JP2004010513A - Imidazole derivative - Google Patents
Imidazole derivative Download PDFInfo
- Publication number
- JP2004010513A JP2004010513A JP2002163980A JP2002163980A JP2004010513A JP 2004010513 A JP2004010513 A JP 2004010513A JP 2002163980 A JP2002163980 A JP 2002163980A JP 2002163980 A JP2002163980 A JP 2002163980A JP 2004010513 A JP2004010513 A JP 2004010513A
- Authority
- JP
- Japan
- Prior art keywords
- group
- alkyl
- alkoxy
- formula
- substituted
- 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.)
- Withdrawn
Links
- 150000002460 imidazoles Chemical class 0.000 title claims abstract description 11
- -1 1-phenyl-2-propynyl group Chemical group 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- NNDIXBJHNLFJJP-UHFFFAOYSA-N 20-Hydroxyeicosatetraenoic acid Chemical compound OCCCCCC=CCC=CCC=CCC=CCCCC(O)=O NNDIXBJHNLFJJP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000000532 dioxanyl group Chemical group 0.000 claims description 9
- 125000005879 dioxolanyl group Chemical group 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
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000006267 biphenyl group Chemical group 0.000 claims description 3
- 229940125532 enzyme inhibitor Drugs 0.000 claims description 3
- 239000002532 enzyme inhibitor Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 8
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 2
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 abstract description 9
- 108090000790 Enzymes Proteins 0.000 abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- 210000003734 kidney Anatomy 0.000 abstract description 5
- 210000004204 blood vessel Anatomy 0.000 abstract description 3
- 230000002490 cerebral effect Effects 0.000 abstract description 3
- 210000000056 organ Anatomy 0.000 abstract description 3
- 230000010261 cell growth Effects 0.000 abstract 1
- 230000010339 dilation Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 150000001448 anilines Chemical class 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 238000001816 cooling Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- CYKCUAPYWQDIKR-UHFFFAOYSA-N 4-(1h-imidazol-1-yl)phenol Chemical class C1=CC(O)=CC=C1N1C=NC=C1 CYKCUAPYWQDIKR-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 3
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- GMTFWFRCTPYXAW-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-methylimidazole Chemical compound C1=CC(OC)=CC=C1N1C(C)=NC=C1 GMTFWFRCTPYXAW-UHFFFAOYSA-N 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 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
- LJPLOQIJTWHHOM-UHFFFAOYSA-N 4-(2-methylimidazol-1-yl)phenol Chemical compound CC1=NC=CN1C1=CC=C(O)C=C1 LJPLOQIJTWHHOM-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KYQXXNZONRTCAC-UHFFFAOYSA-N Cl.C1=CC(CCC)=CC=C1N1C=NC=C1 Chemical compound Cl.C1=CC(CCC)=CC=C1N1C=NC=C1 KYQXXNZONRTCAC-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 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
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 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
- 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000005181 nitrobenzenes Chemical class 0.000 description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical class O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- IABMLFHMYWXZPC-UHFFFAOYSA-J titanium(4+);toluene;tetrachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Ti+4].CC1=CC=CC=C1 IABMLFHMYWXZPC-UHFFFAOYSA-J 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- SXLHAMYMTUEALX-UHFFFAOYSA-N (4-methoxyphenoxy)boronic acid Chemical compound COC1=CC=C(OB(O)O)C=C1 SXLHAMYMTUEALX-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- DIVNKPFJAVQFJM-UHFFFAOYSA-N 1-(4-butoxyphenyl)-2-methylimidazole Chemical compound C1=CC(OCCCC)=CC=C1N1C(C)=NC=C1 DIVNKPFJAVQFJM-UHFFFAOYSA-N 0.000 description 1
- LFONVJDFVSWSEH-UHFFFAOYSA-N 1-(4-propoxyphenyl)imidazole Chemical compound C1=CC(OCCC)=CC=C1N1C=NC=C1 LFONVJDFVSWSEH-UHFFFAOYSA-N 0.000 description 1
- OMDXZWUHIHTREC-UHFFFAOYSA-N 1-[2-(dimethylamino)ethoxy]ethanol Chemical compound CC(O)OCCN(C)C OMDXZWUHIHTREC-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-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
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 description 1
- RZPSWTNPBLYCCK-UHFFFAOYSA-N 2-[2-(4-imidazol-1-ylphenoxy)ethoxy]-N,N-dimethylethanamine Chemical compound C1=CC(OCCOCCN(C)C)=CC=C1N1C=NC=C1 RZPSWTNPBLYCCK-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000006049 2-methyl-2-pentenyl group Chemical group 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])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
- OAPDPORYXWQVJE-UHFFFAOYSA-N 4-propylaniline Chemical compound CCCC1=CC=C(N)C=C1 OAPDPORYXWQVJE-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- WOPARNADUHOTNV-UHFFFAOYSA-N C1=CC(CCC)=CC=C1N1C=NC=C1 Chemical compound C1=CC(CCC)=CC=C1N1C=NC=C1 WOPARNADUHOTNV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- RGUKBIDYUXXROT-UHFFFAOYSA-N [2-(1h-imidazol-2-yl)phenyl]-phenylmethanone Chemical class C=1C=CC=C(C=2NC=CN=2)C=1C(=O)C1=CC=CC=C1 RGUKBIDYUXXROT-UHFFFAOYSA-N 0.000 description 1
- NYRAVIYBIHCEGB-UHFFFAOYSA-N [K].[Ca] Chemical compound [K].[Ca] NYRAVIYBIHCEGB-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 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
- 239000011230 binding agent Substances 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 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
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 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
- 239000003054 catalyst Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- LWJYMKDMGMOTSB-UHFFFAOYSA-L dichlorotin;hydrate Chemical compound O.Cl[Sn]Cl LWJYMKDMGMOTSB-UHFFFAOYSA-L 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000007884 disintegrant Substances 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
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 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
- 229940015043 glyoxal Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 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
- 230000001939 inductive effect Effects 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
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 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
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)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
- 239000010410 layer Substances 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 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
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 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
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 210000002569 neuron Anatomy 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
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000002071 phenylalkoxy group Chemical group 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
- 229910000073 phosphorus hydride Inorganic materials 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
- 125000004193 piperazinyl group Chemical group 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 238000003756 stirring Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository 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
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 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
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 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
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-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 class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、アラキドン酸から生合成される２０−ヒドロキシエイコサテトラエン酸（２０−ＨＥＴＥ）の産生酵素を阻害するイミダゾール誘導体に関する。
【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、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ロイコトリエン類が広く知られている。しかし、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。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． Ｖａｓｃｕｌａｒ Ｒｅｓｅａｒｃｈ，第３２巻，第７９頁， １９９５年、Ａｍ． Ｊ． Ｐｈｙｓｉｏｌ．，第２７７巻， Ｒ６０７頁，１９９９年、Ｐｈｙｓｉｏｌ． Ｒｅｖ．，第８２巻，第１３１項，２００２年）。
【０００３】
また、本発明の化合物と類似した構造を有する化合物が多数報告されている。例えば、式（１）においてＲ２が置換Ｃ１〜Ｃ４アルキル基である誘導体がニトリックオキシド合成酵素阻害活性を有すると報告されている（国際特許公開ＷＯ９７１５５５５号明細書）。式（１）においてＲ２が置換アルカノイル基である誘導体が脳神経細胞死抑制効果を有すると報告されている（国際特許公開ＷＯ９４１８１７２号明細書）。また、式（１）においてＲ２が置換フェニルアルコキシ基である誘導体が抗高脂血症または動脈硬化に有効であると報告されている（国際特許公開ＷＯ９５２９１６３号明細書）。そして、式（１）においてＲ２が置換アルコキシ基である誘導体が抗不整脈、抗高血圧または高虚血治療剤として有効であると報告されている（ヨーロッパ特許公開ＥＰ０３０６４４０号明細書、米国特許ＵＳ５２０２３４６号明細書）。しかし、いずれにおいても２０−ＨＥＴＥ産生酵素阻作用を有することについては報告されていない。
【０００４】
一方、イミダゾリルベンゾフェノン誘導体が２０−ＨＥＴＥ産生酵素阻作用を示すことを報告されていが（国際特許公開ＷＯ０１６８６１０号明細書）、活性あるいは物性は必ずしも満足できるものではない。
【０００５】
【発明が解決しようとする課題】
本発明は、腎臓、脳血管等の主要臓器における微小血管収縮又は拡張、或いは、細胞増殖惹起等に関与する２０−ＨＥＴＥの産生を阻害する薬剤を提供することを目的としている。
【０００６】
【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、ある特異な部分構造を有する芳香族化合物、特に様々な置換基を有する１−（４−置換フェニル）−１Ｈ−イミダゾール誘導体が意外にも選択的に２０−ＨＥＴＥの産生酵素の阻害作用を有することを見出し、本発明を完成した。
【０００７】
すなわち、本発明は、下記式（１）
【０００８】
【化３】
｛式中、Ｑは水素原子またはＣ１〜Ｃ４アルキル基であり、Ｒ１は、水素原子、Ｃ１〜Ｃ６アルキル基、ハロゲン原子であり、Ｒ２はＣ１〜Ｃ１４アルキル基、Ｃ２〜Ｃ１４アルカノイル基、モルホリノ基又は式Ｒ３−Ｏ−［式中、Ｒ３は、Ｃ１〜Ｃ１４アルキル基、Ｃ２〜Ｃ１４アルケニル基、Ｃ３〜Ｃ１４アルキニル基、Ｃ３〜Ｃ１０シクロアルキル基、１−フェニル−２−プロピニル基又は式Ｒ４−Ａ−（式中、Ｒ４はＣ３〜Ｃ１０シクロアルキル基、Ｃ１〜Ｃ１０アルコキシ基、Ｃ２〜Ｃ１０アルカノイル基、Ｃ２〜Ｃ６アルコキシカルボニル基、ジオキソラニル基、Ｃ１〜Ｃ６アルキル基で置換されたジオキソラニル基、オキサニル基、ジオキサニル基、Ｃ１〜Ｃ６アルキル基で置換されたジオキサニル基、ベンゾジオキサニル基、ビシクロ［２．２．１］ヘプタン−２−イル基、Ｃ１〜Ｃ６アルキルチオ基、ピロリジニル基、Ｃ１〜Ｃ６アルキル基で置換されたピロリジニル基、ピペリジニル基、Ｃ１〜Ｃ６アルキル基で置換されたピペリジニル基、モルホリノ基、４−Ｃ２〜Ｃ６アルコキシカルボニルピペラジン−１−イル基、ピロリル基、ピリジル基、Ｎ，Ｎ−ジＣ１〜Ｃ６アルキルアミノ基、Ｎ，Ｎ−ジＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルコキシ基、フェノキシ基、フェニル基、「Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルコキシ基、ハロゲン原子、フェニルエチル基、フェノキシ基、ニトリル及びメチルチオ基」から選ばれる基の１又は２個で置換されたフェニル基、ビフェニル基、フェニルチオ基、フリル基、チエニル基、チアゾリル基、Ｃ１〜Ｃ６アルキル基で置換されたチアゾリル基、トルイジノ基、Ｎ−Ｃ１〜Ｃ６アルキルトルイジノ基、ピロリドン−１−イル基であり、ＡはＣ１〜Ｃ１０アルキレン基である。）で示される基である。］で示される基である。｝で表されるイミダゾール誘導体又はその製薬学的に許容される塩を有効成分として含むことを特徴とする２０−ＨＥＴＥ産生酵素阻害剤である。
【００１０】
また、他の本発明は下記式（２）
【００１１】
【化４】
｛式中、Ｑ’は水素原子またはＣ１〜Ｃ４アルキル基であり、Ｒ１１は、水素原子、Ｃ１〜Ｃ６アルキル基、ハロゲン原子であり、Ｒ１２はモルホリノ基又は式Ｒ１３−Ｏ−［式中、Ｒ１３は、Ｃ３〜Ｃ１４アルキニル基、Ｃ３〜Ｃ１０シクロアルキル基、１−フェニル−２−プロピニル基又は式Ｒ１４−Ａ’−（式中、Ｒ１４はＣ３〜Ｃ１０シクロアルキル基、Ｃ１〜Ｃ１０アルコキシ基、Ｃ２〜Ｃ１０アルカノイル基、ジオキソラニル基、Ｃ１〜Ｃ６アルキル基で置換されたジオキソラニル基、オキサニル基、ジオキサニル基、Ｃ１〜Ｃ６アルキル基で置換されたジオキサニル基、ベンゾジオキサニル基、ビシクロ［２．２．１］ヘプタン−２−イル基、Ｃ１〜Ｃ６アルキルチオ基、４−Ｃ２〜Ｃ６アルコキシカルボニルピペラジン−１−イル基、ピロリル基、Ｎ，Ｎ−ジＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルコキシ基、フリル基、チエニル基、ピロリドン−１−イル基であり、Ａ’はＣ１〜Ｃ１０アルキレン基である。）で示される基である。］で示される基である。｝で表されるイミダゾール誘導体又はその製薬学的に許容される塩を提供するものである。
【００１３】
他の本発明は、上記のイミダゾール誘導体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を提供するものである。
他の本発明は、上記のイミダゾール誘導体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を提供するものである。
【００１４】
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、「Ｃｘ〜Ｃｙ」とは、その後に続く基がｘ〜ｙ個の炭素原子を有することを示す。
【００１５】
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り、好ましくはフッ素原子、塩素原子又は臭素原子であり、より好ましくはフッ素原子又は塩素原子である。
Ｃ１〜Ｃ１４アルキル基は、炭素原子を１〜１４個有する直鎖状又は分枝状のアルキル基を意味し、Ｃ１〜Ｃ８アルキル基が好ましい。Ｃ１〜Ｃ８アルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ヘキシル基、ｎ−ヘプチル基、ｎ−オクチル基、イソブチル基、ｓｅｃ−ブチル基、イソペンチル基、イソヘキシル基、３−メチルヘプチル基、３，３−ジメチルブチル基などがより好ましい
Ｃ３〜Ｃ１０シクロアルキル基は、炭素原子を３〜１０個有する環状アルキル基を意味し、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基などが挙げられる。中でも、シクロプロピル基、シクロペンチル基、シクロヘキシル基が好ましい。
【００１６】
Ｃ２〜Ｃ１４アルケニル基は、少なくとも１つの二重結合及び炭素原子を２〜１４個有する直鎖状又は分枝状のアルケニル基を意味し、例えば、エテニル基、プロペニル基、２−ブテニル基、３−メチル−２−ブテニル基、ペンテニル基、２−メチル−２−ペンテニル基、ヘキセニル基、２，４−ヘキサジエニル基、ヘプテニル基、オクテニル基、３，７−ジメチル−２，６−オクタジエニル基などが挙げられる。
Ｃ２〜Ｃ１４アルキニル基は、少なくとも１つの三重結合及び炭素原子を２〜６個有する直鎖状又は分枝状のアルキニル基を意味し、例えば、エチニル基、２−プロピニル基、ブチニル基、５−ペンチニル基、ヘキセニル基、ヘプチニル基、オクチニル基などが挙げられる。
【００１７】
Ｃ１〜Ｃ１０アルコキシ基は、炭素原子を１〜１０個有する直鎖状又は分枝状のアルコキシ基を意味し、Ｃ１〜Ｃ８アルコキシ基が好ましい。Ｃ１〜Ｃ８アルコキシ基としては、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、ｎ−ブトキシ基、イソブトキシ基、ｔｅｒｔ−ブトキシ基、ヘキシルオキシ基、ヘプチルオキシ基などが挙げられる。
【００１８】
Ｃ１〜Ｃ６アルコキシＣ１〜Ｃ６アルコキシ基は、Ｃ１〜Ｃ６アルコキシ基とＣ１〜Ｃ６アルコキシ基が複合した形態を有するものであり、Ｃ１〜Ｃ４アルコキシＣ１〜Ｃ４アルコキシ基が好ましい。中でも、メトキシエトキシ基、ｎ−ブトキシエトキシ基などがより好ましい。
Ｃ２〜Ｃ６アルコキシカルボニル基は、炭素原子を２〜５個有する直鎖状又は分枝状のアルコキシ基と１個のカルボニル基（−ＣＯ−）が複合した形態を有するものであり、Ｃ２〜Ｃ４アルコキシカルボニル基が好ましい。中でも、メトキシカルボニル基、エトキシカルボニル基などがより好ましい。
【００１９】
ジオキソラニル基は、ヘテロ原子として酸素原子を２個有する飽和五員環（ジオキソラン）、好ましくは１，３−ジオキソランの環から水素を除いて誘導される１価の基を意味する。
オキサニル基は、ヘテロ原子として酸素原子を１個有する飽和六員環の形態を有するもので、２−オキサニル基、３−オキサニル基を含む。
ジオキサニル基は、ヘテロ原子として酸素原子を２個有する飽和六員環（ジオキサン）、好ましくは１，３−ジオキサンの環から水素を除いて誘導される１価の基を意味する。Ｃ１〜Ｃ６アルキル基で置換されたジオキサニル基は、その基の環がＣ１〜Ｃ６アルキル基で置換されていてもよく、例えば５，５−ジメチル−１，３−ジオキサン−２−イル基などである。
【００２０】
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枝状のアルキル基と１個のチオ基（−Ｓ−）が複合した形態を有しており、Ｃ１〜Ｃ４アルキルチオ基が好ましい。例えば、メチルチオ基、エチルチオ基などがより好ましい。
【００２１】
ピロリジニル基は、ピロリジンの環状の窒素原子又は炭素原子上から水素原子を除いて誘導される１価の基を意味し、例えば、１−ピロリジニル基、２−ピロリジニル基、３−ピロリジニル基などが挙げられる。Ｃ１〜Ｃ６アルキル基で置換されたピロリジニル基は、その基上の少なくとも１つの水素原子がＣ１〜Ｃ６アルキル基、好ましくはＣ１〜Ｃ４アルキル基によって置換されたピロリジニル基であり、例えば、Ｎ−メチルピロリジン−２−イル基などが挙げられる。
ピペリジニル基は、ピペリジンの炭素原子上から水素原子を除いて誘導される１価の基を意味する。Ｃ１〜Ｃ６アルキル基で置換されたピペリジニル基は、その基の窒素原子がＣ１〜Ｃ６アルキル基によって置換されたピペリジニル基であり、例えば、Ｎ−メチルピペリジン−２−イル基、Ｎ−メチルピペリジン−３−イル基などが挙げられる。
４−Ｃ２〜Ｃ６アルコキシカルボニルピペラジン−１−イル基は、ピペラジンの４位の窒素原子がＣ２〜Ｃ６アルコキシカルボニル基で修飾され、１位の窒素原子上から水素原子を除いて誘導される１価の基を意味する。
モルホリノ基は、モルホリンの窒素原子上から水素原子を除いて誘導される１価の基を意味する。
【００２２】
フリル基は、２−フリル基、３−フリル基を含む。
チエニル基は、２−チエニルル基、３−チエニル基を含む。
チアゾリル基は、２−チアゾリル基、４−チアゾリル基、５−チアゾリル基を含む。また、Ｃ１〜Ｃ６アルキル基で置換されたチアゾリル基は、その環上の少なくとも１つの水素原子がＣ１〜Ｃ６アルキル、好ましくはＣ１〜Ｃ４アルキル基、より好ましくはメチル基によって置換されたチアゾリル基であり、例えば４−メチルチアゾール−５−イル基などが挙げられる。
ピリジル基は、２−ピリジル基、３−ピリジル基、４−ピリジル基を含む。 ピロリル基は、１−ピロリル基、２−ピロリル基、３−ピロリル基を含み、１−ピロリル基（Ｎ−ピロリル基）が好ましい。
【００２３】
Ｎ，Ｎ−ジＣ１〜Ｃ６アルキルアミノＣ１〜Ｃ６アルコキシ基は、Ｎ，Ｎ−ジＣ１〜Ｃ６アルキルアミノ基とＣ１〜Ｃ６アルコキシ基が複合した形態を有するものであり、例えば、Ｎ，Ｎ−ジエチルアミノエトキシ基などが挙げられる。
ピロリドン−１−イル基は２−ピロリドン−１−イル基、３−ピロリドン−１−イル基を含む。
【００２４】
Ａ及びＡ’で定義されるＣ１〜Ｃ１０アルキレン基は、炭素原子を１〜１０個有する直鎖状又は分枝状のアルキレン基を意味し、例えば、メチレン基、メチルメチレン基、エチレン基、プロピレン基、ヘプチレン基、２，２−ジメチルプロピレン基、ヘキシレン基などが挙げられる。
【００２５】
そして、上記した各種の基は、上記に挙げた置換された形態の他にも、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、ヨウ素原子等のハロゲン原子；ニトロ基；アミノ基；ヒドロキシ基；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、ビフェニル基、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。なお、これらの置換基中の炭素原子数は、上記したｘ又はｙには含まれない。
【００２６】
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。
【００２７】
【発明の実施の形態】
本発明化合物（１）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。
【００２８】
【化５】
製造法１； Ｊ． Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．，第２５巻，１６４９項（１９８８）を参照にアニリン誘導体（ａ）を酢酸または塩酸等の酸触媒の存在下或いは非存在下に、オルトギ酸トリメチル、オルトギ酸トリエチル等のオルトギ酸エステル類と、反応させ、イミノエーテル誘導体（ｂ）を得る。反応温度は室温から１５０℃、好ましくは７０〜１００℃で反応時間は２〜７２時間である。次に、イミノエーテル誘導体（ｂ）を適当な溶媒中（メタノール、エタノール、プロパノール、テトラヒドロフラン、ジオキサン、トルエン、塩化メチレン、クロロホルム、アセトニトリル、酢酸エチル、ジメチルスルホキシド、ジメチルホルムアミド等）アミノアセトアルデヒドジメチルアセタールと反応させホルムアミジン誘導体（ｃ）を得る。この時の反応温度は室温〜１５０℃、好ましくは７０〜１００℃であり、反応時間は２〜２４時間である。次に、ホルムアミジン誘導体（ｃ）を適当な溶媒中（エーテル、テトラヒドロフラン、ジメトキシエタン、ジオキサン等）にルイス酸あるいは酸触媒（四塩化チタン、トリフルオロボランエーテラート、酢酸等）の共存下反応させ、本発明化合物（１）を合成することができる（式中Ｒ１、Ｒ２は前記と同義である）。また、この方法で合成した本発明化合物（１）のＲ２を相互に変換することによって他の本発明化合物（１）に導くこともできる。
【００３０】
【化６】
製造法２；化合物（１）はアニリン誘導体（ａ）から直接合成することもできる。すなわち、アニリン誘導体とアンモニア、ホルムアルデヒド、そしてグリオキサールを１：１：１：１の比率で混合し水またはアルコール／水の混合溶媒中にて、反応温度は室温〜１５０℃、好ましくは７０〜１２０℃で反応することによって本発明化合物（１）を合成することができる（式中Ｒ１、Ｒ２は前記と同義である）。
【００３２】
【化７】
製造法３；合成中間体であるアニリン誘導体（ａ’）（Ｒ２が置換アルコキシ基すなわちＲ２＝Ｒ３Ｏを示す）を以下のようにして合成することができる。すなわち、ニトロベンゼン誘導体（ｄ）（式中Ｘはフッ素、塩素等の脱離基を示し、他の記号は前記と同義である）を適当な溶媒中（メタノール、エタノール、プロパノール、テトラヒドロフラン、ジオキサン、トルエン、塩化メチレン、クロロホルム、アセトニトリル、酢酸エチル、ジメチルスルホキシド、ジメチルホルムアミド等）必要に応じて塩基（トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン、炭酸カリウム、炭酸カルシウム、炭酸セシウム、水素化ナトリウム、ナトリウムメトキシド、ｔ−ブトキシカリウム等）の存在下、対応する種々のアルコール類と反応し化合物（ｅ）を製造することができる。この時反応温度は０℃〜８０℃、好ましくは０℃〜室温で、反応時間は１〜１２時間、好ましくは１〜２時間である。次に、化合物（ｅ）を適当な溶媒中（メタノール、エタノール、プロパノール、テトラヒドロフラン、ジオキサン、トルエン、塩化メチレン、クロロホルム、アセトニトリル、酢酸エチル等）、還元剤（パラジウム活性炭／水素雰囲気下、パラジウム活性炭／ヒドラジン水和物、パラジウム活性炭／ぎ酸アンモニウム、塩化スズ（ＩＩ）１水和物、鉄／塩化アンモニウム、ラネーニッケル／ヒドラジン水和物等、好ましくはパラジウム活性炭／水素雰囲気下）を用いてニトロ基を還元することでアニリン誘導体（ａ’）を製造することができる。反応温度は室温〜１５０℃、好ましくは室温〜１００℃で、反応時間は１時間〜２４時間である。
【００３４】
【化８】
製造法４；化合物（１）は中間体（ｈ）を経て以下の様にして製造することができる。フェニルボロン酸またはハロゲン化フェニル誘導体（ｆ）（式中ＹはＢ（ＯＨ）２またはハロゲン原子を表し、その他の記号は前記と同義である）を適当な溶媒中（メタノール、エタノール、プロパノール、テトラヒドロフラン、ジオキサン、トルエン、塩化メチレン、クロロホルム、アセトニトリル、酢酸エチル、ジメチルスルホキシド、ジメチルホルムアミド等）で銅触媒（［Ｃｕ（ＯＨ）ＴＭＥＤＡ］２Ｃｌ２、（ＣｕＯＴｆ）２ｂｅｎｚｅｎｅ等）存在下、好ましくは酸素雰囲気下でイミダゾール誘導体と縮合し中間体（ｇ）を製造することができる［Ｏｒｇａｎｉｃ Ｌｅｔｔ．，第２巻，１２３７項（２０００）］。反応温度は室温が好ましく、反応時間は１２〜２４時間である。次いで、中間体（ｇ）を４８％臭化水素中１００℃〜１５０℃で反応し中間体化合物（ｈ）を製造することができる。反応時間は１２時間〜７２時間、好ましくは１２時間〜２４時間である。
【００３６】
【化９】
次に、４−（イミダゾール−１−イル）−フェノール誘導体（ｈ）と対応する種々のアルコールを光延反応（Ｏｒｇ． Ｒｅａｃｔｉｏｎｓ，第４２巻，第３３５項）を利用し製造することができる。すなわち、化合物（ｈ）を適当な溶媒（テトラヒドロフラン、ジオキサン、トルエン、塩化メチレン、クロロホルム、アセトニトリル、酢酸エチル、ジメチルスルホキシド、ジメチルホルムアミド等）中で、ホスフィン試薬（トリフェニルホスフィン、トリブチルホスフィンやジフェニル−２−ピリジルホスフィン等）、ジアゾ試薬（ジエチルアゾジカルボキシレートやジ−ｔｅｒｔ−ブチルアゾジカルボキシレート等）、及び対応する種々のアルコール類とを、０℃〜室温、好ましくは室温にて２〜１２時間反応し、本発明化合物（１）（式中記号は前記と同意義である。）を製造することができる。或いは、種々のハロゲン化アルキル類（Ｒ３Ｘ、Ｘはハロゲンを表し、その他の記号は前記と同義である）と、適当な溶媒（アセトン、ジメチルホルムアミド、テトラヒドロフラン、エーテル等）中適当な塩基（トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン、炭酸カリウム、炭酸カルシウム、炭酸セシウム、水素化ナトリウム、ナトリウムメトキシド、ｔ−ブトキシカリウム等）の存在下、で、０℃〜室温、好ましくは室温にて２〜２４時間反応し、Ｒ２がＲ３Ｏである本発明化合物（１）を製造することができる。
【００３８】
本発明化合物及び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１４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。
【００３９】
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。
【００４０】
【発明の効果】
本発明に係る化合物及びその製薬学的に許容される塩は、優れた２０−ＨＥＴＥ産生阻害作用を有し、溶解度などの物性的にも優れるものである。従って、本発明に係る化合物は、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。
【００４１】
【実施例】
以下、実施例を挙げて本発明を更に詳しく説明する。
実施例１
１−［４−プロピルフェニル］−イミダゾール塩酸（化合物１０８）の製造
４−プロピルアニリン （２．０３ｇ， ０．０１５０ｍｏｌ）とオルトギ酸トリエチル （４．９９ｇ， ０．３３７ｍｏｌ）の混合物を１００℃で７時間攪拌した。室温に冷却した後に、反応液にメタノール （１５ｍＬ）とアミノアセトアルデヒドジメチルアセタール（５．６９ｇ， ０．０５４１ｍｏｌ）を加え、室温にて３０分攪拌し、さらに１００℃で４時間攪拌した。室温に冷却した後に、反応液を濃縮して得られた残査にジメトキシエタン（２０ｍＬ）と１Ｍ四塩化チタン−トルエン溶液 （２１ｍＬ， ０．０２１ｍｏｌ）を加え室温にて１時間さらに加熱還流下で４時間攪拌した。室温に冷却した後に、反応液に水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸マグネシウムで乾燥し、濃縮した。得られた残査をシリカゲルクロマトグラフィー（クロロホルム−メタノール＝９７：３）で精製し１−［４−プロピルフェニル］−イミダゾール （２．０ｇ）を褐色油状物として得た。生成物に４Ｎ塩酸−酢酸エチル溶液を加え、酢酸エチル−クロロホルムの混合溶媒から再結晶し、無色粉末状の標題化合物 （１．３８ｇ， ４１．２％）を得た。融点１５５．５−１５７．０℃
【００４２】
実施例２
｛２−［２−（４−イミダゾール−１−イル−フェノキシ）−エトキシ］−エチル｝−ジメチルアミン２塩酸（化合物１１６）の製造
水素化ナトリウム （６０％ ｏｉｌ， １．０ｇ， ０．２６ｍｏｌ）のジメチルホルムアミド （３．０ｍｌ）懸濁液に氷冷下、Ｎ，Ｎ−ジメチルアミノエチルオキシエタノール （２．３ｇ， ０．２６ｍｏｌ）のジメチルホルムアミド溶液 （５ｍｌ）を滴下し、１０分間攪拌した。この反応混合物に４−フルオロニトロベンゼン （３ｇ， ０．０２１ｍｏｌ）のジメチルホルムアミド溶液 （１０ｍＬ）を滴下し、室温にて２時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水洗浄後、ＭｇＳＯ４乾燥し、減圧下濃縮しジメチル−｛２−［２−（４−ニトロフェノキシ）−エトキシ］−エチル｝アミン （５．９ｇ）を得た。上記で得た化合物をメタノール （１００ｍＬ）に溶解し、１０％パラジウム活性炭 （０．６ｇ）を加え、水素雰囲気下で室温にて３時間攪拌した。ＴＬＣ分析により原料の消失を確認した後に、セライトを用いて不溶物を濾過し、濾液を濃縮してアニリン誘導体 （５．０ｇ）を褐色油状物として得た。次に、このアニリン誘導体にオルトギ酸トリエチル （１０ｍＬ， ０．０６０ｍｏｌ）を加えて１００℃で２０時間攪拌した。室温に冷却した後に、反応液にメタノール（８０ｍＬ）とアミノアセトアルデヒドジメチルアセタール （６．８ｍＬ， ０．０６３ｍｏｌ）を加え、１００℃で１．５時間攪拌した。反応液を濃縮して得られた残査にジメトキシエタン （３０ｍＬ）と１Ｍ四塩化チタン−トルエン溶液 （２５ｍＬ， ０．０２５ｍｏｌ）を加え加熱還流下で５時間攪拌した。室温に冷却した後に、反応液に水酸化ナトリウム水溶液を加えた。析出した不溶物を濾過した後に濾液を酢酸エチルで抽出した。有機層を飽和食塩水洗浄後、硫酸マグネシウムで乾燥し、濃縮した。得られた残査をＮＨ型シリカゲルクロマトグラフィー（ヘキサン−酢酸エチル＝１：２）で精製し ｛２−［２−（４−イミダゾール−１−イル−フェノキシ）−エトキシ］−エチル｝−ジメチルアミン（０．４０ｇ， ６．９％）を油状物として得た。生成物をエーテルに溶解し、４Ｍ塩酸−酢酸エチル溶液を加え、濃縮して析出した粉末を酢酸エチルで洗い、標題化合物を得た （４２８ｍｇ）。融点１７４．０−１７９．０℃
【００４３】
実施例３
１−［４−プロピルオキシフェニル］−イミダゾールトルエンスルホネート（化合物９４）の製造
４−（イミダゾール−１−イル）フェノール （１．０ｇ， ６．２５ｍｍｏｌ）、プロパノール （５６３ｍｇ， ９．３８ｍｍｏｌ）、トリフェニルホスフィン （２．４６ｇ， ９．３８ｍｍｏｌ）及びテトラヒドロフラン （２０ｍＬ）の混合物にジエチルアゾジカルボキシレート（１．４８ｍＬ， ９．３８ｍｍｏｌ）を加え、室温にて６時間攪拌した。反応混合物を濃縮した後に、酢酸エチル（４０ｍＬ）を加え、１Ｍ塩酸（２０ｍＬ）で抽出した。水層を５Ｍ水酸化ナトリウムで中和した後に、酢酸エチルで抽出した。有機層を飽和食塩水洗浄後、硫酸マグネシウムで乾燥し、濃縮した。得られた残査をＮＨ型シリカゲルクロマトグラフィー（ヘキサン−酢酸エチル＝１：２）で精製し１−［４−プロピルオキシフェニル］−１Ｈ−イミダゾール （１．１７ｇ， ９２％）を無色油状物として得た。これをエタノールに溶解しｐ−トルエンスルホン酸１水和物 （１．１ｇ， ５．７８ｍｍｏｌ）のエタノール溶液を加え析出した結晶を濾過し、無色粉末状の標題化合物 （１．９８ｇ， ８５％）を得た。融点１４８．０−１５０．０℃
【００４４】
実施例４
１−［４−ブトキシフェニル］−２−メチル−イミダゾールトルエンスルホネート（化合物１１７）の製造
（１）４−メトキシフェニルボレート （３．７ｇ， ２４．４ｍｍｏｌ）と１−Ｈ−２−メチルイミダゾール （１．０ｇ， １２．２ｍｍｏｌ）、塩化メチレン （４８ｍＬ）の混合物に、［Ｃｕ（ＯＨ）ＴＭＥＤＡ］２Ｃｌ２（０．５７ｇ， １．２２ｍｍｏｌ）を加え、酸素雰囲気下、室温にて１８時間攪拌した。反応混合物を濾過して不溶物を除いた後、濾液を濃縮した。得られた残査をＮＨ型シリカゲルクロマトグラフィー（ヘキサン−酢酸エチル＝４：１）で精製し、１−［４−メトキシフェニル］−２−メチル−イミダゾール （２．３５ｇ）を得た。
【００４５】
（２）１−［４−メトキシフェニル］−２−メチル−イミダゾール （２．０ｇ）と４８％臭化水素 （２０ｍＬ）の混合物を１００℃で１６時間反応した。反応液を室温に冷却した後に、６Ｍ水酸化ナトリウムで中和後析出した結晶を濾過し、４−（２−メチル−イミダゾール−１−イル）フェノール （０．７５ｇ， ４０％）を得た。
【００４６】
（３）４−（２−メチル−イミダゾール−１−イル）フェノール （０．２０ｇ， １．２ｍｍｏｌ）とジメチルホルムアミド （２ｍＬ）溶液に、１−イオド−ｎ−ブタン （０．２５ｇ， １．３８ｍｍｏｌ）と炭酸カリウム （０．１９ｇ， １．３８ｍｍｏｌ）を加え、室温で６４時間攪拌した。反応液に水を加え、ヘキサン−酢酸エチル＝１：１の混合溶媒で抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、濃縮した。得られた残査をＮＨ型シリカゲルクロマトグラフィー（ヘキサン−酢酸エチル＝４：１）で精製し、１−［４−ブトキシフェニル］−２−メチル−イミダゾール （０．１７ｇ， ６４％）を得た。これをエタノールに溶解しｐ−トルエンスルホン酸１水和物のエタノール溶液を加え、析出した結晶を濾過し、無色粉末状の標題化合物 （０．１８ｇ， ３９％）を得た。融点１４８．０−１４９．０℃
【００４７】
各々対応する出発原料を用いて実施例１〜４と同様な反応操作を行うことにより、表１に示す化合物を合成した。尚、表１には実施例１〜４で合成した化合物を併せて標記した。
【００４８】
【表１】
【表２】
【表３】
【表４】
【表５】
【表６】
【表７】
【表８】
【表９】
【表１０】
【表１１】
【表１２】
【表１３】
【表１４】
【表１５】
【表１６】
【表１７】
【表１８】
試験例［ヒ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。
ＤＭＳＯで１μＭに調製した被験薬溶液を、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ッドジソディウムソルト（ＥＤＴＡ）を含む５０ｍＭの３−モルホリノプロパンスルホン酸 （ＭＯＰＳ）（ｐＨ７．４）緩衝液に加え、酵素源としてヒト腎ミクロソーム画分（Ｈｕｍａｎ Ｃｅｌｌ Ｃｕｌｔｕｒｅ Ｃｅｎｔｅｒ， Ａｎａｔｏｍｉｃ Ｇｉｆｔ Ｆｏｕｎｄａｔｉｏｎ）、基質として［５，６，８，９，１１，１２，１４，１５］トリチウム−アラキドン酸、そして補酵素としてＮＡＤＰＨを添加し、３７度で１．５時間反応させた。反応液にギ酸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％）を加えた。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を用いて２０−ＨＥＴＥの産生量を測定した。
【００６７】
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。その結果を上記表１に併せて示す。
また、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産生が５０％阻害される化合物濃度（ＩＣ５０値）も算出した。その結果についても上記表１に併せて示す。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an imidazole derivative that inhibits an enzyme that produces 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesized from arachidonic acid.
[0002]
[Prior art]
As physiologically active substances produced from arachidonic acid, prostaglandins produced by cyclooxygenase and leukotrienes produced by lipoxygenase are widely known. However, in recent years, it has been revealed that 20-HETE produced from arachidonic acid by an enzyme belonging to the genus cytochrome p450 plays various functions in vivo. So far, 20-HETE has been shown to contract or expand microvessels or induce cell proliferation in major organs such as kidneys and cerebral blood vessels, and plays important physiological actions in vivo. It has been suggested that it is deeply involved in the pathology of various renal diseases, cerebrovascular diseases, cardiovascular diseases and the like (J. Vascular Research, Vol. 32, p. 79, 1995, Am. J. Physiol., 277, R607, 1999, Physiol. Rev., 82, 131, 2002).
[0003]
Also, many compounds having a structure similar to the compound of the present invention have been reported. For example, in the formula (1), R 2 Is the substitution C 1 ~ C 4 It is reported that a derivative which is an alkyl group has a nitric oxide synthase inhibitory activity (International Patent Publication WO9715555). In the formula (1), R 2 Is a substituted alkanoyl group, which is reported to have a brain nerve cell death inhibitory effect (International Patent Publication WO9418172). In the formula (1), R 2 Is a substituted phenylalkoxy group is reported to be effective for antihyperlipidemia or arteriosclerosis (International Patent Publication WO9529163). Then, in equation (1), R 2 Have been reported to be effective as antiarrhythmic, antihypertensive or hyperischemic therapeutics (European Patent Publication EP 0 306 440, US Pat. No. 5,202,346). However, none of them has been reported to have a 20-HETE-producing enzyme inhibitory effect.
[0004]
On the other hand, it has been reported that an imidazolylbenzophenone derivative exhibits a 20-HETE-producing enzyme inhibitory effect (International Patent Publication WO0168610), but its activity or physical properties are not always satisfactory.
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a drug that inhibits the production or production of 20-HETE involved in microvascular contraction or expansion in major organs such as the kidney and cerebral blood vessels, or inducing cell proliferation.
[0006]
[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 aromatic compounds having a specific partial structure, particularly 1- (4-substituted phenyl) -1H-imidazole derivatives having various substituents, have been obtained. Surprisingly, they have found that they have an inhibitory effect on 20-HETE-producing enzyme, and completed the present invention.
[0007]
That is, the present invention provides the following formula (1)
[0008]
Embedded image
Ｑwherein Q is a hydrogen atom or C 1 ~ C 4 An alkyl group; 1 Is a hydrogen atom, C 1 ~ C 6 An alkyl group or a halogen atom; 2 Is C 1 ~ C 14 Alkyl group, C 2 ~ C 14 Alkanoyl group, morpholino group or formula R 3 -O- [wherein, R 3 Is C 1 ~ C 14 Alkyl group, C 2 ~ C 14 Alkenyl group, C 3 ~ C 14 Alkynyl group, C 3 ~ C 10 A cycloalkyl group, a 1-phenyl-2-propynyl group or a compound of the formula R 4 -A- (wherein, R 4 Is C 3 ~ C 10 Cycloalkyl group, C 1 ~ C 10 Alkoxy group, C 2 ~ C 10 Alkanoyl group, C 2 ~ C 6 Alkoxycarbonyl group, dioxolanyl group, C 1 ~ C 6 Dioxolanyl group, oxanyl group, dioxanyl group, 1 ~ C 6 A dioxanyl group, a benzodioxanyl group, a bicyclo [2.2.1] heptane-2-yl group substituted with an alkyl group, 1 ~ C 6 Alkylthio group, pyrrolidinyl group, C 1 ~ C 6 Pyrrolidinyl group, piperidinyl group substituted by alkyl group, C 1 ~ C 6 Piperidinyl group, morpholino group, 4-C substituted with an alkyl group 2 ~ C 6 Alkoxycarbonylpiperazin-1-yl group, pyrrolyl group, pyridyl group, N, N-diC 1 ~ C 6 Alkylamino group, N, N-diC 1 ~ C 6 Alkylamino C 1 ~ C 6 Alkoxy group, C 1 ~ C 6 Alkoxy C 1 ~ C 6 Alkoxy group, phenoxy group, phenyl group, "C 1 ~ C 6 Alkyl group, C 1 ~ C 6 An alkoxy group, a halogen atom, a phenylethyl group, a phenoxy group, a nitrile and a methylthio group ", a phenyl group, a biphenyl group, a phenylthio group, a furyl group, a thienyl group, a thiazole group, 1 ~ C 6 Thiazolyl group, toluidino group, N-C 1 ~ C 6 Alkyl toluidino group, pyrrolidone-1-yl group, A is C 1 ~ C 10 It is an alkylene group. ). ] It is a group shown by these. A 20-HETE-producing enzyme inhibitor comprising an imidazole derivative represented by｝ or a pharmaceutically acceptable salt thereof as an active ingredient.
[0010]
Further, the present invention also provides the following formula (2)
[0011]
Embedded image
Ｑwherein Q ′ is a hydrogen atom or C 1 ~ C 4 An alkyl group; 11 Is a hydrogen atom, C 1 ~ C 6 An alkyl group or a halogen atom; 12 Is a morpholino group or a formula R 13 -O- [wherein, R 13 Is C 3 ~ C 14 Alkynyl group, C 3 ~ C 10 A cycloalkyl group, a 1-phenyl-2-propynyl group or a compound of the formula R 14 -A '-(wherein, R 14 Is C 3 ~ C 10 Cycloalkyl group, C 1 ~ C 10 Alkoxy group, C 2 ~ C 10 Alkanoyl group, dioxolanyl group, C 1 ~ C 6 Dioxolanyl group, oxanyl group, dioxanyl group, 1 ~ C 6 A dioxanyl group, a benzodioxanyl group, a bicyclo [2.2.1] heptane-2-yl group substituted with an alkyl group, 1 ~ C 6 Alkylthio group, 4-C 2 ~ C 6 Alkoxycarbonylpiperazin-1-yl group, pyrrolyl group, N, N-diC 1 ~ C 6 Alkylamino C 1 ~ C 6 Alkoxy group, C 1 ~ C 6 Alkoxy C 1 ~ C 6 An alkoxy group, a furyl group, a thienyl group, a pyrrolidone-1-yl group; 1 ~ C 10 It is an alkylene group. ). ] It is a group shown by these. The present invention provides an imidazole derivative represented by｝ or a pharmaceutically acceptable salt thereof.
[0013]
Another object of the present invention is to provide a medicament comprising the above-mentioned imidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
Another object of the present invention is to provide a remedy for renal disease, cerebrovascular disease or cardiovascular disease, comprising the above-mentioned imidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
[0014]
The terms used in the present invention are defined below.
In the present invention, "C x ~ C y "Indicates that the group that follows has xy carbon atoms.
[0015]
The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a fluorine atom or a chlorine atom.
C 1 ~ C 14 An alkyl group means a linear or branched alkyl group having 1 to 14 carbon atoms, 1 ~ C 8 Alkyl groups are preferred. C 1 ~ C 8 Examples of the alkyl group include methyl, ethyl, n-propyl, n-butyl, n-hexyl, n-heptyl, n-octyl, isobutyl, sec-butyl, isopentyl, and isohexyl. Group, 3-methylheptyl group, 3,3-dimethylbutyl group and the like are more preferable.
C 3 ~ C 10 The cycloalkyl group means a cyclic alkyl group having 3 to 10 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Among them, a cyclopropyl group, a cyclopentyl group and a cyclohexyl group are preferred.
[0016]
C 2 ~ C 14 The alkenyl group means a linear or branched alkenyl group having at least one double bond and 2 to 14 carbon atoms, and includes, for example, an ethenyl group, a propenyl group, a 2-butenyl group, a 3-methyl- Examples thereof include a 2-butenyl group, a pentenyl group, a 2-methyl-2-pentenyl group, a hexenyl group, a 2,4-hexadienyl group, a heptenyl group, an octenyl group, and a 3,7-dimethyl-2,6-octadienyl group.
C 2 ~ C 14 An alkynyl group means a linear or branched alkynyl group having at least one triple bond and 2 to 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a butynyl group, a 5-pentynyl group, Examples include a hexenyl group, a heptynyl group and an octynyl group.
[0017]
C 1 ~ C 10 The alkoxy group means a linear or branched alkoxy group having 1 to 10 carbon atoms, 1 ~ C 8 Alkoxy groups are preferred. C 1 ~ C 8 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a hexyloxy group, and a heptyloxy group.
[0018]
C 1 ~ C 6 Alkoxy C 1 ~ C 6 The alkoxy group is C 1 ~ C 6 Alkoxy group and C 1 ~ C 6 Having a complex form of an alkoxy group, 1 ~ C 4 Alkoxy C 1 ~ C 4 Alkoxy groups are preferred. Among them, a methoxyethoxy group, an n-butoxyethoxy group and the like are more preferable.
C 2 ~ C 6 The alkoxycarbonyl group has a form in which a linear or branched alkoxy group having 2 to 5 carbon atoms and one carbonyl group (—CO—) are complexed, 2 ~ C 4 Alkoxycarbonyl groups are preferred. Among them, a methoxycarbonyl group and an ethoxycarbonyl group are more preferred.
[0019]
The dioxolanyl group means a saturated 5-membered ring having two oxygen atoms as a hetero atom (dioxolane), preferably a monovalent group derived by removing hydrogen from the ring of 1,3-dioxolane.
The oxanyl group has a form of a saturated six-membered ring having one oxygen atom as a hetero atom, and includes a 2-oxanyl group and a 3-oxanyl group.
The dioxanyl group means a saturated 6-membered ring having two oxygen atoms as a hetero atom (dioxane), preferably a monovalent group derived by removing hydrogen from the ring of 1,3-dioxane. C 1 ~ C 6 A dioxanyl group substituted with an alkyl group has a ring of C 1 ~ C 6 It may be substituted with an alkyl group, such as a 5,5-dimethyl-1,3-dioxan-2-yl group.
[0020]
C 1 ~ C 6 The alkylthio group has a form in which a linear or branched alkyl group having 1 to 6 carbon atoms and one thio group (-S-) are complexed, 1 ~ C 4 Alkylthio groups are preferred. For example, a methylthio group, an ethylthio group and the like are more preferable.
[0021]
The pyrrolidinyl group means a monovalent group derived by removing a hydrogen atom from a cyclic nitrogen or carbon atom of pyrrolidine, and examples thereof include a 1-pyrrolidinyl group, a 2-pyrrolidinyl group, and a 3-pyrrolidinyl group. Can be C 1 ~ C 6 A pyrrolidinyl group substituted with an alkyl group is such that at least one hydrogen atom on the group is C 1 ~ C 6 An alkyl group, preferably C 1 ~ C 4 A pyrrolidinyl group substituted by an alkyl group, such as an N-methylpyrrolidin-2-yl group.
The piperidinyl group means a monovalent group derived by removing a hydrogen atom from a carbon atom of piperidine. C 1 ~ C 6 A piperidinyl group substituted by an alkyl group has a nitrogen atom of C 1 ~ C 6 It is a piperidinyl group substituted by an alkyl group, and examples thereof include an N-methylpiperidin-2-yl group and an N-methylpiperidin-3-yl group.
4-C 2 ~ C 6 The alkoxycarbonylpiperazin-1-yl group is such that the nitrogen atom at the 4-position of piperazine is C 2 ~ C 6 It means a monovalent group modified with an alkoxycarbonyl group and derived by removing a hydrogen atom from the nitrogen atom at the 1-position.
The morpholino group means a monovalent group derived by removing a hydrogen atom from a nitrogen atom of morpholine.
[0022]
The furyl group includes a 2-furyl group and a 3-furyl group.
The thienyl group includes a 2-thienyl group and a 3-thienyl group.
The thiazolyl group includes a 2-thiazolyl group, a 4-thiazolyl group, and a 5-thiazolyl group. Also, C 1 ~ C 6 A thiazolyl group substituted with an alkyl group has at least one hydrogen atom on the ring as C 1 ~ C 6 Alkyl, preferably C 1 ~ C 4 A thiazolyl group substituted by an alkyl group, more preferably a methyl group, such as a 4-methylthiazol-5-yl group.
The pyridyl group includes a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group. The pyrrolyl group includes a 1-pyrrolyl group, a 2-pyrrolyl group, and a 3-pyrrolyl group, and a 1-pyrrolyl group (N-pyrrolyl group) is preferable.
[0023]
N, N-di C 1 ~ C 6 Alkylamino C 1 ~ C 6 The alkoxy group is N, N-diC 1 ~ C 6 Alkylamino group and C 1 ~ C 6 It has a form in which an alkoxy group is combined, and examples thereof include an N, N-diethylaminoethoxy group.
The pyrrolidone-1-yl group includes a 2-pyrrolidone-1-yl group and a 3-pyrrolidone-1-yl group.
[0024]
C defined by A and A ' 1 ~ C 10 The alkylene group means a linear or branched alkylene group having 1 to 10 carbon atoms, for example, methylene, methylmethylene, ethylene, propylene, heptylene, 2,2-dimethylpropylene And a hexylene group.
[0025]
In the above-mentioned various groups, in addition to the above-mentioned substituted forms, at least one hydrogen atom on the group may be a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; Nitro group; amino group; hydroxy group; thiol group; formyl group; carboxyl group; cyano group; carbamoyl group; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Alkyl groups such as group, pentyl group, isopentyl group, neopentyl group and tert-pentyl group; aryl groups such as phenyl group, naphthyl group, biphenyl group and anthranyl group; heterocyclic groups such as pyrrolyl group, pyridyl group and thienyl group; Alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; acetyl group, benzoyl Acyl group such as a methoxy group, an ethoxy group, an alkoxy group such as a propoxy group, may be substituted by a non-hydrogen atom or a group such as, methylthio group, ethylthio group, an alkylthio group such as a propylthio group. Note that the number of carbon atoms in these substituents is not included in x or y described above.
[0026]
The pharmaceutically acceptable salt is a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, for example, a sodium salt, a potassium salt Calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinic acid Salt, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfonate , Lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine and Salt, salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoic acid Salts, salts with acrylic acid polymers, salts with carboxyvinyl polymers and the like can be mentioned.
[0027]
BEST MODE FOR CARRYING OUT THE INVENTION
The compound (1) of the present invention can be synthesized, for example, by the following method.
[0028]
Embedded image
Production method 1; Heterocyclic Chem. , Vol. 25, Item 1649 (1988), by converting an aniline derivative (a) to an orthoformate such as trimethyl orthoformate or triethyl orthoformate in the presence or absence of an acid catalyst such as acetic acid or hydrochloric acid; The reaction is performed to obtain an imino ether derivative (b). The reaction temperature is from room temperature to 150 ° C, preferably 70 to 100 ° C, and the reaction time is 2 to 72 hours. Next, the iminoether derivative (b) is reacted with aminoacetaldehyde dimethyl acetal in a suitable solvent (methanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate, dimethylsulfoxide, dimethylformamide, etc.). To give the formamidine derivative (c). At this time, the reaction temperature is from room temperature to 150 ° C, preferably 70 to 100 ° C, and the reaction time is 2 to 24 hours. Next, the formamidine derivative (c) is reacted in a suitable solvent (ether, tetrahydrofuran, dimethoxyethane, dioxane, etc.) in the presence of a Lewis acid or an acid catalyst (titanium tetrachloride, trifluoroborane etherate, acetic acid, etc.). The compound (1) of the present invention can be synthesized (wherein R 1 , R 2 Is as defined above). In addition, R of the compound (1) of the present invention synthesized by this method 2 Can be converted into each other to lead to another compound (1) of the present invention.
[0030]
Embedded image
Production method 2: Compound (1) can also be directly synthesized from aniline derivative (a). That is, the aniline derivative is mixed with ammonia, formaldehyde, and glyoxal at a ratio of 1: 1: 1: 1, and the reaction temperature is room temperature to 150 ° C., preferably 70 to 120 ° C. in water or a mixed solvent of alcohol / water. The compound (1) of the present invention can be synthesized by reacting 1 , R 2 Is as defined above).
[0032]
Embedded image
Production method 3: aniline derivative (a ') (R 2 Is a substituted alkoxy group, ie, R 2 = R 3 O) can be synthesized as follows. That is, a nitrobenzene derivative (d) (wherein X represents a leaving group such as fluorine and chlorine, and other symbols are as defined above) in a suitable solvent (methanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene). , Methylene chloride, chloroform, acetonitrile, ethyl acetate, dimethylsulfoxide, dimethylformamide, etc.) if necessary bases (triethylamine, N, N-diisopropylethylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride, sodium methoxy) Compound (e) can be produced by reacting with various corresponding alcohols in the presence of potassium, t-butoxy potassium and the like. At this time, the reaction temperature is 0 ° C to 80 ° C, preferably 0 ° C to room temperature, and the reaction time is 1 to 12 hours, preferably 1 to 2 hours. Next, the compound (e) is placed in a suitable solvent (methanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate, etc.), and a reducing agent (palladium activated carbon / palladium activated carbon / The nitro group is formed using hydrazine hydrate, palladium activated carbon / ammonium formate, tin (II) chloride monohydrate, iron / ammonium chloride, Raney nickel / hydrazine hydrate, etc., preferably in an atmosphere of palladium activated carbon / hydrogen. The aniline derivative (a ′) can be produced by reduction. The reaction temperature is from room temperature to 150 ° C, preferably from room temperature to 100 ° C, and the reaction time is from 1 hour to 24 hours.
[0034]
Embedded image
Production method 4: Compound (1) can be produced via intermediate (h) as follows. Phenylboronic acid or a halogenated phenyl derivative (f) (where Y is B (OH) 2 Or a halogen atom, and other symbols are as defined above, in an appropriate solvent (methanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate, dimethyl sulfoxide, dimethylformamide, etc.). ) With a copper catalyst ([Cu (OH) TMEDA] 2 Cl 2 , (CuOTf) 2 benzene, etc.), preferably in an oxygen atmosphere, to produce an intermediate (g) by condensing with an imidazole derivative [Organic Lett. , Vol. 2, Item 1237 (2000)]. The reaction temperature is preferably room temperature, and the reaction time is 12 to 24 hours. Next, the intermediate (g) is reacted in a 48% hydrogen bromide at 100 ° C. to 150 ° C. to produce an intermediate compound (h). The reaction time is 12 hours to 72 hours, preferably 12 hours to 24 hours.
[0036]
Embedded image
Next, the 4- (imidazol-1-yl) -phenol derivative (h) and various alcohols corresponding thereto can be produced by utilizing the Mitsunobu reaction (Org. Reactions, Vol. 42, No. 335). That is, compound (h) is dissolved in a suitable solvent (tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate, dimethylsulfoxide, dimethylformamide, etc.) in a phosphine reagent (triphenylphosphine, tributylphosphine, diphenyl-2, or the like). -Pyridylphosphine), a diazo reagent (such as diethylazodicarboxylate or di-tert-butylazodicarboxylate) and various corresponding alcohols at 0 ° C. to room temperature, preferably at room temperature for 2 to 12 hours. After reacting for a time, compound (1) of the present invention (the symbols in the formula are as defined above) can be produced. Alternatively, various alkyl halides (R 3 X and X represent halogen, and other symbols are as defined above, and a suitable base (triethylamine, N, N-diisopropylethylamine, pyridine, or the like) in a suitable solvent (acetone, dimethylformamide, tetrahydrofuran, ether, or the like). In the presence of potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride, sodium methoxide, potassium t-butoxide) at 0 ° C. to room temperature, preferably at room temperature for 2 to 24 hours. 2 Is R 3 The compound (1) of the present invention, which is O, can be produced.
[0038]
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. 14th 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.), disintegrants (eg, calcium carboxymethylcellulose) and the like can be used.
[0039]
The dose of the compound according to the present invention and a pharmaceutically acceptable salt thereof is 1 to 2,000 mg per day when treating an adult, and these are administered once or several times a day. This dosage can be adjusted appropriately according to the age, weight and condition of the patient.
[0040]
【The invention's effect】
The compound according to the present invention and a pharmaceutically acceptable salt thereof have an excellent 20-HETE production inhibitory action and are also excellent in physical properties such as solubility. Therefore, the compound according to the present invention is useful as a therapeutic agent for 20-HETE-related diseases in humans and animals, such as various renal diseases, cerebrovascular diseases, and various cardiovascular diseases.
[0041]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1
Production of 1- [4-propylphenyl] -imidazole hydrochloride (Compound 108)
A mixture of 4-propylaniline (2.03 g, 0.0150 mol) and triethyl orthoformate (4.99 g, 0.337 mol) was stirred at 100 ° C. for 7 hours. After cooling to room temperature, methanol (15 mL) and aminoacetaldehyde dimethyl acetal (5.69 g, 0.0541 mol) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and further at 100 ° C. for 4 hours. After cooling to room temperature, dimethoxyethane (20 mL) and a 1M titanium tetrachloride-toluene solution (21 mL, 0.021 mol) were added to the residue obtained by concentrating the reaction solution, and the mixture was further heated under reflux at room temperature for 1 hour. Stir for 4 hours. After cooling to room temperature, an aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 97: 3) to obtain 1- [4-propylphenyl] -imidazole (2.0 g) as a brown oil. A 4N hydrochloric acid-ethyl acetate solution was added to the product, and the mixture was recrystallized from a mixed solvent of ethyl acetate-chloroform to give the title compound (1.38 g, 41.2%) as a colorless powder. Melting point 155.5-157.0 ° C
[0042]
Example 2
Production of {2- [2- (4-Imidazol-1-yl-phenoxy) -ethoxy] -ethyl} -dimethylamine dihydrochloride (Compound 116)
N, N-dimethylaminoethyloxyethanol (2.3 g, 0.26 mol) was added to a suspension of sodium hydride (60% oil, 1.0 g, 0.26 mol) in dimethylformamide (3.0 ml) under ice cooling. A dimethylformamide solution (5 ml) was added dropwise, and the mixture was stirred for 10 minutes. To this reaction mixture was added dropwise a solution of 4-fluoronitrobenzene (3 g, 0.021 mol) in dimethylformamide (10 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 4 It was dried and concentrated under reduced pressure to obtain dimethyl- {2- [2- (4-nitrophenoxy) -ethoxy] -ethyl} amine (5.9 g). The compound obtained above was dissolved in methanol (100 mL), 10% palladium activated carbon (0.6 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After confirming the disappearance of the raw materials by TLC analysis, insolubles were filtered using celite, and the filtrate was concentrated to obtain an aniline derivative (5.0 g) as a brown oil. Next, triethyl orthoformate (10 mL, 0.060 mol) was added to the aniline derivative, and the mixture was stirred at 100 ° C. for 20 hours. After cooling to room temperature, methanol (80 mL) and aminoacetaldehyde dimethyl acetal (6.8 mL, 0.063 mol) were added to the reaction solution, and the mixture was stirred at 100 ° C. for 1.5 hours. Dimethoxyethane (30 mL) and a 1 M titanium tetrachloride-toluene solution (25 mL, 0.025 mol) were added to the residue obtained by concentrating the reaction solution, and the mixture was stirred under heating and reflux for 5 hours. After cooling to room temperature, an aqueous sodium hydroxide solution was added to the reaction solution. After filtering the precipitated insoluble matter, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The obtained residue was purified by NH-type silica gel chromatography (hexane-ethyl acetate = 1: 2) to give {2- [2- (4-imidazol-1-yl-phenoxy) -ethoxy] -ethyl} -dimethylamine. (0.40 g, 6.9%) as an oil. The product was dissolved in ether, 4M hydrochloric acid-ethyl acetate solution was added, and the mixture was concentrated, and the precipitated powder was washed with ethyl acetate to obtain the title compound (428 mg). 174.0-179.0 ° C.
[0043]
Example 3
Production of 1- [4-propyloxyphenyl] -imidazole toluenesulfonate (Compound 94)
Diethyl was added to a mixture of 4- (imidazol-1-yl) phenol (1.0 g, 6.25 mmol), propanol (563 mg, 9.38 mmol), triphenylphosphine (2.46 g, 9.38 mmol) and tetrahydrofuran (20 mL). Azodicarboxylate (1.48 mL, 9.38 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After concentrating the reaction mixture, ethyl acetate (40 mL) was added, and the mixture was extracted with 1 M hydrochloric acid (20 mL). After the aqueous layer was neutralized with 5M sodium hydroxide, it was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The obtained residue was purified by NH-type silica gel chromatography (hexane-ethyl acetate = 1: 2), and 1- [4-propyloxyphenyl] -1H-imidazole (1.17 g, 92%) was obtained as a colorless oil. Obtained. This was dissolved in ethanol, and an ethanol solution of p-toluenesulfonic acid monohydrate (1.1 g, 5.78 mmol) was added. The precipitated crystals were filtered, and the title compound was obtained as a colorless powder (1.98 g, 85%). Got. 148.0-150.0 ° C
[0044]
Example 4
Preparation of 1- [4-butoxyphenyl] -2-methyl-imidazole toluenesulfonate (Compound 117)
(1) To a mixture of 4-methoxyphenyl borate (3.7 g, 24.4 mmol), 1-H-2-methylimidazole (1.0 g, 12.2 mmol), and methylene chloride (48 mL), [Cu (OH) TMEDA] 2 Cl 2 (0.57 g, 1.22 mmol), and the mixture was stirred at room temperature for 18 hours under an oxygen atmosphere. After the reaction mixture was filtered to remove insolubles, the filtrate was concentrated. The obtained residue was purified by NH-type silica gel chromatography (hexane-ethyl acetate = 4: 1) to obtain 1- [4-methoxyphenyl] -2-methyl-imidazole (2.35 g).
[0045]
(2) A mixture of 1- [4-methoxyphenyl] -2-methyl-imidazole (2.0 g) and 48% hydrogen bromide (20 mL) was reacted at 100 ° C for 16 hours. After the reaction solution was cooled to room temperature, the precipitated crystals were neutralized with 6 M sodium hydroxide, and the precipitated crystals were filtered to obtain 4- (2-methyl-imidazol-1-yl) phenol (0.75 g, 40%).
[0046]
(3) In a solution of 4- (2-methyl-imidazol-1-yl) phenol (0.20 g, 1.2 mmol) and dimethylformamide (2 mL), 1-iodo-n-butane (0.25 g, 1.38 mmol) was added. ) And potassium carbonate (0.19 g, 1.38 mmol) were added, and the mixture was stirred at room temperature for 64 hours. Water was added to the reaction solution, and extracted with a mixed solvent of hexane-ethyl acetate = 1: 1. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The obtained residue was purified by NH-type silica gel chromatography (hexane-ethyl acetate = 4: 1) to obtain 1- [4-butoxyphenyl] -2-methyl-imidazole (0.17 g, 64%). . This was dissolved in ethanol, an ethanol solution of p-toluenesulfonic acid monohydrate was added, and the precipitated crystals were filtered to give the title compound (0.18 g, 39%) as a colorless powder. 148.0-149.0 ° C
[0047]
The compounds shown in Table 1 were synthesized by performing the same reaction operations as in Examples 1 to 4 using the corresponding starting materials. Table 1 also shows the compounds synthesized in Examples 1 to 4.
[0048]
[Table 1]
[Table 2]
[Table 3]
[Table 4]
[Table 5]
[Table 6]
[Table 7]
[Table 8]
[Table 9]
[Table 10]
[Table 11]
[Table 12]
[Table 13]
[Table 14]
[Table 15]
[Table 16]
[Table 17]
[Table 18]
Test example [Inhibition of 20-HETE-producing enzyme derived from human kidney microsomes]
The compounds described in the above table were tested for their 20-HETE production inhibitory activity.
This test is described in J. Pharmacol. Exp. Ther. 268, p. 474 (1994).
The test drug solution adjusted to 1 μM with DMSO was added to a 50 mM 3-morpholinopropanesulfonic acid (MOPS) (pH 7.4) buffer containing 5 mM magnesium chloride and 1 mM ethylenediaminetetraacetic acid disodium salt (EDTA). In addition, human kidney microsomal fraction (Human Cell Culture Center, Anatomical Gift Foundation) as enzyme source, [5,6,8,9,11,12,14,15] tritium-arachidonic acid as substrate and NADPH as coenzyme Was added and reacted at 37 ° C. for 1.5 hours. After formic acid was added to the reaction solution to stop the reaction, acetonitrile (final concentration 50%) was added. The amount of 20-HETE produced was measured using high performance liquid chromatography with a radioactive substance detector equipped with an ODS column (Biosil C18, Biorad).
[0067]
The amount of 20-HETE produced when no compound was added was defined as 100%, and the inhibition rate (%) was calculated from the amount of 20-HETE produced when the compound was added. The results are shown in Table 1 above.
In addition, the amount of 20-HETE produced when no compound was added was defined as 100%, and the concentration of the compound at which 20-HETE production was inhibited by 50% when the compound was added (IC 50 Value) was also calculated. The results are also shown in Table 1 above.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002163980A JP2004010513A (en) | 2002-06-05 | 2002-06-05 | Imidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002163980A JP2004010513A (en) | 2002-06-05 | 2002-06-05 | Imidazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2004010513A true JP2004010513A (en) | 2004-01-15 |
Family
ID=30432255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002163980A Withdrawn JP2004010513A (en) | 2002-06-05 | 2002-06-05 | Imidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2004010513A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7576102B2 (en) | 2005-12-21 | 2009-08-18 | Decode Genetics Ehf | Biaryl substituted nitrogen containing heterocycle inhibitors of LTA4H for treating inflammation |
| US7674802B2 (en) | 2005-12-21 | 2010-03-09 | Decode Genetics, Ehf | N-linked aryl heteroaryl inhibitors of LTA4H for treating inflammation |
| CN109896986A (en) * | 2017-12-07 | 2019-06-18 | 中国医学科学院药物研究所 | The structure of lignanoids natural products 4-O- methyl saururus chinensis alcohol simplifies object, preparation method and its pharmaceutical composition and purposes |
-
2002
- 2002-06-05 JP JP2002163980A patent/JP2004010513A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7576102B2 (en) | 2005-12-21 | 2009-08-18 | Decode Genetics Ehf | Biaryl substituted nitrogen containing heterocycle inhibitors of LTA4H for treating inflammation |
| US7674802B2 (en) | 2005-12-21 | 2010-03-09 | Decode Genetics, Ehf | N-linked aryl heteroaryl inhibitors of LTA4H for treating inflammation |
| CN109896986A (en) * | 2017-12-07 | 2019-06-18 | 中国医学科学院药物研究所 | The structure of lignanoids natural products 4-O- methyl saururus chinensis alcohol simplifies object, preparation method and its pharmaceutical composition and purposes |
| CN109896986B (en) * | 2017-12-07 | 2022-03-15 | 中国医学科学院药物研究所 | Structure simplification of lignan natural product 4-O-methyl saururus chinensis alcohol, preparation method thereof, pharmaceutical composition thereof and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210330651A1 (en) | Estrogen receptor modulators | |
| AU2016391377B2 (en) | 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (Chk1) inhibitors, and their preparations and applications | |
| AU2008202731A1 (en) | Azole derivatives and pharmaceutical compositions containing them | |
| SK2622002A3 (en) | N-heterocyclic derivatives as nitric oxide synthase inhibitors and pharmaceutical compositions containing these compounds | |
| JP2016538252A (en) | Substituted (S)-(2R, 3R, 5R) -3-hydroxy- (5-pyrimidin-1-yl) tetrahydrofuran-2-ylmethylaryl phosphoramidate | |
| EP4163272A1 (en) | Benzothiazole derivative and application thereof | |
| TWI426909B (en) | Radiation therapy enhancer | |
| US20230109134A1 (en) | Pyridazinone or pyridazine compound and derivative and pharmaceutical composition thereof | |
| JP4833832B2 (en) | Pyrazole compounds | |
| TW200932217A (en) | Substituted hydantoins | |
| WO2017204319A1 (en) | Glucosylceramide synthase inhibitor | |
| EP2044957A1 (en) | Treatment agent for inflammatory bowel disease | |
| JPWO2003022821A1 (en) | Heterocyclic derivatives having 20-HETE-producing enzyme inhibitory activity | |
| JPH03287584A (en) | Substituted allylamine derivative | |
| JP2004010513A (en) | Imidazole derivative | |
| JP4904659B2 (en) | Hydroxyformamidine derivatives and medicaments containing them | |
| KR102628246B1 (en) | Selective A2A receptor antagonist | |
| JP2004010514A (en) | Triazole derivative | |
| WO2019001307A1 (en) | Amide compound, composition containing same, and use thereof | |
| KR20190140005A (en) | Method of Using Trisubstituted Benzotriazole Derivatives as Dihydroorotate Oxygenase Inhibitors | |
| JP2023551019A (en) | Deuterated 2-aromatic heterocyclic-3-oxo-2,3-dihydropyridazine-4-carboxamide inhibitor and its production method and application | |
| JP7354245B2 (en) | Novel carbonate compound having a pyrrolopyrimidine skeleton or a pharmaceutically acceptable salt thereof | |
| CN114685472B (en) | Polysubstituted uracil derivative and use thereof | |
| US20230293539A1 (en) | Mll1-wdr5 protein-protein interaction inhibitor compounds and uses thereof | |
| CN114671878B (en) | Substituted nitrogen-containing bicyclic compounds and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050526 |
|
| A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20080812 |