JP2001354658A - Hydroxyformamidine compound and its salt and medicine comprising the same - Google Patents
Hydroxyformamidine compound and its salt and medicine comprising the sameInfo
- Publication number
- JP2001354658A JP2001354658A JP2000180474A JP2000180474A JP2001354658A JP 2001354658 A JP2001354658 A JP 2001354658A JP 2000180474 A JP2000180474 A JP 2000180474A JP 2000180474 A JP2000180474 A JP 2000180474A JP 2001354658 A JP2001354658 A JP 2001354658A
- Authority
- JP
- Japan
- Prior art keywords
- group
- ring
- hydroxyformamidine
- atom
- pharmaceutically acceptable
- 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
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 8
- -1 Hydroxyformamidine compound Chemical class 0.000 title claims description 102
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- NFHHBIGYIAIGFH-UHFFFAOYSA-N 2h-cyclohepta[b]thiophene Chemical group C1=CC=CC2=CCSC2=C1 NFHHBIGYIAIGFH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 210000003734 kidney Anatomy 0.000 abstract description 4
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- 125000001424 substituent group Chemical group 0.000 abstract description 3
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- 230000002490 cerebral effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
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- 230000010261 cell growth Effects 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- 230000025033 vasoconstriction Effects 0.000 abstract 1
- 229940124549 vasodilator Drugs 0.000 abstract 1
- 239000003071 vasodilator agent Substances 0.000 abstract 1
- NNDIXBJHNLFJJP-UHFFFAOYSA-N 20-Hydroxyeicosatetraenoic acid Chemical compound OCCCCCC=CCC=CCC=CCC=CCCCC(O)=O NNDIXBJHNLFJJP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- KLKQGSISBRVCTK-UHFFFAOYSA-N methyl 5-aminofuran-2-carboxylate Chemical compound COC(=O)C1=CC=C(N)O1 KLKQGSISBRVCTK-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- KVPBSBOTFRNKOM-UHFFFAOYSA-N 2h-cyclopenta[b]thiophene Chemical group C1=CC2=CCSC2=C1 KVPBSBOTFRNKOM-UHFFFAOYSA-N 0.000 description 2
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 102000003820 Lipoxygenases Human genes 0.000 description 2
- 108090000128 Lipoxygenases Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 102220240796 rs553605556 Human genes 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- RHFWLPWDOYJEAL-UHFFFAOYSA-N 1,2-oxazol-3-amine Chemical compound NC=1C=CON=1 RHFWLPWDOYJEAL-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KELIOZMTDOSCMM-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1-benzothiophene Chemical group C1C=CC=C2SCCC21 KELIOZMTDOSCMM-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- CMDRVSNHYRLGBQ-UHFFFAOYSA-N 4-butyl-1,3-thiazol-2-amine Chemical compound CCCCC1=CSC(N)=N1 CMDRVSNHYRLGBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XQPAPBLJJLIQGV-UHFFFAOYSA-N 4-methoxy-1,3-benzothiazole Chemical class COC1=CC=CC2=C1N=CS2 XQPAPBLJJLIQGV-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- QMUXKZBRYRPIPQ-UHFFFAOYSA-N 5,6-dimethyl-1,3-benzothiazole Chemical group C1=C(C)C(C)=CC2=C1SC=N2 QMUXKZBRYRPIPQ-UHFFFAOYSA-N 0.000 description 1
- LJUQGASMPRMWIW-UHFFFAOYSA-N 5,6-dimethylbenzimidazole Chemical group C1=C(C)C(C)=CC2=C1NC=N2 LJUQGASMPRMWIW-UHFFFAOYSA-N 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- 125000003277 amino group Chemical group 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- CGDDISBFSPJVPK-UHFFFAOYSA-N dimethyl thiophene-2,3-dicarboxylate Chemical compound COC(=O)C=1C=CSC=1C(=O)OC CGDDISBFSPJVPK-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- RYMBKZQBXZDQAA-UHFFFAOYSA-N n'-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-n-hydroxymethanimidamide Chemical compound CC(C)(C)C1=NN=C(N=CNO)S1 RYMBKZQBXZDQAA-UHFFFAOYSA-N 0.000 description 1
- IONSZLINWCGRRI-UHFFFAOYSA-N n'-hydroxymethanimidamide Chemical compound NC=NO IONSZLINWCGRRI-UHFFFAOYSA-N 0.000 description 1
- AGZRKAARPCYPIC-UHFFFAOYSA-N n-hydroxy-n'-(5-methyl-1,2-oxazol-3-yl)methanimidamide Chemical compound CC1=CC(N=CNO)=NO1 AGZRKAARPCYPIC-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 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
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 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
- 239000000213 tara gum Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000004867 thiadiazoles Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明はアラキドン酸から２
０−ヒドロキシエイコサテトラエン酸（２０−ＨＥＴ
Ｅ）の産生を阻害するヒドロキシホルムアミジン化合物
及びその医薬としての使用に関する。The present invention relates to arachidonic acid,
0-Hydroxyeicosatetraenoic acid (20-HET
The present invention relates to a hydroxyformamidine compound that inhibits the production of E) and its use as a medicament.
【０００２】[0002]
【従来の技術】アラキドン酸から産生される生理活性物
質として従来シクロオキシゲナーゼによって産生される
プロスタグランジン類及びリポキシゲナーゲによって産
生されるリポキシゲナーゼ類が広く知られているが、近
年チトクロームｐ４５０属に属する酵素によってアラキ
ドン酸から産生される２０−ＨＥＴＥが生体内で多彩な
働きをしていることが明らかとされつつある（J.Vascul
ar Research, 第32巻,第79頁(1995)）。これまでに２０
−ＨＥＴＥは腎臓、脳血管等の主要臓器において微小血
管を収縮又は拡張させることや細胞増殖を惹起すること
が明らかにされており、生体内で重要な生理作用を演じ
ていると共に各種腎疾患、脳血管疾患、循環器疾患等の
病態に深く関与していることが示唆されている（J.Vasc
ular Research,第32巻,第79頁(1995)、Am.J.Physiol.,
第277巻,R607頁 (1999)等）。2. Description of the Related Art Prostaglandins produced by cyclooxygenase and lipoxygenases produced by lipoxygenase are widely known as physiologically active substances produced from arachidonic acid. It has been revealed that 20-HETE produced from acid has various functions in vivo (J. Vascul).
ar Research, Vol. 32, p. 79 (1995)). So far 20
-HETE has been shown to shrink or dilate microvessels and induce cell proliferation in major organs such as kidneys and cerebral blood vessels, and plays important physiological actions in vivo, as well as various renal diseases, It has been suggested that it is deeply involved in pathological conditions such as cerebrovascular diseases and cardiovascular diseases (J. Vasc
ular Research, Vol. 32, p. 79 (1995), Am. J. Physiol.,
Volume 277, R607 (1999), etc.).
【０００３】[0003]
【発明が解決しようとする課題】本発明は２０−ＨＥＴ
Ｅの産生を阻害し、２０−ＨＥＴＥが関連する疾患を治
療することの可能な薬剤を提供することを目的としてい
る。The present invention relates to a 20-HET.
An object of the present invention is to provide an agent capable of inhibiting the production of E and treating a disease associated with 20-HETE.
【０００４】[0004]
【課題を解決するための手段】本発明者らは前記課題を
解決する目的で鋭意探索研究した結果、ある種のヒドロ
キシホルムアミジン化合物が２０−ＨＥＴＥの産生を阻
害することを見出し、本発明を完成した。すなわち、本
発明は、下記式Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a certain hydroxyformamidine compound inhibits the production of 20-HETE. completed. That is, the present invention provides the following formula
【化２】 （式中、Ｘ1〜Ｘ4は、それぞれ独立して、少なくとも１
つは窒素原子、酸素原子又は硫黄原子であり；ｎは０〜
４のうちの任意の整数であり；Ｒは、独立して、各々同
一あるいは相異なって、Ｃ1〜Ｃ6アルキル基、Ｃ3〜Ｃ6
シクロアルキル基、アリール基、アリールＣ1〜Ｃ4アル
キル基、ハロゲン原子、シアノ基、Ｃ1〜Ｃ6アルキルチ
オ基、Ｃ1〜Ｃ6アルキルスルホニル基、アリールスルホ
ニル基、カルバモイル基、Ｃ1〜Ｃ6アルコキシカルボニ
ル基、チエニル基、フリル基、キノリルチオ基又はベン
ゾジオキセパニル基を示し；或いは、ｎ≧２の場合に、
隣接するＲは一緒になって、酸素原子、窒素原子又は硫
黄原子からなる群から選択されるヘテロ原子を含んでも
よい環を形成することができる）で表されるヒドロキシ
ホルムアミジン化合物又はその製薬学的に許容される塩
である。Embedded image (Wherein X 1 to X 4 are each independently at least 1
One is a nitrogen atom, an oxygen atom or a sulfur atom;
R is any of the same or different and is independently a C 1 -C 6 alkyl group, a C 3 -C 6
Cycloalkyl group, aryl group, aryl C 1 -C 4 alkyl group, halogen atom, cyano group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfonyl group, arylsulfonyl group, carbamoyl group, C 1 -C 6 represents an alkoxycarbonyl group, a thienyl group, a furyl group, a quinolylthio group or a benzodioxepanyl group; or, when n ≧ 2,
Adjacent R may together form a ring which may contain a heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom or a sulfur atom) or a pharmaceutical preparation thereof. It is an acceptable salt.
【０００５】上記式で表される化合物では、前記ヘテロ
原子を含んでもよい環が飽和又は不飽和の５〜８員環を
形成し、また、Ｘ1〜Ｘ4を含む環がチアゾール環、ピラ
ゾール環、チオフェン環、フラン環、イソキサゾール
環、トリアゾール環又はチアジアゾール環を形成するこ
とが好ましい。これらの環は、一緒になって、ベンゾチ
アゾール環、ベンゾイミダゾール環、４，５，６，７−
テトラヒドロベンゾ［ｂ］チオフェン環、シクロペンタ
［ｂ］チオフェン環又はシクロヘプタ［ｂ］チオフェン
環を形成することができる。なお、前記ベンゾチアゾー
ル環又はベンゾイミダゾール環上の少なくとも１つの水
素原子がＣ1〜Ｃ4アルキル基又はＣ1〜Ｃ4アルコキシ基
で置換されていることが好ましい。In the compound represented by the above formula, the ring which may contain a hetero atom forms a saturated or unsaturated 5- to 8-membered ring, and the ring containing X 1 to X 4 is a thiazole ring or a pyrazole ring. It is preferable to form a ring, a thiophene ring, a furan ring, an isoxazole ring, a triazole ring or a thiadiazole ring. These rings together form a benzothiazole ring, a benzimidazole ring, 4,5,6,7-
A tetrahydrobenzo [b] thiophene ring, a cyclopenta [b] thiophene ring, or a cyclohepta [b] thiophene ring can be formed. It is preferable that at least one hydrogen atom on the benzothiazole ring or benzimidazole ring is substituted by C 1 -C 4 alkyl or C 1 -C 4 alkoxy group.
【０００６】前記Ｒが独立してアリール基、アリールス
ルホニル基、キノリルチオ基又はチエニル基のいずれか
を意味する場合は、当該基のアリール環又はチオフェン
環上の少なくとも１つの水素原子が、Ｃ1〜Ｃ6アルキル
基、ニトロ基又はハロゲン原子で置換されていることが
好ましい。アリール基としてはフェニル基が好ましい。When R independently represents any one of an aryl group, an arylsulfonyl group, a quinolylthio group and a thienyl group, at least one hydrogen atom on the aryl ring or thiophene ring of the group is a C 1 to C 1 It is preferably substituted with a C 6 alkyl group, nitro group or halogen atom. As the aryl group, a phenyl group is preferable.
【０００７】上記式［化２］の範疇に含まれる具体的な
化合物のうち、特に好ましいものは、Ｎ−（５−クロロ
チアゾール−２−イル）−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−（２−エチルチオ−１，３，４−チアジアゾ
ール−５−イル）−Ｎ′−ヒドロキシホルムアミジン、
Ｎ−（４−ブロモ−５−メチルイソキサゾール−３−イ
ル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（４−ブ
ロモ−３−メチルピラゾール−５−イル）−Ｎ′−ヒド
ロキシホルムアミジン、Ｎ−（４−ブロモ−１−メチル
ピラゾール−５−イル）−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−（４−ブロモピラゾール−３−イル）−Ｎ′
−ヒドロキシホルムアミジン、Ｎ−（２−カルバモイル
チオフェン−３−イル）−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−（５，６−ジメチルベンゾチアゾール−２−
イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（３−
（４−クロロフェニルスルホニルチオフェン−４−イ
ル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（３−フ
ェニルスルホニルチオフェン−４−イル）−Ｎ′−ヒド
ロキシホルムアミジン、Ｎ−（２，３−ジメトキシカル
ボニルチオフェン−４−イル）−Ｎ′−ヒドロキシホル
ムアミジン、Ｎ−（３−イソプロピルスルホニル−２−
メチルチオチオフェン−４−イル）−Ｎ′−ヒドロキシ
ホルムアミジン、Ｎ−（５，６−ジメチルベンゾイミダ
ゾール−２−イル）−Ｎ′−ヒドロキシホルムアミジ
ン、Ｎ−（３−エトキシカルボニル−４，５，６，７−
テトラヒドロベンゾチオフェン−２−イル）−Ｎ′−ヒ
ドロキシホルムアミジン、Ｎ−（３−フェニルピラゾー
ル−５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ
−（４−ｔ−ブチルチアゾール−２−イル）−Ｎ′−ヒ
ドロキシホルムアミジン、Ｎ−［３−（チオフェン−２
−イル）ピラゾール−５−イル］−Ｎ′−ヒドロキシホ
ルムアミジン、Ｎ−（５−ブロモ−４−ｔ−ブチルチア
ゾール−２−イル）−Ｎ′−ヒドロキシホルムアミジ
ン、Ｎ−［３−（フラン−２−イル）ピラゾール−５−
イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−［３−
（４−クロロフェニル）ピラゾール−５−イル］−Ｎ′
−ヒドロキシホルムアミジン、Ｎ−［５−（２′−ブロ
モ−５′−チエニル）チアゾール−２−イル］−Ｎ′−
ヒドロキシホルムアミジン、Ｎ−（４−ブロモ−３−フ
ェニルピラゾール−５−イル）−Ｎ′−ヒドロキシホル
ムアミジン、Ｎ−（１−メチル−３−ｔ−ブチルピラゾ
ール−５−イル）−Ｎ′−ヒドロキシホルムアミジン、
Ｎ−（２−メトキシカルボニル−５−ｔ−ブチルチオフ
ェン−３−イル）−Ｎ′−ヒドロキシホルムアミジン、
Ｎ−（２−カルバモイル−５−ｔ−ブチルチオフェン−
３−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（５−メチルピラゾール−３−イル）−Ｎ′−ヒドロキ
シホルムアミジン、Ｎ−（４−ブロモ−５−フェニルピ
ラゾール−３−イル）−Ｎ′−ヒドロキシホルムアミジ
ン、Ｎ−［５−（フラン−２−イル）ピラゾール−３−
イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−［３−
（４−メチルフェニル）ピラゾール−５−イル］−Ｎ′
−ヒドロキシホルムアミジン、Ｎ−（３−エトキシカル
ボニル−シクロペンタ［ｂ］チオフェン−２−イル）−
Ｎ′−ヒドロキシホルムアミジン、Ｎ−（５−フェニル
ピラゾール−３−イル）−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−（３−エトキシカルボニル−シクロヘプタ
［ｂ］チオフェン−２−イル）−Ｎ′−ヒドロキシホル
ムアミジン、Ｎ−（４−エトキシカルボニル−１−フェ
ニルピラゾール−５−イル）−Ｎ′−ヒドロキシホルム
アミジン、Ｎ−（４−エトキシカルボニル−１−メチル
ピラゾール−５−イル）−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−［１−（４−フルオロフェニル）−４−エト
キシカルボニルピラゾール−５−イル］−Ｎ′−ヒドロ
キシホルムアミジン、Ｎ−（５−エトキシカルボニル−
４−フェニルチアゾール−２−イル）−Ｎ′−ヒドロキ
シホルムアミジン、Ｎ−［４−（４−クロロフェニル）
チアゾール−２−イル］−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−［４−（４−ブロモフェニル）チアゾール−
２−イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
［１−（４−クロロフェニル）−４−シアノピラゾール
−５−イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
［３−（４−クロロフェニル）−１−メチルピラゾール
−５−イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（４−シアノ−３−メチルチオ−１−フェニルピラゾー
ル−５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ
−［２−（７−クロロキノリルチオ）−１，３，４−チ
アジアゾール−５−イル］−Ｎ′−ヒドロキシホルムア
ミジン、Ｎ−［２−シアノ−５−（４−フルオロフェニ
ル）チオフェン−３−イル］−Ｎ′−ヒドロキシホルム
アミジン、Ｎ−［２−（４−イソブチルフェニル）−５
−メトキシカルボニルチオフェン−４−イル］−Ｎ′−
ヒドロキシホルムアミジン、Ｎ−（５−ベンゾジオキセ
パニルチアゾール−２−イル）−Ｎ′−ヒドロキシホル
ムアミジン、Ｎ−［５−（４−ニトロフェニルスルホニ
ル）チアゾール−２−イル］−Ｎ′−ヒドロキシホルム
アミジン、Ｎ−（２−メトキシカルボニルチオフェン−
３−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
［４−（ナフタレン−２−イル）チアゾール−２−イ
ル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−［１−メ
チル−３−（４−ｔ−ブチルフェニル）ピラゾール−５
−イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−［２
−（４−フルオロフェニル）−５−メトキシカルボニル
チオフェン−４−イル］−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−（２−メトキシカルボニル−５−フェニルチ
オフェン−３−イル）−Ｎ′−ヒドロキシホルムアミジ
ン、Ｎ−（１，３−ジフェニルピラゾール−５−イル）
−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（１−ベンジ
ルベンゾイミダゾール−２−イル）−Ｎ′−ヒドロキシ
ホルムアミジン、Ｎ−［４−（ナフタレン−１−イル）
チアゾール−２−イル］−Ｎ′−ヒドロキシホルムアミ
ジン、Ｎ−（４−シアノ−２，３−ジフェニルフラン−
５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（３−メチルイソキサゾール−５−イル）−Ｎ′−ヒド
ロキシホルムアミジン、Ｎ−（５−メチルイソキサゾー
ル−３−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ
−（３−フェニル−１，２，４−チアジアゾール−５−
イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（４−
メトキシベンゾチアゾール−２−イル）−Ｎ′−ヒドロ
キシホルムアミジン、Ｎ−（４−メチルベンゾチアゾー
ル−２−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ
−（１−エチルピラゾール−５−イル）−Ｎ′−ヒドロ
キシホルムアミジン、Ｎ−（３−メチルイソチアゾール
−５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（４，５−ジメチルチアゾール−２−イル）−Ｎ′−ヒ
ドロキシホルムアミジン、Ｎ−（４−メチルチアゾール
−２−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（イソキサゾール−３−イル）−Ｎ′−ヒドロキシホル
ムアミジン、Ｎ−（３，４−ジメチルイソキサゾール−
５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（２−シクロプロピル−１，３，４−チアジアゾール−
５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
（２−メトキシカルボニルフラン−５−イル）−Ｎ′−
ヒドロキシホルムアミジン、Ｎ−（３−エトキシカルボ
ニル−４−メチルチオフェン−２−イル）−Ｎ′−ヒド
ロキシホルムアミジン、Ｎ−（２−メトキシカルボニル
−４−メチルチオフェン−３−イル）−Ｎ′−ヒドロキ
シホルムアミジン、Ｎ−（１，３，５−トリメチルピラ
ゾール−４−イル）−Ｎ′−ヒドロキシホルムアミジ
ン、Ｎ−（３−シクロプロピル−１−メチルピラゾール
−５−イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−
［１−メチル−３−（２′−チエニル）ピラゾール−５
−イル］−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（１
−メチルピラゾール−２−イル）−Ｎ′−ヒドロキシホ
ルムアミジン、Ｎ−（５−メチルチアゾール−２−イ
ル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（３−メ
トキシカルボニルチオフェン−４−イル）−Ｎ′−ヒド
ロキシホルムアミジン、Ｎ−（ベンゾチアゾール−２−
イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（１，
３−ジメチルピラゾール−５−イル）−Ｎ′−ヒドロキ
シホルムアミジン、Ｎ−［１−（４−メチルフェニル）
−３−メチルピラゾール−５−イル］−Ｎ′−ヒドロキ
シホルムアミジン、Ｎ−（３−メチル−１−フェニルピ
ラゾール−５−イル）−Ｎ′−ヒドロキシホルムアミジ
ン、Ｎ−（１−フェニルピラゾール−５−イル）−Ｎ′
−ヒドロキシホルムアミジン、Ｎ−（１−メチル−３−
フェニルピラゾール−５−イル）−Ｎ′−ヒドロキシホ
ルムアミジン、Ｎ−（３−シクロプロピル−１−フェニ
ルピラゾール−５−イル）−Ｎ′−ヒドロキシホルムア
ミジン、Ｎ−（１−メチルベンゾイミダゾール−２−イ
ル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（４−フ
ェニルチアゾール−２−イル）−Ｎ′−ヒドロキシホル
ムアミジン、Ｎ−［４−（４−メチルフェニル）チアゾ
ール−２−イル］−Ｎ′−ヒドロキシホルムアミジン、
Ｎ−（２−エチル−１，３，４−チアジアゾール−５−
イル）−Ｎ′−ヒドロキシホルムアミジン、Ｎ−（５−
ｔ−ブチルイソキサゾール−３−イル）−Ｎ′−ヒドロ
キシホルムアミジン、及び、Ｎ−（２−ｔ−ブチル−
１，３，４−チアジアゾール−５−イル）−Ｎ′−ヒド
ロキシホルムアミジンである。Of the specific compounds included in the category of the above formula [2], particularly preferred are N- (5-chlorothiazol-2-yl) -N'-hydroxyformamidine and N- (2 -Ethylthio-1,3,4-thiadiazol-5-yl) -N'-hydroxyformamidine,
N- (4-bromo-5-methylisoxazol-3-yl) -N'-hydroxyformamidine, N- (4-bromo-3-methylpyrazol-5-yl) -N'-hydroxyformamidine, N- (4-bromo-1-methylpyrazol-5-yl) -N'-hydroxyformamidine, N- (4-bromopyrazol-3-yl) -N '
-Hydroxyformamidine, N- (2-carbamoylthiophen-3-yl) -N'-hydroxyformamidine, N- (5,6-dimethylbenzothiazole-2-
Yl) -N'-hydroxyformamidine, N- (3-
(4-chlorophenylsulfonylthiophen-4-yl) -N'-hydroxyformamidine, N- (3-phenylsulfonylthiophen-4-yl) -N'-hydroxyformamidine, N- (2,3-dimethoxycarbonylthiophene) -4-yl) -N'-hydroxyformamidine, N- (3-isopropylsulfonyl-2-
Methylthiothiophen-4-yl) -N'-hydroxyformamidine, N- (5,6-dimethylbenzimidazol-2-yl) -N'-hydroxyformamidine, N- (3-ethoxycarbonyl-4,5, 6,7-
Tetrahydrobenzothiophen-2-yl) -N'-hydroxyformamidine, N- (3-phenylpyrazol-5-yl) -N'-hydroxyformamidine, N
-(4-t-butylthiazol-2-yl) -N'-hydroxyformamidine, N- [3- (thiophen-2
-Yl) pyrazol-5-yl] -N'-hydroxyformamidine, N- (5-bromo-4-t-butylthiazol-2-yl) -N'-hydroxyformamidine, N- [3- (furan -2-yl) pyrazole-5-
Yl] -N'-hydroxyformamidine, N- [3-
(4-Chlorophenyl) pyrazol-5-yl] -N '
-Hydroxyformamidine, N- [5- (2'-bromo-5'-thienyl) thiazol-2-yl] -N'-
Hydroxyformamidine, N- (4-bromo-3-phenylpyrazol-5-yl) -N'-hydroxyformamidine, N- (1-methyl-3-t-butylpyrazol-5-yl) -N'- Hydroxyformamidine,
N- (2-methoxycarbonyl-5-t-butylthiophen-3-yl) -N'-hydroxyformamidine;
N- (2-carbamoyl-5-t-butylthiophene-
3-yl) -N'-hydroxyformamidine, N-
(5-methylpyrazol-3-yl) -N'-hydroxyformamidine, N- (4-bromo-5-phenylpyrazol-3-yl) -N'-hydroxyformamidine, N- [5- (furan- 2-yl) pyrazole-3-
Yl] -N'-hydroxyformamidine, N- [3-
(4-Methylphenyl) pyrazol-5-yl] -N '
-Hydroxyformamidine, N- (3-ethoxycarbonyl-cyclopenta [b] thiophen-2-yl)-
N'-hydroxyformamidine, N- (5-phenylpyrazol-3-yl) -N'-hydroxyformamidine, N- (3-ethoxycarbonyl-cyclohepta [b] thiophen-2-yl) -N'-hydroxy Formamidine, N- (4-ethoxycarbonyl-1-phenylpyrazol-5-yl) -N'-hydroxyformamidine, N- (4-ethoxycarbonyl-1-methylpyrazol-5-yl) -N'-hydroxy Formamidine, N- [1- (4-fluorophenyl) -4-ethoxycarbonylpyrazol-5-yl] -N'-hydroxyformamidine, N- (5-ethoxycarbonyl-
4-phenylthiazol-2-yl) -N'-hydroxyformamidine, N- [4- (4-chlorophenyl)
Thiazol-2-yl] -N'-hydroxyformamidine, N- [4- (4-bromophenyl) thiazole-
2-yl] -N'-hydroxyformamidine, N-
[1- (4-Chlorophenyl) -4-cyanopyrazol-5-yl] -N'-hydroxyformamidine, N-
[3- (4-chlorophenyl) -1-methylpyrazol-5-yl] -N'-hydroxyformamidine, N-
(4-cyano-3-methylthio-1-phenylpyrazol-5-yl) -N'-hydroxyformamidine, N
-[2- (7-chloroquinolylthio) -1,3,4-thiadiazol-5-yl] -N'-hydroxyformamidine, N- [2-cyano-5- (4-fluorophenyl) thiophene- 3-yl] -N'-hydroxyformamidine, N- [2- (4-isobutylphenyl) -5
-Methoxycarbonylthiophen-4-yl] -N'-
Hydroxyformamidine, N- (5-benzodioxepanylthiazol-2-yl) -N'-hydroxyformamidine, N- [5- (4-nitrophenylsulfonyl) thiazol-2-yl] -N'- Hydroxyformamidine, N- (2-methoxycarbonylthiophene-
3-yl) -N'-hydroxyformamidine, N-
[4- (Naphthalen-2-yl) thiazol-2-yl] -N'-hydroxyformamidine, N- [1-methyl-3- (4-t-butylphenyl) pyrazole-5
-Yl] -N'-hydroxyformamidine, N- [2
-(4-Fluorophenyl) -5-methoxycarbonylthiophen-4-yl] -N'-hydroxyformamidine, N- (2-methoxycarbonyl-5-phenylthiophen-3-yl) -N'-hydroxyformamidine , N- (1,3-diphenylpyrazol-5-yl)
-N'-hydroxyformamidine, N- (1-benzylbenzimidazol-2-yl) -N'-hydroxyformamidine, N- [4- (naphthalen-1-yl)
Thiazol-2-yl] -N'-hydroxyformamidine, N- (4-cyano-2,3-diphenylfuran-
5-yl) -N'-hydroxyformamidine, N-
(3-methylisoxazol-5-yl) -N'-hydroxyformamidine, N- (5-methylisoxazol-3-yl) -N'-hydroxyformamidine, N
-(3-Phenyl-1,2,4-thiadiazole-5-
Yl) -N'-hydroxyformamidine, N- (4-
Methoxybenzothiazol-2-yl) -N'-hydroxyformamidine, N- (4-methylbenzothiazol-2-yl) -N'-hydroxyformamidine, N
-(1-ethylpyrazol-5-yl) -N'-hydroxyformamidine, N- (3-methylisothiazol-5-yl) -N'-hydroxyformamidine, N-
(4,5-dimethylthiazol-2-yl) -N'-hydroxyformamidine, N- (4-methylthiazol-2-yl) -N'-hydroxyformamidine, N-
(Isoxazol-3-yl) -N'-hydroxyformamidine, N- (3,4-dimethylisoxazole-
5-yl) -N'-hydroxyformamidine, N-
(2-cyclopropyl-1,3,4-thiadiazole-
5-yl) -N'-hydroxyformamidine, N-
(2-methoxycarbonylfuran-5-yl) -N'-
Hydroxyformamidine, N- (3-ethoxycarbonyl-4-methylthiophen-2-yl) -N'-hydroxyformamidine, N- (2-methoxycarbonyl-4-methylthiophen-3-yl) -N'- Hydroxyformamidine, N- (1,3,5-trimethylpyrazol-4-yl) -N'-hydroxyformamidine, N- (3-cyclopropyl-1-methylpyrazol-5-yl) -N'-hydroxy Formamidine, N-
[1-Methyl-3- (2'-thienyl) pyrazole-5
-Yl] -N'-hydroxyformamidine, N- (1
-Methylpyrazol-2-yl) -N'-hydroxyformamidine, N- (5-methylthiazol-2-yl) -N'-hydroxyformamidine, N- (3-methoxycarbonylthiophen-4-yl)- N'-hydroxyformamidine, N- (benzothiazole-2-
Yl) -N'-hydroxyformamidine, N- (1,
3-dimethylpyrazol-5-yl) -N'-hydroxyformamidine, N- [1- (4-methylphenyl)
-3-methylpyrazol-5-yl] -N'-hydroxyformamidine, N- (3-methyl-1-phenylpyrazol-5-yl) -N'-hydroxyformamidine, N- (1-phenylpyrazole- 5-yl) -N '
-Hydroxyformamidine, N- (1-methyl-3-
Phenylpyrazol-5-yl) -N'-hydroxyformamidine, N- (3-cyclopropyl-1-phenylpyrazol-5-yl) -N'-hydroxyformamidine, N- (1-methylbenzimidazole-2) -Yl) -N'-hydroxyformamidine, N- (4-phenylthiazol-2-yl) -N'-hydroxyformamidine, N- [4- (4-methylphenyl) thiazol-2-yl] -N '-Hydroxyformamidine,
N- (2-ethyl-1,3,4-thiadiazole-5
Yl) -N'-hydroxyformamidine, N- (5-
t-butylisoxazol-3-yl) -N'-hydroxyformamidine and N- (2-t-butyl-
1,3,4-thiadiazol-5-yl) -N'-hydroxyformamidine.
【０００８】上記の化合物又はその製薬学的に許容され
る塩は、それらを有効成分とする医薬として使用するこ
とが好ましく、具体的には、２０−ヒドロキシエイコサ
テトラエン酸産生阻害剤として、或いは、腎疾患、脳血
管疾患又は循環器疾患治療薬として使用することが好ま
しい。The above-mentioned compound or a pharmaceutically acceptable salt thereof is preferably used as a medicament containing them as an active ingredient. Specifically, as a 20-hydroxyeicosatetraenoic acid production inhibitor, Alternatively, it is preferably used as a therapeutic agent for renal disease, cerebrovascular disease or cardiovascular disease.
【０００９】本発明において使用される用語が以下に定
義される。本発明において、「Ｃn〜Ｃm」とは、その後
に続く基がｎ〜ｍ個の炭素原子を有することを示す。The terms used in the present invention are defined below. In the present invention, “C n -C m ” indicates that the following group has nm carbon atoms.
【００１０】Ｃ1〜Ｃ6アルキル基は、炭素原子を１〜６
個有する直鎖状又は分岐鎖状のアルキル基を示し、例え
ばメチル基、エチル基、プロピル基、イソプロピル基、
ブチル基、イソブチル基、ｔ−ブチル基、ペンチル基、
イソペンチル基、ヘキシル基、イソヘキシル基などであ
る。A C 1 -C 6 alkyl group has 1 to 6 carbon atoms.
Represents a linear or branched alkyl group having, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group, t-butyl group, pentyl group,
And isopentyl, hexyl, and isohexyl groups.
【００１１】Ｃ3〜Ｃ6シクロアルキル基は、炭素原子を
３〜６個有する環状アルキル基を示し、例えばシクロプ
ロピル基、シクロペンチル基、シクロヘキシル基などで
ある。The C 3 -C 6 cycloalkyl group is a cyclic alkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclopentyl group and a cyclohexyl group.
【００１２】アリール基は、フェニル基、ナフチル基等
であり、好ましくはフェニル基である。アリールＣ1〜
Ｃ6アルキル基は、少なくとも１つ以上のアリール基、
好ましくはフェニル基、で置換された、炭素原子を１〜
６個有する直鎖状又は分岐鎖状のアルキル基を示し、例
えばベンジル基、ジフェニルメチル基、１−フェニルエ
チル基、２−フェニルエチル基などである。The aryl group is a phenyl group, a naphthyl group or the like, and is preferably a phenyl group. Aryl C 1-
A C 6 alkyl group is at least one or more aryl groups;
A phenyl group, preferably substituted with 1 to 1 carbon atoms
It represents a linear or branched alkyl group having six, such as a benzyl group, a diphenylmethyl group, a 1-phenylethyl group, and a 2-phenylethyl group.
【００１３】ハロゲン原子は、フッ素原子、塩素原子、
臭素原子又はヨウ素原子である。A halogen atom is a fluorine atom, a chlorine atom,
It is a bromine atom or an iodine atom.
【００１４】Ｃ1〜Ｃ6アルキルチオ基は、炭素原子を１
〜６個有する直鎖状又は分岐鎖状のアルキルチオ基を指
し、例えば、メチルチオ基、エチルチオ基、プロピルチ
オ基、イソプロピルチオ基、ブチルチオ基、イソブチル
チオ基、ｔ−ブチルチオ基、ペンチルチオ基、イソペン
チルチオ基などである。A C 1 -C 6 alkylthio group has one carbon atom.
Refers to a linear or branched alkylthio group having up to six, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, t-butylthio, pentylthio, isopentylthio And the like.
【００１５】Ｃ1〜Ｃ6アルキルスルホニル基は、スルホ
ニル基（−ＳＯ2−）とＣ1〜Ｃ6アルキル基が複合した
形態を有しており、例えば、−ＳＯ2−メチル基、−Ｓ
Ｏ2−エチル基、−ＳＯ2−イソプロピル基などが挙げら
れる。[0015] C 1 -C 6 alkylsulfonyl group, a sulfonyl group (-SO 2 -) and C 1 -C 6 alkyl group has a structure composed of, for example, -SO 2 - methyl, -S
O 2 - ethyl, -SO 2 - and an isopropyl group.
【００１６】アリールスルホニル基は、スルホニル基
（−ＳＯ2−）とアリール基が複合した形態を有してお
り、例えば、−ＳＯ2−フェニル基、−ＳＯ2−ナフチル
基などが挙げられる。The arylsulfonyl group is a sulfonyl group (-SO 2 -) and the aryl group has a structure composed of, for example, -SO 2 - phenyl group, -SO 2 - and a naphthyl group.
【００１７】Ｃ1〜Ｃ6アルコキシカルボニル基は、Ｃ1
〜Ｃ6アルコキシ基とカルボニル基（−Ｃ＝Ｏ）が複合
した形態を有している。ここで、Ｃ1〜Ｃ6アルコキシ基
は、炭素原子を１〜６個有する直鎖状又は分岐鎖状のア
ルコキシ基を指し、例えば、メトキシ基、エトキシ基、
プロポキシ基、イソプロポキシ基、ブトキシ基、イソブ
トキシ基、ｔ−ブトキシ基、ペンチルオキシ基、イソペ
ンチルオキシ基などである。したがって、Ｃ1〜Ｃ6アル
コキシカルボニル基の例には、メトキシカルボニル基、
エトキシカルボニル基などが含まれる。[0017] C 1 -C 6 alkoxycarbonyl groups, C 1
It has a form in which a ＣC 6 alkoxy group and a carbonyl group (—C ＝ O) are combined. Here, the C 1 -C 6 alkoxy group refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group,
Examples include a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, a pentyloxy group and an isopentyloxy group. Thus, examples of C 1 -C 6 alkoxycarbonyl groups include a methoxycarbonyl group,
An ethoxycarbonyl group and the like are included.
【００１８】チエニル基は２−チエニル基及び３−チエ
ニル基を含み、同様に、フリル基は２−フリル基及び３
−フリル基を含む。キノリルチオ基はキノリル基とチオ
基（−Ｓ−）が複合した形態を有しており、例えば、４
−キノリルチオ基などが挙げられる。カルバモイル基は
−ＣＯＮＨ2基を指す。ベンゾジオキセパニル基はA thienyl group includes a 2-thienyl group and a 3-thienyl group, and similarly, a furyl group includes a 2-furyl group and a 3-thienyl group.
-Including a furyl group. The quinolylthio group has a form in which a quinolyl group and a thio group (-S-) are complexed.
-Quinolylthio group and the like. Carbamoyl group refers to -CONH 2 groups. Benzodioxepanyl group
【化３】 の化学構造を有する１価の基である。Embedded image Is a monovalent group having the chemical structure
【００１９】上記した各種の基は、その基上の少なくと
も１つの水素原子が、例えば、フッ素原子、塩素原子、
臭素原子、ヨウ素原子といったハロゲン原子；ニトロ
基；アミノ基；ヒドロキシル基；チオール基；ホルミル
基；カルボキシル基；シアノ基；カルバモイル基；メチ
ル基、エチル基、プロピル基、イソプロピル基、ブチル
基、イソブチル基、sec-ブチル基、tert-ブチル基、ペ
ンチル基、イソペンチル基、ネオペンチル基、tert-ペ
ンチル基等のアルキル基；フェニル基、ナフチル基、ビ
フェニル、アントラニル基等のアリール基；ピロリル
基、ピリジル基、チエニル基等の複素環基；メトキシカ
ルボニル基、エトキシカルボニル基等のアルコキシカル
ボニル基；アセチル基、ベンゾイル基等のアシル基；メ
トキシ基、エトキシ基、プロポキシ基等のアルコキシ
基；メチルチオ基、エチルチオ基、プロピルチオ基等の
アルキルチオ基；等の非水素原子又は基によって置換さ
れていてもよい。特に、炭素数が１〜６のアルキル基或
いはハロゲン原子による置換が好ましい。したがって、
例えば、４−イソプロピルフェニル基、４−メチルフェ
ニル基、４−ｔ−ブチルフェニル基、４−クロロフェニ
ル基、４−フルオロフェニル基、４−ブロモフェニル
基、４−クロロフェニルスルホニル基、４−ニトロフェ
ニルスルホニル基及び２−ブロモチエニル基なども上記
のいずれかの置換基の範囲に含まれる。なお、これらの
置換基中の炭素原子数は上記したｎ又はｍには含まれな
い。In the above various groups, at least one hydrogen atom on the group is, for example, a fluorine atom, a chlorine atom,
Halogen atom such as bromine atom and iodine atom; nitro group; amino group; hydroxyl group; thiol group; formyl group; carboxyl group; cyano group; carbamoyl group; methyl group, ethyl group, propyl group, isopropyl group, butyl group, and isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, alkyl group such as tert-pentyl group; phenyl group, naphthyl group, biphenyl, aryl group such as anthranyl group; pyrrolyl group, pyridyl group, A heterocyclic group such as a thienyl group; an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group; an acyl group such as an acetyl group and a benzoyl group; an alkoxy group such as a methoxy group, an ethoxy group and a propoxy group; a methylthio group and an ethylthio group; Non-hydrogen sources such as alkylthio groups such as propylthio groups; Or it may be substituted by group. Particularly, substitution with an alkyl group having 1 to 6 carbon atoms or a halogen atom is preferable. Therefore,
For example, 4-isopropylphenyl group, 4-methylphenyl group, 4-t-butylphenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-chlorophenylsulfonyl group, 4-nitrophenylsulfonyl Group and 2-bromothienyl group are also included in the range of any of the above substituents. The number of carbon atoms in these substituents is not included in n or m described above.
【００２０】更に、上記式［化２］において、隣接する
Ｒ基が一緒になって酸素原子、窒素原子又は硫黄原子か
らなる群から選択されるヘテロ原子を含んでもよい環を
形成する場合は当該環上の少なくとも１つの水素原子
が、上記の非水素原子又は基によって置換されてもよ
く、特にＣ1〜Ｃ4アルキル基又はＣ1〜Ｃ4アルコキシ基
による置換が好ましい。したがって、前記ヘテロ原子を
含んでもよい環が飽和又は不飽和の５〜８員環を形成す
る場合、並びに、Ｘ1〜Ｘ4を含む環と一緒になってベン
ゾチアゾール環、ベンゾイミダゾール環、４，５，６，
７−テトラヒドロ［ｂ］ベンゾチオフェン環、シクロペ
ンタ［ｂ］チオフェン環又はシクロヘプタ［ｂ］チオフ
ェン環を形成する場合についても、それらの環上の少な
くとも１つの水素原子が、上記の非水素原子又は基、好
ましくはＣ1〜Ｃ4アルキル基又はＣ1〜Ｃ4アルコキシ
基、によって置換されてもよく、例えば、５，６−ジメ
チルベンゾイミダゾール環、５，６−ジメチルベンゾチ
アゾール環及び４−メトキシベンゾチアゾール環を有す
る化合物も上記式［化２］の範疇に含まれる。Further, in the above formula [2], when adjacent R groups together form a ring which may contain a hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom or a sulfur atom, At least one hydrogen atom on the ring may be substituted by the above-mentioned non-hydrogen atom or group, particularly preferably a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group. Therefore, when the ring that may contain a hetero atom forms a saturated or unsaturated 5- to 8-membered ring, and together with a ring containing X 1 to X 4 , a benzothiazole ring, a benzimidazole ring, , 5,6
Also in the case of forming a 7-tetrahydro [b] benzothiophene ring, cyclopenta [b] thiophene ring or cyclohepta [b] thiophene ring, at least one hydrogen atom on those rings is the above-mentioned non-hydrogen atom or group, It may be preferably substituted by a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, for example, a 5,6-dimethylbenzimidazole ring, a 5,6-dimethylbenzothiazole ring and a 4-methoxybenzothiazole Compounds having a ring are also included in the above formula [Chemical Formula 2].
【００２１】また、製薬学的に許容される塩とは、アル
カリ金属類、アルカリ土類金属類、アンモニウム、アル
キルアンモニウムなどとの塩、鉱酸又は有機酸との塩で
あり、例えば、ナトリウム塩、カリウム塩、カルシウム
塩、アンモニウム塩、アルミニウム塩、トリエチルアン
モニウム塩、酢酸塩、プロピオン酸塩、酪酸塩、ぎ酸
塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、ク
エン酸塩、ステアリン酸塩、コハク酸塩、エチルコハク
酸塩、ラクトビオン酸塩、グルコン酸塩、グルコヘプト
ン酸塩、安息香酸塩、メタンスルホン酸塩、エタンスル
ホン酸塩、2−ヒドロキシエタンスルホン酸塩、ベンゼ
ンスルホン酸塩、パラトルエンスルホン酸塩、ラウリル
硫酸塩、リンゴ酸塩、アスパラギン酸塩、グルタミン酸
塩、アジピン酸塩、システインとの塩、Ｎ−アセチルシ
ステインとの塩、塩酸塩、臭化水素酸塩、リン酸塩、硫
酸塩、よう化水素酸塩、ニコチン酸塩、シュウ酸塩、ピ
クリン酸塩、チオシアン酸塩、ウンデカン酸塩、アクリ
ル酸ポリマーとの塩、カルボキシビニルポリマーとの塩
などを挙げることができる。The pharmaceutically acceptable salts include salts with alkali metals, alkaline earth metals, ammonium, alkylammonium, etc., and salts with mineral acids or organic acids, such as sodium salt. , Potassium, calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate , Succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluene Sulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, Salt with stain, salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate , Undecanoate, a salt with an acrylic acid polymer, a salt with a carboxyvinyl polymer, and the like.
【００２２】[0022]
【発明の実施の形態】本発明化合物は、例えば以下に示
す方法によって合成することができる。すなわち、本発
明の化合物は下記式（１ａ）BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention can be synthesized, for example, by the following method. That is, the compound of the present invention has the following formula (1a)
【化４】 （式中、Ｘ1〜Ｘ4、Ｒは上記と同じである）で示される
化合物を触媒量の酸あるいはアミン類の鉱酸塩の存在下
あるいは非存在下にオルト蟻酸エステルと反応した後生
成物を単離あるいは単離せずにヒドロキシルアミンで処
理することによって合成することができる。Embedded image Wherein X 1 to X 4 and R are the same as defined above, after reacting with a formic acid ester in the presence or absence of a catalytic amount of an acid or a mineral acid salt of an amine. The compound can be synthesized by treating the product with hydroxylamine without isolation or isolation.
【００２３】本発明に係る化合物並びにその製薬学的に
許容される塩は、経口又は非経口的に投与することがで
きる。その投与剤型は錠剤、カプセル剤、顆粒剤、散
剤、粉剤、トローチ剤、軟膏剤、クリーム剤、乳剤、懸
濁剤、坐剤、注射剤などであり、いずれも慣用の製剤技
術（例えば、第１２改正日本薬局方に規定する方法）に
よって製造することができる。これらの投与剤型は、患
者の症状、年齢及び治療の目的に応じて適宜選択するこ
とができる。各種剤型の製剤の製造においては、常用の
賦形剤（例えば、結晶セルロース、デンプン、乳糖、マ
ンニトールなど）、結合剤（例えば、ヒドロキシプロピ
ルセルロース、ポリビニルピロリドンなど）、滑沢剤
（例えば、ステアリン酸マグネシウム、タルクなど）、
崩壊剤（例えば、カルボキシメチルセルロースカルシウ
ムなど）などを用いることができる。The compound of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally. The dosage form is a tablet, capsule, granule, powder, powder, troche, ointment, cream, emulsion, suspension, suppository, injection, etc. (The method prescribed in the 12th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected depending on the condition, age and purpose of treatment of the patient. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose, mannitol, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, stearin Magnesium acid, talc, etc.),
Disintegrators (eg, calcium carboxymethyl cellulose) and the like can be used.
【００２４】本発明に係る化合物の投与量は、成人を治
療する場合で１日１〜２０００ｍｇであり、これを１日
１回又は数回に分けて投与する。この投与量は、患者の
年齢、体重及び症状によって適宜増減することができ
る。The dose of the compound according to the present invention is 1 to 2000 mg per day when treating an adult, and is administered once or several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.
【００２５】[0025]
【発明の効果】本発明に係る化合物又はその製薬学的に
許容される塩は２０−ＨＥＴＥ産生阻害作用を有し、ヒ
ト及び動物における２０−ＨＥＴＥが関わる疾病、例え
ば各種腎疾患、脳血管疾患、各種循環器疾患治療薬とし
て有用である。EFFECT OF THE INVENTION The compound according to the present invention or a pharmaceutically acceptable salt thereof has an inhibitory effect on 20-HETE production, and diseases associated with 20-HETE in humans and animals, such as various renal diseases and cerebrovascular diseases. It is useful as a therapeutic drug for various cardiovascular diseases.
【００２６】[0026]
【実施例】以下実施例を挙げて本発明を更に詳細に説明
する。 実施例１：N-(5-メトキシカルボニルフラン-2-イル)-
N′-ヒドロキシホルムアミジンの合成 2-アミノ-5-メトキシカルボニルフラン(0.933g)，オル
トギ酸エチル(2.33g)と酢酸エチル(10ml)の混合物を加
熱環流下４時間攪拌した後、過剰のオルトギ酸エチルを
留去した。残渣のメタノール溶液(10ml)に塩酸ヒドロキ
シルアミン(0.558g)とナトリウムメトキシド(0.44g)か
ら調製したヒドロキシルアミンのメタノール溶液(20ml)
を加え室温で18時間攪拌した。溶媒留去後残渣に酢酸エ
チルを加え水及び飽和食塩水で順次洗浄後無水硫酸マグ
ネシウムで乾燥した．溶媒を留去後た残渣をヘキサン：
酢酸エチル(4:1)で再結晶して無色粉末状の標題化合物
を得た(0.627g)。 融点 １５８.０〜１５８．５℃The present invention will be described in more detail with reference to the following examples. Example 1: N- (5-methoxycarbonylfuran-2-yl)-
Synthesis of N'-hydroxyformamidine A mixture of 2-amino-5-methoxycarbonylfuran (0.933 g), ethyl orthoformate (2.33 g) and ethyl acetate (10 ml) was stirred for 4 hours under reflux with heating, and then excess orthogidium was added. Ethyl acid was distilled off. Methanol solution of hydroxylamine (20 ml) prepared from hydroxylamine hydrochloride (0.558 g) and sodium methoxide (0.44 g) in a methanol solution of the residue (10 ml)
Was added and stirred at room temperature for 18 hours. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline in that order and dried over anhydrous magnesium sulfate. The residue obtained after distilling off the solvent is hexane:
Recrystallization from ethyl acetate (4: 1) gave the title compound as a colorless powder (0.627 g). 158.0-158.5 ° C
【００２７】実施例２：N-(5-メチルイソキサゾリル−
３−イル)-N′-ヒドロキシホルムアミジンの合成 2-アミノ-5-メトキシカルボニルフランの代わりに3-ア
ミノ-5-メチルイソキサゾールを用いて実施例１と同様
の操作を行うことによって標題化合物を得た。 融点 １８３．０〜１８３．５℃Example 2: N- (5-methylisoxazolyl-
Synthesis of 3-yl) -N'-hydroxyformamidine The title compound was obtained by performing the same operation as in Example 1 using 3-amino-5-methylisoxazole instead of 2-amino-5-methoxycarbonylfuran. The compound was obtained. 183.0-183.5 ° C
【００２８】実施例３：N-(3-イソキサゾリル)-N′-ヒ
ドロキシホルムアミジンの合成 2-アミノ-5-メトキシカルボニルフランの代わりに3-ア
ミノイソキサゾールを用いて実施例１と同様の操作を行
うことによって標題化合物を得た。 融点 １４９．５〜１５０．０℃Example 3 Synthesis of N- (3-isoxazolyl) -N'-hydroxyformamidine Same as Example 1 except that 3-aminoisoxazole was used instead of 2-amino-5-methoxycarbonylfuran. The title compound was obtained by performing the procedure. 149.5-150.0 ° C
【００２９】実施例４：N-(2-メトキシカルボニル-4-メ
チルチオフェン-3-イル)-N′-ヒドロキシホルムアミジ
ンの合成 2-アミノ-5-メトキシカルボニルフランの代わりに3-ア
ミノ-2-メトキシカルボニル-4-メチルチオフェンを用い
て実施例１と同様の操作を行うことによって標題化合物
を得た。 融点 １６４．５〜１６５．５℃Example 4: Synthesis of N- (2-methoxycarbonyl-4-methylthiophen-3-yl) -N'-hydroxyformamidine 3-amino-2 instead of 2-amino-5-methoxycarbonylfuran The title compound was obtained by performing the same operation as in Example 1 using -methoxycarbonyl-4-methylthiophene. Melting point 164.5-165.5 ° C
【００３０】実施例５：N-(4-t-ブチルチアゾール−２
−イル)-N′-ヒドロキシホルムアミジンの合成 2-アミノ-5-メトキシカルボニルフランの代わりに4-t-
ブチル-2-アミノチアゾールを用いて実施例１と同様の
操作を行うことによって標題化合物を得た。融点 １８
２．５〜１８３．０℃Example 5: N- (4-t-butylthiazole-2)
-Yl) -N'-Hydroxyformamidine Synthesis of 4-t- instead of 2-amino-5-methoxycarbonylfuran
The title compound was obtained by performing the same operation as in Example 1 using butyl-2-aminothiazole. Melting point 18
2.5-183.0 ° C
【００３１】実施例６〜８９：上記と同様に、各々対応
する出発原料を用いて実施例１と同様の反応操作を行
い、表１〜表１８に示す化合物を合成した。化合物６
８、５７、６５、７０及び１６として実施例１〜５で得
られた化合物も併せて示す。Examples 6 to 89: In the same manner as described above, the same operation as in Example 1 was carried out using the corresponding starting materials to synthesize the compounds shown in Tables 1 to 18. Compound 6
The compounds obtained in Examples 1 to 5 as 8, 57, 65, 70 and 16 are also shown.
【表１】 [Table 1]
【００３２】[0032]
【表２】 [Table 2]
【００３３】[0033]
【表３】 [Table 3]
【００３４】[0034]
【表４】 [Table 4]
【００３５】[0035]
【表５】 [Table 5]
【００３６】[0036]
【表６】 [Table 6]
【００３７】[0037]
【表７】 [Table 7]
【００３８】[0038]
【表８】 [Table 8]
【００３９】[0039]
【表９】 [Table 9]
【００４０】[0040]
【表１０】 [Table 10]
【００４１】[0041]
【表１１】 [Table 11]
【００４２】[0042]
【表１２】 [Table 12]
【００４３】[0043]
【表１３】 [Table 13]
【００４４】[0044]
【表１４】 [Table 14]
【００４５】[0045]
【表１５】 [Table 15]
【００４６】[0046]
【表１６】 [Table 16]
【００４７】[0047]
【表１７】 [Table 17]
【００４８】[0048]
【表１８】 [Table 18]
【００４９】試験例［ラット腎ミクロソーム由来２０−
ＨＥＴＥ産生酵素の阻害作用］上記表記載の化合物につ
いて、２０−ＨＥＴＥ産生阻害作用を試験した。本試験
はJ.Pharmacol.Exp.Ther.,第268巻,第474頁(1994)に記
載の方法に準拠して行った。被験薬を、５０ｍＭの３−
モルホリノプロパンスルホン酸(MOPS)（ｐＨ７.４）、
５ｍＭの塩化マグネシウム及び１ｍＭのエチレンジアミ
ンテトラアセティックアシド ジソディウムソルト(EDT
A)を含む組成の緩衝液に加えた後、酵素源として自然発
症高血圧ラット（オス，６週齢）の腎臓から調製したミ
クロソーム画分を、基質として[5,6,8,9,11,12,14,15]
トリチウム−アラキドン酸（アマシャム社製）及び補酵
素としてＮＡＤＰＨ（シグマ社製）を添加し３７度で
１.５時間反応させた。反応液にギ酸（和光純薬製）を
添加して反応を停止させた後、アセトニトリル（終濃度
５０％）を加えて１時間３０分室温で放置しＯＤＳカラ
ム（バイオシルＣ１８, バイオラッド社製）を装着した
放射性物質検出器付き高速液体クロマトグラフィー（ギ
ルソン社製）により２０−ＨＥＴＥの産生量を測定し
た。化合物無添加時の２０−ＨＥＴＥの産生量を１００
％とし、化合物を添加した時の２０−ＨＥＴＥ産生量か
ら、抑制率（％）を算出した。Test Example [rat kidney microsome-derived 20-
Inhibitory Effect of HETE-producing Enzyme] The compounds described in the above table were tested for their 20-HETE-producing inhibitory effect. This test was performed according to the method described in J. Pharmacol. Exp. Ther., Vol. 268, p. 474 (1994). The test drug was treated with 50 mM 3-
Morpholinopropanesulfonic acid (MOPS) (pH 7.4),
5 mM magnesium chloride and 1 mM ethylenediaminetetraacetic acid disodium salt (EDT
A microsomal fraction prepared from the kidney of a spontaneously hypertensive rat (male, 6 weeks old) was used as a source of enzyme after addition to a buffer having a composition containing A), and [5,6,8,9,11, 12,14,15]
Tritium-arachidonic acid (manufactured by Amersham) and NADPH (manufactured by Sigma) as a coenzyme were added and reacted at 37 ° C. for 1.5 hours. After the reaction was stopped by adding formic acid (manufactured by Wako Pure Chemical Industries, Ltd.) to the reaction solution, acetonitrile (final concentration: 50%) was added, and the mixture was allowed to stand at room temperature for 1 hour and 30 minutes. ODS column (Biosil C18, manufactured by Bio-Rad) The amount of 20-HETE produced was measured by high performance liquid chromatography with a radioactive substance detector equipped with (manufactured by Gilson). The production amount of 20-HETE when no compound was added was 100
%, And the inhibition rate (%) was calculated from the amount of 20-HETE produced when the compound was added.
【００５０】結果を上記表１〜１８に併せて示す。The results are shown in Tables 1 to 18 above.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 31/4155 Ａ６１Ｋ 31/4155 ４Ｃ０８６ 31/4184 31/4184 31/42 31/42 31/425 31/425 31/426 31/426 31/427 31/427 31/428 31/428 31/433 31/433 31/4709 31/4709 Ａ６１Ｐ 9/10 Ａ６１Ｐ 9/10 13/12 13/12 43/00 １１１ 43/00 １１１ Ｃ０７Ｄ 235/30 Ｃ０７Ｄ 235/30 Ａ Ｂ 261/14 261/14 275/03 277/46 277/46 277/82 277/82 307/66 285/135 333/38 307/66 333/68 333/38 333/78 333/68 333/80 333/78 407/04 333/80 409/04 407/04 417/04 409/04 417/12 417/04 285/12 Ｅ 417/12 275/02 (72)発明者 石井 孝明 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 小林 結子 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 天田 英明 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 Ｆターム(参考） 4C023 HA03 4C033 AD13 AD16 AD17 AD20 AE03 AE06 AE13 AE17 AE20 4C036 AD08 AD20 AD21 AD27 AD30 4C056 AA01 AB01 AC01 AD01 AE03 4C063 AA01 BB01 CC75 CC83 CC92 DD14 DD22 DD62 DD67 EE01 4C086 AA01 AA02 AA03 BA03 BA16 BB02 BB03 BC36 BC39 BC67 BC79 BC82 BC84 BC85 GA02 GA04 GA06 GA10 MA01 MA04 NA14 ZA36 ZA81 ZC20 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI theme coat ゛ (Reference) A61K 31/4155 A61K 31/4155 4C086 31/4184 31/4184 31/42 31/42 31/425 31/425 31/426 31/426 31/427 31/427 31/428 31/428 31/433 31/433 31/4709 31/4709 A61P 9/10 A61P 9/10 13/12 13/12 43/00 111 43 / 00 111 C07D 235/30 C07D 235/30 AB B 261/14 261/14 275/03 277/46 277/46 277/82 277/82 307/66 285/135 333/38 307/66 333/68 333 / 38 333/78 333/68 333/80 333/78 407/04 333/80 409/04 407/04 417/04 409/04 417/12 417/04 285/12 E 417/12 275/02 (72) Inventor Takaaki Ishii 3- 24-1, Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Yuko Kobayashi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. (72) Inventor Hideaki Amada Tokyo 3-24-1, Takada, Shima-ku Taisho Seiyaku Co., Ltd. F-term (reference) 4C023 HA03 4C033 AD13 AD16 AD17 AD20 AE03 AE06 AE13 AE17 AE20 4C036 AD08 AD20 AD21 AD27 AD30 4C056 AA01 AB01 AC01 AD01 AE03 4C063 AA83 CC DD14 DD22 DD62 DD67 EE01 4C086 AA01 AA02 AA03 BA03 BA16 BB02 BB03 BC36 BC39 BC67 BC79 BC82 BC84 BC85 GA02 GA04 GA06 GA10 MA01 MA04 NA14 ZA36 ZA81 ZC20
Claims (10)
つは窒素原子、酸素原子又は硫黄原子であり；ｎは０〜
４のうちの任意の整数であり；Ｒは、独立して、各々同
一あるいは相異なって、Ｃ1〜Ｃ6アルキル基、Ｃ3〜Ｃ6
シクロアルキル基、アリール基、アリールＣ1〜Ｃ4アル
キル基、ハロゲン原子、シアノ基、Ｃ1〜Ｃ6アルキルチ
オ基、Ｃ1〜Ｃ6アルキルスルホニル基、アリールスルホ
ニル基、カルバモイル基、Ｃ1〜Ｃ6アルコキシカルボニ
ル基、チエニル基、フリル基、キノリルチオ基又はベン
ゾジオキセパニル基を示し；或いは、ｎ≧２の場合に、
隣接するＲは一緒になって、酸素原子、窒素原子又は硫
黄原子からなる群から選択されるヘテロ原子を含んでも
よい環を形成することができる）で表されるヒドロキシ
ホルムアミジン化合物又はその製薬学的に許容される
塩。[Claim 1] The formula: (Wherein X 1 to X 4 are each independently at least 1
One is a nitrogen atom, an oxygen atom or a sulfur atom;
R is any of the same or different and is independently a C 1 -C 6 alkyl group, a C 3 -C 6
Cycloalkyl group, aryl group, aryl C 1 -C 4 alkyl group, halogen atom, cyano group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfonyl group, arylsulfonyl group, carbamoyl group, C 1 -C 6 represents an alkoxycarbonyl group, a thienyl group, a furyl group, a quinolylthio group or a benzodioxepanyl group; or, when n ≧ 2,
Adjacent R may together form a ring which may contain a heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom or a sulfur atom) or a pharmaceutical preparation thereof. Acceptable salts.
又は不飽和の５〜８員環である、請求項１記載の化合物
又はその製薬学的に許容される塩。2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ring which may contain a hetero atom is a saturated or unsaturated 5- to 8-membered ring.
ゾール環、チオフェン環、フラン環、イソキサゾール
環、トリアゾール環又はチアジアゾール環である、請求
項１又は２記載の化合物又はその製薬学的に許容される
塩。3. The compound according to claim 1 or 2, wherein the ring containing X 1 to X 4 is a thiazole ring, a pyrazole ring, a thiophene ring, a furan ring, an isoxazole ring, a triazole ring or a thiadiazole ring. Acceptable salts.
記Ｘ1〜Ｘ4を含む環が、一緒になって、ベンゾチアゾー
ル環、ベンゾイミダゾール環、４，５，６，７−テトラ
ヒドロ［ｂ］ベンゾチオフェン環、シクロペンタ［ｂ］
チオフェン環又はシクロヘプタ［ｂ］チオフェン環を形
成する、請求項２又は３記載の化合物又はその製薬学的
に許容される塩。4. The ring which may contain a hetero atom and the ring which contains X 1 to X 4 together form a benzothiazole ring, a benzimidazole ring, 4,5,6,7-tetrahydro [b]. Benzothiophene ring, cyclopenta [b]
The compound according to claim 2 or 3, which forms a thiophene ring or a cyclohepta [b] thiophene ring, or a pharmaceutically acceptable salt thereof.
ダゾール環上の少なくとも１つの水素原子がＣ1〜Ｃ4ア
ルキル基又はＣ1〜Ｃ4アルコキシ基で置換されている、
請求項４記載の化合物又はその製薬学的に許容される
塩。5. At least one hydrogen atom on the benzothiazole ring or benzimidazole ring is substituted with a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group,
A compound according to claim 4 or a pharmaceutically acceptable salt thereof.
ール基、アリールスルホニル基、キノリルチオ基又はチ
エニル基であって、かつ、当該基のアリール環又はチオ
フェン環上の少なくとも１つの水素原子が、Ｃ1〜Ｃ6ア
ルキル基、ニトロ基又はハロゲン原子で置換されてい
る、請求項１記載の化合物又はその製薬学的に許容され
る塩。6. Independently, at least one R is an aryl group, an arylsulfonyl group, a quinolylthio group or a thienyl group, and at least one hydrogen atom on the aryl ring or the thiophene ring of the group is C 1 -C 6 alkyl group, substituted with a nitro group or a halogen atom, a compound or a pharmaceutically acceptable salt thereof according to claim 1.
ル基である、請求項１記載の化合物又はその製薬学的に
許容される塩。7. The compound according to claim 1, wherein at least one R is a phenyl group, or a pharmaceutically acceptable salt thereof.
物又はその製薬学的に許容される塩を有効成分とする医
薬。8. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
物又はその製薬学的に許容される塩を有効成分とする２
０−ヒドロキシエイコサテトラエン酸産生阻害剤。9. An active ingredient comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
0-Hydroxyeicosatetraenoic acid production inhibitor.
合物又はその製薬学的に許容される塩を有効成分とする
腎疾患、脳血管疾患又は循環器疾患治療薬。10. A remedy for renal disease, cerebrovascular disease or cardiovascular disease, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000180474A JP2001354658A (en) | 2000-06-15 | 2000-06-15 | Hydroxyformamidine compound and its salt and medicine comprising the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000180474A JP2001354658A (en) | 2000-06-15 | 2000-06-15 | Hydroxyformamidine compound and its salt and medicine comprising the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2001354658A true JP2001354658A (en) | 2001-12-25 |
Family
ID=18681561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000180474A Pending JP2001354658A (en) | 2000-06-15 | 2000-06-15 | Hydroxyformamidine compound and its salt and medicine comprising the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2001354658A (en) |
Cited By (8)
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| WO2002088071A1 (en) * | 2001-04-26 | 2002-11-07 | Taisho Pharmaceutical Co., Ltd. | 20-hydroxyeicosatetraenoic acid production inhibitors |
| WO2003022821A1 (en) * | 2001-09-06 | 2003-03-20 | Taisho Pharmaceutical Co., Ltd. | Heterocycle derivative having 20-hete-producing enzyme inhibitory activity |
| WO2004058753A1 (en) | 2002-05-06 | 2004-07-15 | Vertex Pharmaceuticals Incorporated | Thiadiazoles or oxadiazoles and their use as inhibitors of jak protein kinase |
| US7288566B2 (en) | 2002-09-12 | 2007-10-30 | Taisho Pharmaceutical Co., Ltd. | N-hydroxyformamidine derivatives |
| US7985769B2 (en) | 2001-06-11 | 2011-07-26 | Vertex Pharmaceuticals Incorporated | Compounds and methods for the treatment or prevention of Flavivirus infections |
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| US8329924B2 (en) | 2001-06-11 | 2012-12-11 | Vertex Pharmaceuticals (Canada) Incorporated | Compounds and methods for the treatment or prevention of Flavivirus infections |
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2000
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7214714B2 (en) | 2001-04-26 | 2007-05-08 | Taisho Pharmaceutical Co. Ltd. | 20-hydroxyeicosatetraenoic acid production inhibitors |
| WO2002088071A1 (en) * | 2001-04-26 | 2002-11-07 | Taisho Pharmaceutical Co., Ltd. | 20-hydroxyeicosatetraenoic acid production inhibitors |
| US8329924B2 (en) | 2001-06-11 | 2012-12-11 | Vertex Pharmaceuticals (Canada) Incorporated | Compounds and methods for the treatment or prevention of Flavivirus infections |
| US7985769B2 (en) | 2001-06-11 | 2011-07-26 | Vertex Pharmaceuticals Incorporated | Compounds and methods for the treatment or prevention of Flavivirus infections |
| WO2003022821A1 (en) * | 2001-09-06 | 2003-03-20 | Taisho Pharmaceutical Co., Ltd. | Heterocycle derivative having 20-hete-producing enzyme inhibitory activity |
| US7271179B2 (en) | 2002-05-06 | 2007-09-18 | Vertex Pharmaceuticals Incorporated | Inhibitors of JAK protein kinase |
| EP2316834A1 (en) * | 2002-05-06 | 2011-05-04 | Vertex Pharmaceuticals Incorporated | Thiadiazoles or oxadiazoles and their use as inhibitors of JAK protein kinase |
| JP4681302B2 (en) * | 2002-05-06 | 2011-05-11 | バーテックス ファーマシューティカルズ インコーポレイテッド | Thiadiazole or oxadiazole and their use as inhibitors of JAK protein kinase |
| WO2004058753A1 (en) | 2002-05-06 | 2004-07-15 | Vertex Pharmaceuticals Incorporated | Thiadiazoles or oxadiazoles and their use as inhibitors of jak protein kinase |
| JP2006513192A (en) * | 2002-05-06 | 2006-04-20 | バーテックス ファーマシューティカルズ インコーポレイテッド | Thiadiazole or oxadiazole and their use as inhibitors of JAK protein kinase |
| US7288566B2 (en) | 2002-09-12 | 2007-10-30 | Taisho Pharmaceutical Co., Ltd. | N-hydroxyformamidine derivatives |
| US8357718B2 (en) | 2002-12-10 | 2013-01-22 | Vertex Pharmaceuticals (Canada) Incorporated | Compounds and methods for the treatment or prevention of flavivirus infections |
| US8829030B2 (en) | 2002-12-10 | 2014-09-09 | Vertex Pharmaceuticals (Canada) Incorporated | Compounds and methods for the treatment or prevention of Flavivirus infections |
| US8003685B2 (en) | 2006-11-15 | 2011-08-23 | Vertex Pharmaceuticals (Canada) Incorporated | Thiophene analogues for the treatment or prevention of flavivirus infections |
| US8269014B2 (en) | 2006-11-15 | 2012-09-18 | Vertex Pharmaceuticals (Canada) Incorporated | Thiophene analogues for the treatment or prevention of flavivirus infections |
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