05 |
Family
ID=16452129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20039490A Pending JPH03157331A (en) | 1989-08-03 | 1990-07-26 | Diuretic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03157331A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4517184A (en) * | 1981-04-24 | 1985-05-14 | Ciba-Geigy Corporation | Benzodioxole derivatives |
-
1990
- 1990-07-26 JP JP20039490A patent/JPH03157331A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4517184A (en) * | 1981-04-24 | 1985-05-14 | Ciba-Geigy Corporation | Benzodioxole derivatives |
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