JP4120401B2 - 20−ヒドロキシエイコサテトラエン酸産生阻害剤 - Google Patents
20−ヒドロキシエイコサテトラエン酸産生阻害剤 Download PDFInfo
- Publication number
- JP4120401B2 JP4120401B2 JP2002585375A JP2002585375A JP4120401B2 JP 4120401 B2 JP4120401 B2 JP 4120401B2 JP 2002585375 A JP2002585375 A JP 2002585375A JP 2002585375 A JP2002585375 A JP 2002585375A JP 4120401 B2 JP4120401 B2 JP 4120401B2
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- JP
- Japan
- Prior art keywords
- group
- substituted
- piperazin
- alkyl
- alkoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- NNDIXBJHNLFJJP-UHFFFAOYSA-N 20-Hydroxyeicosatetraenoic acid Chemical compound OCCCCCC=CCC=CCC=CCC=CCCCC(O)=O NNDIXBJHNLFJJP-UHFFFAOYSA-N 0.000 title claims description 19
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- 239000003112 inhibitor Substances 0.000 title claims description 7
- -1 thiomorpholin-1-yl group Chemical group 0.000 claims description 87
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 16
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 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
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 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 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 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
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- LNUYLGUBVHEHEL-UHFFFAOYSA-N 2-phenylbenzenecarboximidamide Chemical compound NC(=N)C1=CC=CC=C1C1=CC=CC=C1 LNUYLGUBVHEHEL-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QTRCULOEXXYXQI-UHFFFAOYSA-N ClC=1C=C(C=CC1F)[N+](=O)[O-].ONC=NC1=CC(=C(C=C1)N1CCSCC1)Cl Chemical compound ClC=1C=C(C=CC1F)[N+](=O)[O-].ONC=NC1=CC(=C(C=C1)N1CCSCC1)Cl QTRCULOEXXYXQI-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
- 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 235000003332 Ilex aquifolium Nutrition 0.000 description 1
- 241000209027 Ilex aquifolium Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 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
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- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
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- 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
- 229910004298 SiO 2 Inorganic materials 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
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
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- 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
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- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
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- 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
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 229940009098 aspartate Drugs 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
- 239000011230 binding agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000006226 butoxyethyl group Chemical group 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- 238000002360 preparation method Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
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- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Description
本発明はアラキドン酸から20−ヒドロキシエイコサテトラエン酸(20−HETE)の産生を阻害するヒドロキシホルムアミジノベンゼン又はヒドロキシアミジノピリジン誘導体に関する。
背景技術
アラキドン酸から産生される生理活性物質として従来シクロオキシゲナーゼによって産生されるプロスタグランジン類及びリポキシゲナーゲによって産生されるロイコトリエン類が広く知られているが、近年チトクロームp450属に属する酵素によってアラキドン酸から産生される20−HETEが生体内で多彩な働きをしていることが明らかとされつつある(J.Vascular Research,第32巻,第79頁(1995))。これまでに20−HETEは腎臓、脳血管等の主要臓器において微小血管を収縮又は拡張させることや細胞増殖を惹起することが明らかにされており、生体内で重要な生理作用を演じていると共に各種腎疾患、脳血管疾患、循環器疾患等の病態に深く関与していることが示唆されている(J.Vascular Research,第32巻,第79頁(1995)、Am.J.Physiol.,第277巻,R607頁(1999)、Physiol.Rev.第82巻,第131項,(2002)等)。
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。
発明の開示
本発明者らは前記課題を解決する目的で鋭意探索研究した結果、ある種の芳香族化合物が20−HETEの産生を阻害することを見出し、本発明を完成した。
すなわち、本発明は、下記式
[式中、R1は置換モルホリノ基、置換ピペリジノ基、ピペラジン−1−イル基、置換ピペラジン−1−イル基、チオモルホリン−1−イル基、ペルヒドロアゼピン−1−イル基、ペルヒドロアゾシン−1−イル基、テトラヒドロピリジン−1−イル基、ピロリン−1−イル基、1,4−ジオキサ−8−アザスピロ[4,5]デカン−8−イル基又はデカヒドロキノリン−1−イル基のうちのいずれかであり、Xは窒素原子又はCR5で表される基であり、R2〜R5は同一又は相異なって水素原子、C1−4アルキル基、C1−4アルコキシ基、トリフルオロメチル基又はハロゲン原子である。]で表されるヒドロキシホルムアミジン化合物又はその製薬学的に許容される塩である。
本発明において使用される用語が以下に定義される。置換モルホリノ基とは、1〜3個のC1−4アルキル基で置換されたモルホリノ基を意味し、例えば2−メチルモルホリノ基、2−エチルモルホリノ基、3−メチルモルホリノ基、2,6−ジメチルモルホリノ基、2,3,5−トリメチルモルホリノ基等であり、2,6−ジメチルモルホリノ基がより好ましい。
置換ピペリジノ基とは、C1−4アルキル基で置換されたピペリジノ基、C1−4アルコキシ基で置換されたピペリジノ基、ヒドロキシ基で置換されたピペリジノ基、C2−5アルコキシカルボニル基で置換されたピペリジノ基、モノ又はジ−C2−7アルキルアミノカルボニル基で置換されたピペリジノ基、C1−4アルコキシ−C1−6アルキル基で置換されたピペリジノ基、C1−6ヒドロキシアルキル基で置換されたピペリジノ基、モノ又はジ−C1−4アルキルアミノ−C1−6アルキル基で置換されたピペリジノ基を意味し、例えば2−メチルピペリジノ基、3−メチルピペリジノ基、4−メチルピペリジノ基、4−エチルピペリジノ基、4−メトキシピペリジノ基、4−ヒドロキシピペリジノ基、4−メトキシカルボニルピペリジノ基、4−エトキシカルボニルピペリジノ基、4−ジメチルアミノカルボニルピペリジノ基、3−ジエチルアミノカルボニルピペリジノ基、4−(2−メトキシエチル)ピペリジノ基、4−(2−ヒドロキシエチル)ピペリジノ基、4−(2−ジメチルアミノエチル)ピペリジノ基等が挙げられ、4−ヒドロキシピペリジノ基、4−(2−ヒドロキシエチル)ピペリジノ基、4−エトキシカルボニルピペリジノ基、3−ジエチルアミノカルボニルピペリジノ基がより好ましい。
置換ピペラジン−1−イル基とは、ピペラジン−1−イル基、C1−4アルキル基で置換されたピペラジン−1−イル基、環員数4〜8のシクロアルキル基で置換されたピペラジン−1−イル基、C1−4アルコキシ−C1−4アルキル基で置換されたピペラジン−1−イル基、C1ー6ヒドロキシアルキル基で置換されたピペラジン−1−イル基、モノ又はジ−C1−4アルキルアミノ−C1−6アルキル基で置換されたピペラジン−1−イル基、ピロリジン−1−イル−C1−6アルキル基で置換されたピペラジン−1−イル基、モルホリノカルボニル−C1−6アルキル基で置換されたピペラジン−1−イル基、C2−6アルカノイル基で置換されたピペラジン−1−イル基、フェニル基で置換されたピペラジン−1−イル基、ピリジル基で置換されたピペラジン−1−イル基を意味し、例えば2−メチルピペラジン−1−イル基、3−メチルピペラジン−1−イル基、4−メチルピペラジン−1−イル基、4−エチルピペラジン−1−イル基、4−シクロヘキシルピペラジン−1−イル基、4−(2−メトキシエチル)ピペラジン−1−イル基、4−(2−ヒドロキシエチル)ピペラジン−1−イル基、4−(2−ジメチルアミノエチル)ピペラジン−1−イル基、4−(2−ピロリジン−1−イル−エチル)ピペラジン−1−イル基、4−(1−モルホリノカルボニルメチル)ピペラジン−1−イル基、4−フェニルピペラジン−1−イル基等が挙げられ、4−メチルピペラジン−1−イル基、4−エチルピペラジン−1−イル基、4−シクロヘキシルピペラジン−1−イル基、4−(2−ヒドロキシエチル)ピペラジン−1−イル基、4−(2−ジメチルアミノエチル)ピペラジン−1−イル基、4−(2−ピロリジン−1−イル−エチル)ピペラジン−1−イル基、4−(モルホリノカルボニルメチル)ピペラジン−1−イル基、4−アセチルピペラジン−1−イル基、4−フェニルピペラジン−1−イル基、4−(2−ピリジル)ピペラジン−1−イル基がより好ましい。
本発明において「Cx−y」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意味する。
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子である。
C1−4及びC1−6アルキル基とは、直鎖状又は分岐鎖状の炭素原子数がそれぞれ1〜4個及び1〜6個のアルキル基を意味し、C1−4アルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、tert−ブチル基等が挙げられ、メチル基がより好ましい。C1− 6アルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、tert−ブチル基、ペンチル基、イソペンチル基、ヘキシル基、イソヘキシル基等が挙げられ、メチル基、エチル基がより好ましい。
C1−4アルコキシ基とは、直鎖状又は分岐鎖状の炭素原子数1〜4個のアルコキシ基を意味し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、tert−ブトキシ基等が挙げられる。
C2−5アルコキシカルボニル基とは、直鎖状又は分岐鎖状の炭素原子数1〜4個のアルコキシ基とカルボニル基との複合した形態の置換基を意味し、例えばメトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基等が挙げられる。
モノ又はジ−C2−7アルキルアミノカルボニル基とは、直鎖状又は分岐鎖状の炭素原子数1〜6個のアルキル基が一つ又は二つ置換したアミノ基とカルボニル基との複合した形態の置換基を意味し、例えばメチルアミノカルボニル基、エチルアミノカルボニル基、ジメチルアミノカルボニル基、ジエチルアミノカルボニル基、ジイソブチルアミノカルボニル基等が挙げられ、ジエチルアミノカルボニル基がより好ましい。
C1−4アルコキシ−C1−4アルキル基とは、直鎖状又は分岐鎖状の炭素原子数1〜4個のアルコキシ基と直鎖状又は分岐鎖状の炭素原子数1〜4個のアルキル基の複合した形態の置換基を意味し、例えばメトキシメチル基、エトキシメチル基、メトキシエチル基、エトキシエチル基、プロポキシエチル基、イソプロポキシエチル基、ブトキシエチル基、tert−ブトキシエチル基等が挙げられる。
C1−6ヒドロキシアルキル基とは、ヒドロキシル基で置換された直鎖状又は分岐鎖状の炭素原子数1〜6個のアルキル基を意味し、例えばヒドロキシメチル基、1−ヒドロキシエチル基、2−ヒドロキシエチル基、3−ヒドロキシプロピル基、5−ヒドロキシペンチル基等が挙げられ、2−ヒドロキシエチル基がより好ましい。
モノ又はジ−C1−4アルキルアミノ−C1−6アルキル基とは、直鎖状又は分岐鎖状の炭素原子数1〜4個のアルキル基が一つ又は二つ置換したアミノ基と直鎖状又は分岐鎖状の炭素原子数1〜6個のアルキル基との複合した形態の置換基を意味し、例えばメチルアミノメチル基、1−メチルアミノエチル基、2−メチルアミノエチル基、3−メチルアミノプロピル基、4−ジメチルアミノブチル基、ジメチルアミノメチル基、1−ジメチルアミノエチル基、2−ジメチルアミノエチル基、3−ジメチルアミノプロピル基等が挙げられ、2−ジメチルアミノエチル基がより好ましい。
環員数4〜8のシクロアルキル基とは、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、シクロオクチル基のことであり、シクロヘキシル基がより好ましい。
ピロリジン−1−イル−C1−6アルキル基とは、ピロリジン−1−イル基で置換された直鎖状又は分岐鎖状の炭素原子数1〜6個のアルキル基を意味し、例えばピロリジン−1−イルメチル基、2−(ピロリジン−1−イル)エチル基、3−(ピロリジン−1−イル)プロピル基、5−(ピロリジン−1−イル)ペンチル基等が挙げられ、2−(ピロリジン−1−イル)エチル基がより好ましい。
モルホリノカルボニル−C1−6アルキル基とは、モルホリノカルボニル基で置換された直鎖状又は分岐鎖状の炭素原子数1〜6個のアルキル基を意味し、例えばモルホリノカルボニルメチル基、2−モルホリノカルボニルエチル基、3−モルホリノカルボニルプロピル基、5−モルホリノカルボニルペンチル基等が挙げられ、モルホリノカルボニルメチル基がより好ましい。
また、これらの化合物の融点、MASS測定値、TLCのRf値、展開溶媒を表1に示す。なお、TLC測定においてはFuji Silysia Chemical LTD.製SiO2(NH)を用いた。
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る。それらは、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。
本発明化合物は、例えば以下に示す方法によって合成することができる。すなわち、下記式(a)
(式中、Yはハロゲン原子を示し、R2
、R3、R4及びXは上記と同意義である。)で表される化合物と下記式(b)
(R1は前記と同意義である。)で表される化合物を適当な溶媒の存在下若しくは非存在下に反応させて下記式(c)で示される化合物を製造することができる。(式中、R1、R2、R3、R4及びXは上記と同意義である。)
次に、化合物(c)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)を用いてニトロ基を還元することでアニリン誘導体(d)を製造することができる。(式中、R1、R2、R3、R4及びXは上記と同意義である。)
次に、化合物(d)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)、ジメチルホルムアミド ジメチルアセタールと室温〜150℃、好ましくは70℃〜100℃で2〜72時間反応する。ここで得られた中間体を適当な溶媒中(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)ヒドロキシルアミン塩酸塩と処理することによって、式(1)の本発明化合物を製造することができる。あるいは、式(d)で示される化合物をオルト蟻酸トリメチル、オルト蟻酸トリエチル等のオルト蟻酸エステル類と、触媒量の酢酸等の有機酸、塩酸等の鉱酸あるいはピリジン塩酸塩等のアミン類の鉱酸塩の存在下あるいは非存在下に反応して中間体得る。反応温度は室温〜150℃、好ましくは70℃〜100℃で、反応時間は2〜72時間である。これを単離あるいは単離せずにヒドロキシルアミンと適当な溶媒中(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)で処理し、式(1)の本発明化合物を製造することができる。
本発明の医薬は、かかる一般式(1)で表される化合物又はその製薬学的に許容される塩を有効成分として含有するものである。かかる医薬は、特に腎疾患、脳血管疾患又は循環器疾患治療薬として有用である。また、本発明の20−HETE産生阻害剤は、一般式(1)で表される化合物又はその製薬学的に許容される塩を有効成分とするものであり、20−HETE産生を有効に阻害する。
本発明に係る医薬、腎疾患、脳血管疾患、循環器疾患治療薬、20−HETE産生阻害剤投与量は、成人を治療する場合で、一般式(1)で表される化合物又はその製薬学的に許容される塩として、1日1〜2000mgが好ましく、これを1日1回又は数回に分けて投与することができる。この投与量は、用途、患者の年齢、体重及び症状等によって適宜増減することができる。
本発明に係る医薬、腎疾患、脳血管疾患、循環器疾患治療薬、20−HETE産生阻害剤は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、乳剤、懸濁剤、坐剤、注射剤などであり、いずれも慣用の製剤技術(例えば、第12改正日本薬局方に規定する方法)によって製造することができる。これらの投与剤型は、患者の症状、年齢及び治療の目的に応じて適宜選択することができる。各種剤型の製剤の製造においては、常用の賦形剤(例えば、結晶セルロース、デンプン、乳糖、マンニトールなど)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドンなど)、滑沢剤(例えば、ステアリン酸マグネシウム、タルクなど)、崩壊剤(例えば、カルボキシメチルセルロースカルシウムなど)などを用いることができる。
発明を実施するための最良の形態
次に実施例を示して本発明をさらに詳細に説明する。
実施例1
N−ヒドロキシ−N’−(3−クロロ−4−チオモルホリノフェニル)ホルムアミジンの合成
3−クロロ−4−フルオロニトロベンゼン(0.070g,0.4mmol)及びチオモルホリン(0.165g,1.6mmol)の混合物を70℃にて16時間攪拌した。反応混合物を室温まで冷却し、減圧下濃縮後、シリカゲルカラムクロマトグラフィー(展開溶媒クロロホルム:メタノール=9:1)にて精製し黄色粉末晶を得た。これに鉄粉(0.27g,4.83mmol)、イソプロパノール(0.5ml)及び1当量塩化アンモニウム水溶液(0.12ml,0.12mmol)を加え、70℃にて16時間攪拌した。反応混合物を室温まで冷却し、テトラヒドロフラン(0.4ml)を加え、セライトにて不溶物を濾去し、酢酸エチル(0.4ml)にて4回洗浄した。濾液を減圧下濃縮後、メタノール(0.4ml)及びジメチルホルムアミド ジメチルアセタール(0.095g,0.8mmol)を加え、70℃にて64時間攪拌した。反応混合物を室温まで冷却し、減圧下濃縮後、メタノール(0.4ml)及びヒドロキシルアミン塩酸塩(0.033g,0.48mmol)を加え、室温にて6時間攪拌した。反応混合物を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液(0.4ml)を加え、酢酸エチルで抽出した。有機層を減圧下濃縮後、NH型シリカゲルカラムクロマトグラフィー(展開溶媒ノルマルヘキサン:酢酸エチル=1:1)にて精製し、酢酸エチル/ノルマルヘキサンにて再結晶して無色粉末の標題化合物(後述する表1の化合物3)を得た(0.026g)。
融点137.0〜138.5℃
実施例2
N−[2−(モルホリノ)ピリジン−5−イル]−N’−ヒドロキシホルムアミジンの合成
2−クロロ−5−ニトロピリジン(2g,12.6mmol)及びモルホリン(4.4g,50.5mmol)の混合物を室温にて1時間攪拌した。反応混合物に水を加え、析出した結晶を濾取し、黄色粉末晶を得た。これにメタノール(30ml)及びパラジウムカーボン(0.25g)を加え、水素雰囲気下、室温にて4時間攪拌し、セライトにて不溶物を濾去した後、濾液を減圧下濃縮した。得られた残査にメタノール(20ml)及びジメチルホルムアミド ジメチルアセタール(1.81g,15.2mmol)を加え、還流下2時間攪拌した。反応混合物を室温まで冷却し、減圧下濃縮後、メタノール(20ml)及びヒドロキシルアミン塩酸塩(1.05g,15.2mmol)を加え、室温にて4時間攪拌した。反応混合物を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液(10ml)を加え、酢酸エチルで抽出した。有機層をMgSO4乾燥、減圧下濃縮後、NH型シリカゲルカラムクロマトグラフィー(展開溶媒ノルマルヘキサン:酢酸エチル=1:1)にて精製し、酢酸エチルにて再結晶して無色粉末の標題化合物(後述する表1の化合物127)を得た(0.985g)。
融点172.0〜174.0℃
以下、各々対応する出発原料を用い、実施例1又は2と同様の反応操作を行い、下記表に示す化合物を合成した。なお、化合物3及び127としてそれぞれ実施例1及び2で得られた化合物も併せて示す。
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。
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)を算出した。その結果についても上記表に併せて示す。
産業上の利用可能性
一般式(1)で表される化合物又はその製薬学的に許容される塩は、20−HETE産生阻害剤として有用である。また、医薬、特に腎疾患、脳血管疾患、循環器疾患治療薬として有用である。
Claims (3)
- 一般式
[式中、R1は置換モルホリノ基、置換ピペリジノ基、ピペラジン−1−イル基、置換ピペラジン−1−イル基、チオモルホリン−1−イル基、ペルヒドロアゼピン−1−イル基、ペルヒドロアゾシン−1−イル基、テトラヒドロピリジン−1−イル基、ピロリン−1−イル基、1,4−ジオキサ−8−アザスピロ[4,5]デカン−8−イル基又はデカヒドロキノリン−1−イル基のうちのいずれかであり、Xは窒素原子又はCR5で表される基であり、R2〜R5は同一又は相異なって水素原子、C1−4アルキル基、C1−4アルコキシ基、トリフルオロメチル基又はハロゲン原子である。]で表されるヒドロキシホルムアミジン化合物又はその製薬学的に許容される塩。 - 一般式
[式中、R1は置換モルホリノ基、置換ピペリジノ基、ピペラジン−1−イル基、置換ピペラジン−1−イル基、チオモルホリン−1−イル基、ペルヒドロアゼピン−1−イル基、ペルヒドロアゾシン−1−イル基、テトラヒドロピリジン−1−イル基、ピロリン−1−イル基、1,4−ジオキサ−8−アザスピロ[4,5]デカン−8−イル基、デカヒドロキノリン−1−イル基、モノ若しくはジ−(C1−4アルコキシ−C1−6アルキル)アミノ基又はモノ若しくはジ−(C1−6ヒドロキシアルキル)アミノ基のうちのいずれかであり、Xは窒素原子又はCR5で表される基であり、R2〜R5は同一又は相異なって水素原子、C1−4アルキル基、C1−4アルコキシ基、トリフルオロメチル基又はハロゲン原子である。]で表されるヒドロキシホルムアミジン化合物又はその製薬学的に許容される塩を有効成分とする20−ヒドロキシエイコサテトラエン酸産生阻害剤。 - 腎疾患、脳血管疾患又は循環器疾患治療薬である請求の範囲第2項記載の20−ヒドロキシエイコサテトラエン酸産生阻害剤。
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EP (1) | EP1389611B1 (ja) |
JP (1) | JP4120401B2 (ja) |
KR (1) | KR100819322B1 (ja) |
CN (1) | CN1272313C (ja) |
AU (1) | AU2002253633B2 (ja) |
CA (1) | CA2445329C (ja) |
HK (1) | HK1075885A1 (ja) |
WO (1) | WO2002088071A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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KR100776095B1 (ko) * | 2000-06-15 | 2007-11-15 | 다이쇼 세이야꾸 가부시끼가이샤 | 히드록시포름아미딘 유도체 및 이들을 포함하는 의약 |
US6818662B2 (en) | 2002-05-28 | 2004-11-16 | Taisho Pharmaceutical Co., Ltd. | Pharmaceutical composition |
WO2008034011A2 (en) | 2006-09-13 | 2008-03-20 | Mcw Research Foundation, Inc. | Methods of modulating cell proliferation and cyst formation in polycystic kidney and liver diseases |
Family Cites Families (7)
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AU3022984A (en) * | 1983-07-15 | 1985-01-17 | Nippon Soda Co., Ltd. | Formamidoxime derivatives |
DE4204686A1 (de) | 1992-02-17 | 1993-08-19 | Gruenenthal Gmbh | Imidazolylphenolderivate, diese enthaltende arzneimittel sowie ein verfahren zur herstellung dieser verbindungen und arzneimitteln |
US6395781B1 (en) | 1998-02-26 | 2002-05-28 | Mcw Research Foundation | 20-HETE antagonists and agonists |
ES2256053T3 (es) | 1999-11-01 | 2006-07-16 | Taisho Pharmaceutical Co., Ltd | Inhibidor de la enzima de produccion de 20-hete. |
JP2001354656A (ja) | 2000-06-15 | 2001-12-25 | Taisho Pharmaceut Co Ltd | ヒドロキシホルムアミジン化合物及びその塩並びにそれらを含む医薬 |
JP2001354658A (ja) | 2000-06-15 | 2001-12-25 | Taisho Pharmaceut Co Ltd | ヒドロキシホルムアミジン化合物及びその塩並びにそれらを含む医薬 |
KR100776095B1 (ko) | 2000-06-15 | 2007-11-15 | 다이쇼 세이야꾸 가부시끼가이샤 | 히드록시포름아미딘 유도체 및 이들을 포함하는 의약 |
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2002
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Also Published As
Publication number | Publication date |
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KR20040015135A (ko) | 2004-02-18 |
EP1389611A4 (en) | 2006-06-07 |
US7214714B2 (en) | 2007-05-08 |
CN1272313C (zh) | 2006-08-30 |
HK1075885A1 (en) | 2005-12-30 |
CA2445329C (en) | 2010-02-16 |
KR100819322B1 (ko) | 2008-04-02 |
AU2002253633B2 (en) | 2007-01-18 |
EP1389611A1 (en) | 2004-02-18 |
CN1633413A (zh) | 2005-06-29 |
CA2445329A1 (en) | 2002-11-07 |
WO2002088071A1 (en) | 2002-11-07 |
JPWO2002088071A1 (ja) | 2004-08-12 |
US20040121997A1 (en) | 2004-06-24 |
EP1389611B1 (en) | 2012-06-27 |
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