CN1250209C - 20-羟基二十碳四烯酸合成酶抑制剂 - Google Patents
20-羟基二十碳四烯酸合成酶抑制剂 Download PDFInfo
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- CN1250209C CN1250209C CNB008148562A CN00814856A CN1250209C CN 1250209 C CN1250209 C CN 1250209C CN B008148562 A CNB008148562 A CN B008148562A CN 00814856 A CN00814856 A CN 00814856A CN 1250209 C CN1250209 C CN 1250209C
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- alkyl
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- replaces
- halogen atom
- base
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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 abstract description 24
- 239000003112 inhibitor Substances 0.000 title abstract 3
- 108090000790 Enzymes Proteins 0.000 title description 3
- 102000004190 Enzymes Human genes 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 8
- 208000017169 kidney disease Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- -1 methoxyl group Chemical group 0.000 claims description 223
- 125000000217 alkyl group Chemical group 0.000 claims description 176
- 125000005843 halogen group Chemical group 0.000 claims description 121
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 62
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 60
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 46
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 30
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 26
- 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 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 24
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000005936 piperidyl group Chemical group 0.000 claims description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 19
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000001544 thienyl group Chemical group 0.000 claims description 18
- 125000002541 furyl group Chemical group 0.000 claims description 17
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 17
- 125000000335 thiazolyl group Chemical group 0.000 claims description 17
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 16
- 125000005504 styryl group Chemical group 0.000 claims description 15
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 14
- 125000003368 amide group Chemical group 0.000 claims description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 13
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 150000002790 naphthalenes Chemical class 0.000 claims description 10
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 9
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 8
- 125000000094 2-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 8
- 241001597008 Nomeidae Species 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 8
- CNMOHEDUVVUVPP-UHFFFAOYSA-N piperidine-2,3-dione Chemical compound O=C1CCCNC1=O CNMOHEDUVVUVPP-UHFFFAOYSA-N 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 239000012622 synthetic inhibitor Substances 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims 3
- 150000002220 fluorenes Chemical group 0.000 claims 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims 1
- 239000004615 ingredient Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 173
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 150000001875 compounds Chemical class 0.000 description 45
- 125000003545 alkoxy group Chemical group 0.000 description 41
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 125000002757 morpholinyl group Chemical group 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 239000002131 composite material Substances 0.000 description 12
- 238000010276 construction Methods 0.000 description 12
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 125000000842 isoxazolyl group Chemical group 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 10
- 239000002175 thienopyridine Substances 0.000 description 10
- 229940125670 thienopyridine Drugs 0.000 description 10
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 10
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 10
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 9
- 125000002098 pyridazinyl group Chemical group 0.000 description 9
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 7
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000006620 amino-(C1-C6) alkyl group Chemical group 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
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 6
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical group C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000004193 piperazinyl group Chemical group 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 description 4
- 125000003566 oxetanyl group Chemical group 0.000 description 4
- 125000005475 oxolanyl group Chemical group 0.000 description 4
- 229960005222 phenazone Drugs 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
- HWJMXFOOQWFOCE-UHFFFAOYSA-N 1,2-dihydroimidazo[2,1-b][1,3]benzothiazole Chemical group C1=CC=C2N3CCN=C3SC2=C1 HWJMXFOOQWFOCE-UHFFFAOYSA-N 0.000 description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical group C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical group O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 3
- 125000005606 carbostyryl group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 description 3
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000005581 pyrene group Chemical group 0.000 description 3
- 229930185107 quinolinone Natural products 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical group OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 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
- 125000005543 phthalimide group Chemical group 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
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003248 quinolines Chemical group 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 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
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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Abstract
本发明是以特定的羟基甲脒衍生物及其药物上可接受的盐作为有效成分的20-羟基二十碳四烯酸合成抑制剂。本发明的化合物特别可用作肾疾病、脑血管疾病或循环器官疾病的治疗剂。此外,本发明还提供新的羟基甲脒衍生物或其药物上可接受的盐。
Description
技术领域
本发明涉及能抑制从花生四烯酸生物合成的20-羟基二十碳四烯酸(20-HETE)的合成酶的羟基亚胺甲基氨基苯衍生物。
背景技术
作为从花生四烯酸合成的生理活性物质,通过环氧酶产生的前列腺素和通过脂氧合酶产生的各种白细胞三烯已广为人知。近年来,已经弄清楚,通过细胞色素p450属的酶的作用从花生四烯酸产生的20-HETE在活体内起着多种作用(J.Vascular Research(血管研究杂志),Vol.32,P.79(1995))。已有报导,20-HETE会引起肾脏和脑血管等主要器官中微血管的收缩或扩张,并引起细胞增殖,因此有人认为20-HETE在活体内起着重要的生理作用,并与各种肾脏疾病、脑血管疾病或循环器官疾病等各种病症有密切关系。(血管研究杂志,Vol.32,P.79(1995),J.Physiol.(生理学杂志),Vol.277,P.R607(1999)等)。
发明的公开内容
本发明的目的是提供一种能抑制与引起肾脏和脑血管等主要器官中微血管的收缩或扩张,或细胞增殖有密切关系的20-HETE的产生的药剂。
本发明者们为了解决上述问题进行了各种研究,结果发现,具有特异部分结构的芳族化合物对20-HETE合成酶具有意想不到的抑制作用,从而完成了本发明。
即,本发明的一种形态是含有下面通式(1)表示的羟基甲脒衍生物及其药物上可接受的盐作为有效成分的20-羟基二十碳四烯酸合成抑制剂:
式中,R1-R5相同或不同,代表氢原子;羟基;羧基;卤原子;C1-14烷基;被1-6个卤原子取代的C1-14烷基;C2-6链烯基;C1-6烷氧基C1-6烷基;C3-6环烷基C1-6烷基;C2-6炔基;C3-8环烷基;C3-8环烷氧基;C2-10链烷酰基;C1-6羟烷基;被1-6个卤原子取代的C1-6羟烷基;C2-6烷氧羰基;3-苯基-2-丙烯氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;一或二-(C1-6烷基)氨基;C2-10链烷酰氨基;被C-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氨基甲酰基;被C1-6烷基或苯基一或二取代的氨基甲酰基;N-(N′,N′-二(C1-6烷基)氨基C1-6烷基)氨基甲酰基;氰基;氰基C1-6烷基;硝基;巯基;苯氧基;被1-3个选自C1-6烷基、C1-6烷氧基和卤原子的基团取代的苯氧基;苯硫基;硝基苯硫基;C1-6烷基磺酰基;苯磺酰基;C1-6烷硫基C1-6烷基;苯环被1-5个卤原子取代的苯磺酰基C1-6烷硫基;苯基;苄基;被1-3个选自氰基、卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;被二环[2.2.1]-庚-5-烯-2,3-二羧基imidyl取代的苄基;苯甲酰基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;吡咯烷子基;哌啶子基;吗啉代基;吡啶基;嘧啶基;被1-3个选自C1-6烷基和C1-6烷氧基的基团取代的嘧啶基;邻苯二甲酰亚氨基;被1-3个卤原子取代的邻苯二甲酰亚氨基;N-卡唑基;被1-3个C1-6烷基取代的二氧代哌啶基;苯磺酰氨基;被1-3个C1-6烷基取代的苯磺酰氨基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;噁二唑基;被1-3个选自卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基取代的噁二唑基;吡咯烷基;吡唑基;被1-3个选自卤原子、C1-6烷基和三氟甲基的基团取代的吡唑基;呋喃基;被1-3个选自卤原子、C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;噻吩并嘧啶基硫基;被1-3个C1-6烷基取代的噻吩并嘧啶基硫基;噻吩并吡啶基硫基;被1-3个C1-6烷基取代的噻吩并吡啶基硫基;苯并噻唑基硫基;被1-3个卤原子取代的苯并噻唑基硫基;通式-Y-(CR61R62)m-(CR63R64)n-R7所示的基团,式中Y是氧原子或硫原子;R61、R62、R63和R64相同或不同,代表氢原子、卤原子、C1-4烷基或三氟甲基;R7代表氢原子;卤原子;C1-14烷基;C3-8环烷基;C3-8环烷氧基;C2-10链烯基;C2-6炔基;苯基;被1-3个选自硝基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6羟烷基;C1-6烷氧基C1-6烷氧基;C1-6烷氧基C1-6烷氧基C1-6烷氧基;C1-6烷硫基;C2-6链烷酰氧基;C2-6链烷酰氧C1-6烷基;苯氧基;苯硫基;N-C1-6烷基甲苯氨基;吡咯烷子基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;被C1-6烷基取代的哌啶子基;被C1-6烷氧基取代的吡啶基;被C1-6烷基取代的吡咯烷子基;被C1-6烷基取代的吗啉代基;吗啉基;被C1-6烷基取代的吗啉基;高吗啉基;硫代吗啉代基;被C1-6烷基取代的硫代吗啉代基;硫代吗啉基,被C1-6烷基取代的硫代吗啉基;哌嗪基;4-位被C1-6烷基取代的哌嗪-1-基;高哌啶基;被C1-6烷基取代的高哌啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基(oxetanyl);氧杂环戊基(oxolanyl);二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基(oxanyl);二噁烷基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;吡咯烷基;N-(C1-6烷基)吡咯烷基;哌啶基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;噻唑基;被1-3个C1-6烷基取代的噻唑基;被C1-6烷基取代的2,6-嘌呤二酮-7-基;糠基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m是1-6的整数;以及n是0-6的整数;或通式-SO2NR8R9所示的基团,式中R8和R9相同或不同,代表氢原子、C1-10烷基、C2-6链烷酰基、异噁唑基、被1-3个C1-6烷基取代的异噁唑基、噻二唑基、被1-3个C1-6烷基取代的噻二唑基、噻唑基、被1-3个C1-6烷基取代的噻唑基、吡啶基、被1-3个C1-6烷基取代的吡啶基、嘧啶基、被1-3个C1-6烷基取代的嘧啶基、被1-3个C1-6烷氧基取代的嘧啶基、哒嗪基、被1-3个C1-6烷氧基取代的哒嗪基、吲唑基或被C1-6烷基一或二取代的氨基甲酰基,或者替代地,与它们所连接的氮原子一起形成一个3,5-二氧代哌嗪-1-基(piperadino)、吡咯烷基、哌啶子基或吗啉代基,或者,替代地,
R1-R5中2个相邻的基团与它们所连接的苯环一起形成一个邻苯二甲酰亚氨环;被C1-6烷基取代的邻苯二甲酰亚氨环;吲哚环;1,2-二氢化茚环;吲唑环;苯并三唑环;S,S-二氧代苯并噻吩环;2,3-二氢化咪唑并[2,1-b]苯并噻唑环;二苯并呋喃环;被C1-6烷氧基取代的二苯并呋喃环;芴环;被卤原子取代的芴环,芘环;喹诺酮(carbostyryl)环;被C1-6烷基取代的喹诺酮环;萘环;被1-3个选自氰基、卤原子、硝基和C1-6烷基的基团取代的萘环;1,2,3,4-四氢萘环;喹啉环;被C1-6烷基取代的喹啉环;异喹啉环;2-氧代-α-苯并二氢吡喃环;被1-3个选自C1-6烷基、C1-6烷氧基和C1-6烷氧基C1-6烷基的基团取代的2-氧代-α-苯并二氢吡喃环;内啉环;被C1-6烷基取代的肉啉环;2,3-二氮杂萘;苯并噻唑环;被C1-6烷基取代的苯并噻唑环;苯并二氧戊环环;或苯并丁内酯环。
在上述通式(1)中,优选的是R1-R5相同或不同,代表氢原子;羟基;羧基;卤原子;C1-14烷基;被1-6个卤原子取代的C1-14烷基;C2-6炔基;C3-8环烷基;C3-8环烷氧基;C2-10链烷酰基;C1-6羟烷基;被1-6个卤原子取代的C1-6羟烷基;C2-6烷氧羰基;3-苯基-2-丙烯氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;一或二一(C1-6烷基)氨基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氨基甲酰基;被C1-6烷基或苯基一或二取代的氨基甲酰基;N-(N′,N′-二(C1-6烷基)氨基C1-6烷基)氨基甲酰基;氰基;氰基C1-6烷基;硝基;巯基;苯氧基;被1-3个选自C1-6烷基、C1-6烷氧基和卤原子的基团取代的苯氧基;苯硫基;硝基苯硫基;C1-6烷基磺酰基;苯磺酰基;C1-6烷硫基C1-6烷基;苯环被1-5个卤原子取代的苯磺酰基C1-6烷硫基;苯基;苄基;被1-3个选自氰基、卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;被二环[2.2.1]-庚-5-烯-2,3-二羧基imidyl取代的苄基;苯甲酰基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;吡咯烷子基;哌啶子基;吗啉代基;吡啶基;嘧啶基;被1-3个选自C1-6烷基和C1-6烷氧基的基团取代的嘧啶基;邻苯二甲酰亚氨基;被1-3个卤原子取代的邻苯二甲酰亚氨基;N-卡唑基;被1-3个C1-6烷基取代的二氧代哌啶基;苯磺酰氨基;被1-3个C1-6烷基取代的苯磺酰氨基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;噁二唑基;被1-3个选自卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基取代的噁二唑基;吡咯烷基;吡唑基;被1-3个选自卤原子、C1-6烷基和三氟甲基的基团取代的吡唑基;呋喃基;被1-3个选自卤原子、C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;噻吩并嘧啶基硫基;被1-3个C1-6烷基取代的噻吩并嘧啶基硫基;噻吩并吡啶基硫基;被1-3个C1-6烷基取代的噻吩并吡啶基硫基;苯并噻唑基硫基;被1-3个卤原子取代的苯并噻唑基硫基;或通式-Y-(CR61R62)m-(CR63R64)n-R7所示的基团,式中y是氧原子或硫原子;R61、R62、R63和R64相同或不同,代表氢原子、卤原子、C1-4烷基或三氟甲基;R7代表氢原子;卤原子;C1-14烷基;C3-8环烷基;C3-8环烷氧基;C2-10链烯基;C2-6炔基;苯基;被1-3个选自硝基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6羟烷基;C1-6烷氧基C1-6烷氧基;C1-6烷氧基C1-6烷氧基C-6烷氧基;C1-6烷硫基;C2-6链烷酰氧基;C2-6链烷酰氧C1-6烷基;苯氧基;苯硫基;N-C1-6烷基甲苯氨基;吡咯烷子基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;被C1-6烷基取代的哌啶子基;被C1-6烷氧基取代的吡啶基;被C1-6烷基取代的吡咯烷子基;被C1-6烷基取代的吗啉代基;吗啉基;被C1-6烷基取代的吗啉基;高吗啉基;硫代吗啉代基;被C1-6烷基取代的硫代吗啉代基;硫代吗啉基,被C1-6烷基取代的硫代吗啉基;哌嗪基;4-位被C1-6烷基取代的哌嗪-1-基;高哌啶基;被C1-6烷基取代的高哌啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基(oxetanyl);氧杂环戊基(oxolanyl);二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基(oxanyl);二噁烷基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;吡咯烷基;N-(C1-6烷基)吡咯烷基;哌啶基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;噻唑基;被1-3个C1-6烷基取代的噻唑基;被C1-6烷基取代的2,6-嘌呤二酮-7-基;糠基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m是1-6的整数;以及n是0-6的整数。
此外,在本发明的20-羟基二十碳四烯酸合成酶抑制剂中,优选的是在通式(1)化合物中,以R1、R2、R3、R4和R5为氢原子的化合物及其药物上可接受的盐作为有效成分。
此外,本发明的其它形态是上述通式(1)化合物中具有新化学结构的羟基甲脒衍生物或其药物上可接受的盐。
即,本发明的其它形态是下面通式(2)表示的羟基甲脒衍生物或其药物上可接受的盐:
式中,R11-R55中至少1个代表C5-14烷基;C2-6链烯基;C3-8环烷基C1-6烷基;C2-6炔基;C3-8环烷基;C3-8环烷氧基;C2-10链烷酰基;C1-6羟烷基;被1-6个卤原子取代的C1-6羟烷基;C2-6烷氧羰基;3-苯基-2-丙烯氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;一或二-(C1-6烷基)氨基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氨基甲酰基;被C1-6烷基或苯基一或二取代的氨基甲酰基;N-(N′,N′-二(C1-6烷基)氨基C1-6烷基)氨基甲酰基;氰基;氰基C1-6烷基;C1-6烷基磺酰基;苯磺酰基;C1-6烷硫基C1-6烷基;苯环被1-5个卤原子取代的苯磺酰基C1-6烷硫基;苯基;苄基;被1-3个选自氰基、卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;被二环[2.2.1]-庚-5-烯-2,3-二羧基imidyl取代的苄基;苯甲酰基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;吡咯烷子基;哌啶子基;吗啉代基;吡啶基;嘧啶基;被1-3个选自C1-6烷基和C1-6烷氧基的基团取代的嘧啶基;邻苯二甲酰亚氨基;被1-3个卤原子取代的邻苯二甲酰亚氨基;N-卡唑基;被1-3个C1-6烷基取代的二氧代哌啶基;苯磺酰氨基;被1-3个C1-6烷基取代的苯磺酰氨基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;噁二唑基;被1-3个选自卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基取代的噁二唑基;吡咯烷基;吡唑基;被1-3个选自卤原子、C1-6烷基和三氟甲基的基团取代的吡唑基;呋喃基;被1-3个选自卤原子、C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;噻吩并嘧啶基硫基;被1-3个C1-6烷基取代的噻吩并嘧啶基硫基;噻吩并吡啶基硫基;被1-3个C1-6烷基取代的噻吩并吡啶基硫基;苯并噻唑基硫基;被1-3个卤原子取代的苯并噻唑基硫基;通式-Y-(CR61R62)m-(CR63R64)n-R77所示的基团,式中Y是氧原子或硫原子;R61、R62、R63和R64相同或不同,代表氢原子、卤原子、C1-4烷基或三氟甲基;R77代表卤原子;C4-14烷基;C3-8环烷基;C3-8环烷氧基;C1-10链烯基;C2-6炔基;苯基;被1-3个选自硝基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6烷氧基C1-6烷氧基;C1-6烷氧基C1-6烷氧基C1-6烷氧基;C1-6羟烷基;C3-8环烷氧基;C1-6烷硫基;C2-6链烷酰氧基;C2-6链烷酰氧C1-6烷基;苯氧基;苯硫基;N-C1-6烷基甲苯氨基;吡咯烷子基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;被C1-6烷基取代的哌啶子基;被C1-6烷氧基取代的吡啶基;被C1-6烷基取代的吡咯烷子基;被C1-6烷基取代的吗啉代基;吗啉基;被C1-6烷基取代的吗啉基;高吗啉基;硫代吗啉代基;被C1-6烷基取代的硫代吗啉代基;硫代吗啉基,被C1-6烷基取代的硫代吗啉基;哌嗪基;4-位被C1-6烷基取代的哌嗪-1-基;高哌啶基;被C1-6烷基取代的高哌啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基(oxetanyl);氧杂环戊基(oxolanyl);二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基(oxanyl);二噁烷基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;吡咯烷基;N-(C1-6烷基)吡咯烷基;哌啶基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;噻唑基;被1-3个C1-6烷基取代的噻唑基;被C1-6烷基取代的2,6-嘌呤二酮-7-基;糠基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m是1-6的整数;以及n是0-6的整数;或通式-SO2NR8R9所示的基团,式中R8和R9相同或不同,代表氢原子、C1-10烷基、C2-6链烷酰基、异噁唑基、被1-3个C1-6烷基取代的异噁唑基、噻二唑基、被1-3个C1-6烷基取代的噻二唑基、噻唑基、被1-3个C1-6烷基取代的噻唑基、吡啶基、被1-3个C1-6烷基取代的吡啶基、嘧啶基、被1-3个C1-6烷基取代的嘧啶基、被1-3个C1-6烷氧基取代的嘧啶基、哒嗪基、被1-3个C1-6烷氧基取代的哒嗪基、吲唑基或被C1-6烷基一或二取代的氨基甲酰基,或者替代地,与它们所连接的氮原子一起形成一个3,5-二氧代哌嗪-1-基(piperadino)、吡咯烷基、哌啶子基或吗啉代基,或者,替代地,
R11-R55中2个相邻的基团与它们所连接的苯环一起形成一个邻苯二甲酰亚氨环;被C1-6烷基取代的邻苯二甲酰亚氨环;吲哚环;1,2-二氢化茚环;吲唑环;苯并三唑环;S,S-二氧代苯并噻吩环;2,3-二氢化咪唑并[2,1-b]苯并噻唑环;二苯并呋喃环;被C1-6烷氧基取代的二苯并呋喃环;芴环;被卤原子取代的芴环,芘环;喹诺酮(carbostyryl)环;被C1-6烷基取代的喹诺酮环;萘环;被1-3个选自氰基、卤原子、硝基和C1-6烷基的基团取代的萘环;1,2,3,4-四氢萘环;喹啉环;被C1-6烷基取代的喹啉环;异喹啉环;2-氧代-α-苯并二氢吡喃环;被1-3个选自C1-6烷基、C1-6烷氧基和C1-6烷氧基C1-6烷基的基团取代的2-氧代-α-苯并二氢吡喃环;肉啉环;被C1-6烷基取代的肉啉环;2,3-二氮杂萘;苯并噻唑环;被C1-6烷基取代的苯并噻唑环;苯并二氧戊环环;或苯并丁内酯环,而R11-R55中的其它基团可以相同或不同,代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基、硝基或卤原子。
在通式(2)的化合物中,R11-R55中至少1个代表C5-14烷基;C2-6炔基;C3-8环烷基;C3-8环烷氧基;C2-10链烷酰基;C1-6羟烷基;被1-6个卤原子取代的C1-6羟烷基;C2-6烷氧羰基;3-苯基-2-丙烯氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;一或二-(C1-6烷基)氨基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氨基甲酰基;被C1-6烷基或苯基一或二取代的氨基甲酰基;N-(N′,N′-二(C1-6烷基)氨基C1-6烷基)氨基甲酰基;氰基;氰基C1-6烷基;C1-6烷基磺酰基;苯磺酰基;C1-6烷硫基C1-6烷基;苯环被1-5个卤原子取代的苯磺酰基C1-6烷硫基;苯基;苄基;被1-3个选自氰基、卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;被二环[2.2.1]-庚-5-烯-2,3-二羧基imidyl取代的苄基;苯甲酰基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;吡咯烷子基;哌啶子基;吗啉代基;吡啶基;嘧啶基;被1-3个选自C1-6烷基和C1-6烷氧基的基团取代的嘧啶基;邻苯二甲酰亚氨基;被1-3个卤原子取代的邻苯二甲酰亚氨基;N-卡唑基;被1-3个C1-6烷基取代的二氧代哌啶基;苯磺酰氨基;被1-3个C1-6烷基取代的苯磺酰氨基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;噁二唑基;被1-3个选自卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基取代的噁二唑基;吡咯烷基;吡唑基;被1-3个选自卤原子、C1-6烷基和三氟甲基的基团取代的吡唑基;呋喃基;被1-3个选自卤原子、C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;噻吩并嘧啶基硫基;被1-3个C1-6烷基取代的噻吩并嘧啶基硫基;噻吩并吡啶基硫基;被1-3个C1-6烷基取代的噻吩并吡啶基硫基;苯并噻唑基硫基;被1-3个卤原子取代的苯并噻唑基硫基;或通式-SO2NR8R9所示的基团,式中R8和R9相同或不同,代表氢原子、C1-10烷基、C2-6链烷酰基、异噁唑基、被1-3个C1-6烷基取代的异噁唑基、噻二唑基、被1-3个C1-6烷基取代的噻二唑基、噻唑基、被1-3个C1-6烷基取代的噻唑基、吡啶基、被1-3个C1-6烷基取代的吡啶基、嘧啶基、被1-3个C1-6烷基取代的嘧啶基、被1-3个C1-6烷氧基取代的嘧啶基、哒嗪基、被1-3个C1-6烷氧基取代的哒嗪基、吲唑基或被C1-6烷基一或二取代的氨基甲酰基,或者替代地,与它们所连接的氮原子一起形成一个3,5-二氧代哌嗪-1-基(piperadino)、吡咯烷基、哌啶子基或吗啉代基,或者,替代地,
R11-R55中2个相邻的基团与它们所连接的苯环一起形成一个邻苯二甲酰亚氨环;被C1-6烷基取代的邻苯二甲酰亚氨环;吲哚环;1,2-二氢化茚环;吲唑环;苯并三唑环;S,S-二氧代苯并噻吩环;2,3-二氢化咪唑并[2,1-b]苯并噻唑环;二苯并呋喃环;被C1-6烷氧基取代的二苯并呋喃环;芴环;被卤原子取代的芴环,芘环;喹诺酮(carbostyryl)环;被C1-6烷基取代的喹诺酮环;萘环;被1-3个选自氰基、卤原子、硝基和C1-6烷基的基团取代的萘环;1,2,3,4-四氢萘环;喹啉环;被C1-6烷基取代的喹啉环;异喹啉环;2-氧代-α-苯并二氢吡喃环;被1-3个选自C1-6烷基、C1-6烷氧基和C1-6烷氧基C1-6烷基的基团取代的2-氧代-α-苯并二氢吡喃环;肉啉环;被C1-6烷基取代的肉啉环;2,3-二氮杂萘;苯并噻唑环;被C1-6烷基取代的苯并噻唑环;苯并二氧戊环环;或苯并丁内酯环,而R11-R55中的其它基团可以相同或不同,代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基、硝基或卤原子。
在这种情况下,优选的是R11-R55中至少1个代表C5-14烷基;C2-6炔基;C3-8环烷基;C3-8环烷氧基;C2-10链烷酰基;C1-6羟烷基;被1-6个卤原子取代的C1-6羟烷基;C2-6烷氧羰基;3-苯基-2-丙烯氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;一或二-(C1-6烷基)氨基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;氨基甲酰基;被C1-6烷基或苯基一或二取代的氨基甲酰基;N-(N′,N′-二(C1-6烷基)氨基C1-6烷基)氨基甲酰基;氰基;氰基C1-6烷基;C1-6烷基磺酰基;苯磺酰基;C1-6烷硫基C1-6烷基;苯基;苄基;被1-3个选自氰基、卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;苯甲酰基;吡咯烷子基;哌啶子基;吗啉代基;吡啶基;嘧啶基;被1-3个选自C1-6烷基和C1-6烷氧基的基团取代的嘧啶基;吡咯烷基;吡唑基;被1-3个选自卤原子、C1-6烷基的三氟甲基的基团取代的吡唑基;呋喃基;被1-3个选自卤原子、C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;或通式-SO2NR8R9所示的基团,式中R8和R9相同或不同,代表氢原子、C1-10烷基、C2-6链烷酰基、异噁唑基、被1-3个C1-6烷基取代的异噁唑基、噻二唑基、被1-3个C1-6烷基取代的噻二唑基、噻唑基、被1-3个C1-6烷基取代的噻唑基、吡啶基、被1-3个C1-6烷基取代的吡啶基、嘧啶基、被1-3个C1-6烷基取代的嘧啶基、被1-3个C1-6烷氧基取代的嘧啶基、哒嗪基、被1-3个C1-6烷氧基取代的哒嗪基、吲唑基或被C1-6烷基一或二取代的氨基甲酰基,或者替代地,与它们所连接的氮原子一起形成一个3,5-二氧代哌嗪-1-基(piperadino)、吡咯烷基、哌啶子基或吗啉代基,而R11-R55中的其它基团可以相同或不同,代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基、硝基或卤原子。
另一方面,在通式(2)的化合物中,R11-R55中至少1个代表通式-Y-(CR61R62)m-(CR63R64)n-R77所示的基团,式中Y是氧原子或硫原子;R61、R62、R63和R64相同或不同,代表氢原子、卤原子、C1-4烷基或三氟甲基;R77代表卤原子;C4-14烷基;C3-8环烷基;C3-8环烷氧基;C2-10链烯基;C2-6炔基;苯基;被1-3个选自硝基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6烷氧基C1-6烷氧基;C1-6烷氧基C1-6烷氧基C1-6烷氧基;C1-6羟烷基;C3-8环烷氧基;C1-6烷硫基;C2-6链烷酰氧基;C2-6链烷酰氧C1-6烷基;苯氧基;苯硫基;N-C1-6烷基甲苯氨基;吡咯烷子基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;被C1-6烷基取代的哌啶子基;被C1-6烷氧基取代的吡啶基;被C1-6烷基取代的吡咯烷子基;被C1-6烷基取代的吗啉代基;吗啉基;被C1-6烷基取代的吗啉基;高吗啉基;硫代吗啉代基;被C1-6烷基取代的硫代吗啉代基;硫代吗啉基,被C1-6烷基取代的硫代吗啉基;哌嗪基;4-位被C1-6烷基取代的哌嗪-1-基;高哌啶基;被C1-6烷基取代的高哌啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基(oxetanyl);氧杂环戊基(oxolanyl);二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基(oxanyl);二噁烷基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;吡咯烷基;N-(C1-6烷基)吡咯烷基;哌啶基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;噻唑基;被1-3个C1-6烷基取代的噻唑基;被C1-6烷基取代的2,6-嘌呤二酮-7-基;糠基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m是1-6的整数;以及n是0-6的整数,而R11-R55中的其它基团可以相同或不同,代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基、硝基或卤原子。
在这种情况下,优选的是,R11-R55中至少1个代表通式-O-(CR61R62)m-(CR63R64)n-R77所示的基团,式中R61、R62、R63和R64相同或不同,代表氢原子、卤原子、C1-4烷基或三氟甲基;R77代表二(C1-6烷基)氨基;二(C1-6烷基)氨基-C1-6烷氧基;哌啶基;被C1-6烷基取代的哌啶基;哌啶子基;被C1-6烷基取代的哌啶子基;吡啶基;被C1-6烷基取代的吡啶基;被C1-6烷氧基取代的吡啶基;吡啶基硫基;吡咯烷子基;被C1-6烷基取代的吡咯烷子基;吡咯烷酮-1-基;吡咯烷基;被C1-6烷基取代的吡咯烷基;吡咯基;噻吩基;噻唑基;吗啉代基;被C1-6烷基取代的吗啉代基;吗啉基;被C1-6烷基取代的吗啉基;高吗啉基;硫代吗啉代基;被C1-6烷基取代的硫代吗啉代基;硫代吗啉基;被C1-6烷基取代的硫代吗啉基;哌嗪基;4位被C1-6烷基取代的哌嗪-1-基;高哌啶基;或被C1-6烷基取代的高哌啶基,m是1-6的整数;以及n是0-6的整数,而R11-R55中的其它基团可以相同或不同,代表氢原子、C1-4烷基、C1-4烷氧基、三氟甲基、硝基或卤原子。
此外,通式(2)的化合物中,优选的是其中R11、R22、R44和R55是氢原子,即只有苯环上羟基亚胺甲基氨基对位上的R33是非氢原子取代基的那些化合物。
本发明者们发现上述通式(1)和(2)的化合物具有抑制20-HETE合成酶的活性。因此,这类化合物可能用作肾脏疾病、脑血管疾病或循环器官疾病的治疗剂。
本发明中使用的术语定义如下。“Cx-y”表示其后的基团含有x-y个碳原子。
术语“卤原子”是指氟原子、氯原子、溴原子或碘原子。
术语“C1-4、C1-6、C1-8和C1-14烷基”是指碳原子数分别为1-4、1-6、1-8和1-14的直链或支化烷基,例如作为C1-14烷基可以列举甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基、异己基、庚基、辛基、壬基、癸基等。
术语“被1-6个卤原子取代的C1-14烷基”是指被1-6个卤原子取代的碳原子数为1-14的直链或支化烷基,优选被1-14个卤原子取代的甲基或乙基,例如可以列举二氟甲基、二溴甲基、三氟甲基、三氟乙基等。
术语“C2-6链烯基”是指含有双键的碳原子数为2-6的直链或支链链烯基,例如可以列举乙烯基、丙烯基、丁烯基等。
术语“C2-6炔基”是指含有三键的碳原子数为2-6的直链或支链炔基,例如可以列举乙炔基、丙炔基、丁炔基等。
术语“C3-8环烷基”是指碳原子数3-8的环状烷基,例如可以列举环丙基、环戊基、环己基等。
术语“C3-8环烷基C1-6烷基”是指具有C3-8环烷基和C1-6烷基的复合结构的基团,其例子有环丙基甲基、环丁甲基、环戊甲基、环己甲基等。
术语“C1-6烷氧基”是指碳原子数1-6的直链或支化烷基,例如可以列举甲氧基、乙氧基、丙氧基、异丙氧基、2,2-二甲基丙氧基、丁氧基、叔丁氧基、3-甲基丁氧基、3,3-二甲基丁氧基、3-甲基戊氧基、4-甲基戊氧基等。
术语“C1-6烷氧基1-6烷基”是指具有C1-6烷氧基和C1-6烷基的复合结构的基团,例如可以列举甲氧甲基、乙氧甲基、甲氧乙基、乙氧乙基、丙氧乙基、异丙氧乙基、丁氧乙基、叔丁氧乙基等。
术语“C3-8环烷氧基”是指碳原子数3-8的环状烷氧基,其例子有环丙氧基、环戊氧基、环己氧基等。
术语“C2-10链烷酰基”是指碳原子数2-10的直链或支化链烷酰基,例如可以列举乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基等,其中优选的是乙酰基。
术语“C1-6羟烷基”是指被羟基取代了的C1-6烷基,例如可以列举羟甲基、1-羟基乙基、2-羟基乙基、3-羟基丙基、2,3-二羟基乙基等,其中特别优选羟甲基、1-羟基乙基、2-羟基乙基、3-羟基丙基。
术语“C2-6链烷酰氧基C1-6烷基”是指前述的C1-6羟烷基中的羟基被C2-6链烷酰氧基取代了的基团,其例子是2,3-二乙酰氧乙基。
术语“被1-6个卤原子取代的C1-6羟烷基”是指被1-6个卤原子取代了的C1-6羟烷基,例如可以列举羟基氟甲基、1-羟基-2-氟乙基、2-羟基-2-氟乙基、3-羟基-2-氯丙基、2,3-二羟基-3-溴丙基、1,1,1,3,3,3-六氟-2-羟基丙基等,其中优选1,1,1,3,3,3-六氟-2-羟基丙基。
术语“C2-6烷氧羰基”是指具有直链或支化的C1-6烷氧基与羰基的复合结构的基团,例如可以列举甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基等,其中优选甲氧羰基、丙氧羰基。
术语“C2-6烷氧羰基C1-6烷基”是指C2-6烷氧羰基与C1-6烷基的复合结构的基团。因此,C2-6烷氧羰基C1-6烷基可用通式-(CH2)k-COOR14表示,式中k为1-6的整数;R14是C1-6烷基,例如包括-CH2COOCH3(甲氧羰基甲基)、-CH2COOCH2CH3(乙氧羰基甲基)、-CH2CH2COOCH3(甲氧羰基乙基)、-CH2CH2COOCH2CH3(乙氧羰基乙基)。其中特别优选乙氧羰基甲基。
术语“二(C1-6烷基)氨基C2-6烷氧羰基”是指具有被2个C1-6烷基取代的氨基与C2-6烷氧羰基的复合结构的基团,例如可以列举N,N-二乙基氨基乙氧羰基、N,N-二丁基氨基丙氧羰基。特别优选N,N-二乙基氨基乙氧羰基。
术语“一或二(C1-6烷基)氨基”是指被1个或2个C1-6烷基取代了的氨基,例如可以列举甲氨基、乙氨基、二甲氨基、二乙氨基等,其中优选二甲氨基。
术语“C2-10链烷酰氨基”是指被C2-10链烷酰基取代的氨基,例如可以举出乙酰氨基。此外,作为“被C1-6烷基取代的C2-10链烷酰氨基”的例子,可以举出N-乙酰基-N-甲基氨基。
作为“被C1-6烷基或苯基一或二取代的氨基甲酰基”的例子,可以列举N-甲基氨基甲酰基、N-丁基氨基甲酰基、N-苯基氨基甲酰基。作为“N-(N′,N′-二(C1-6烷基)氨基C1-6烷基)氨基甲酰基”的例子,可以举出N-(N′,N′-二乙基氨基乙基)氨基甲酰基。
术语“氰基C1-6烷基”是指具有氰基与C1-6烷基的复合结构的基团,例如可以列举氰甲基、氰乙基、氰丙基。其中特别优选氰甲基。
作为“被1-3个选自硝基、巯基、苯氧基、C1-6烷基、C1-6烷氧基和卤原子的基团取代的苯氧基”的例子,可以列举2-甲基苯氧基、3-甲基苯氧基、4-甲基苯氧基、2-甲氧基苯氧基、3-甲氧基苯氧基、4-甲氧基苯氧基、2-氯苯氧基、3-氯苯氧基、4-氯苯氧基等,其中优选2-甲基苯氧基、4-甲基苯氧基、2-甲氧基苯氧基、4-甲氧基苯氧基、4-氯苯氧基。
术语“C1-6烷基磺酰基”是指具有C1-6烷基与磺酰基(-SO2-)的复合结构的基团,例如可以列举甲磺酰基、乙磺酰基、丙磺酰基、异丙磺酰基、丁磺酰基、异丁磺酰基、叔丁磺酰基、戊磺酰基、异戊磺酰基等,优选甲磺酰基。
术语“C1-6烷硫基C1-6烷基”是指具有C1-6烷硫基与C1-6烷基的复合结构的基团,例如可以列举甲硫甲基、2-甲硫基乙基等,优选甲硫甲基。
术语“苯环被1-5个卤原子取代的苯磺酰基C1-6烷硫基”是指具有取代的苯磺酰基与C1-6烷硫基的复合结构的基团,例如可以列举4-氯苯磺酰基甲硫基等。
作为“被1-3个选自氰基、卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基”的例子,可以列举4-氰基苯基、4-氯苯基、4-甲基苯基、4-甲氧基苯基等,其中优选4-氰基苯基。作为“被1-5个卤原子取代的α-氰基苄基”的例子,可以列举α-氰基-4-氯苄基等。
作为“被1-5个选自C1-6烷氧基和C1-6烷氨基烷基的基团取代的苯乙烯基”的例子,可以列举4-甲氧基苯乙烯基、4-N,N-二甲基氨基苯乙烯基等。
作为“被1-3个选自C1-6烷基和C1-6烷氧基的基团取代的嘧啶基”的例子,可以列举6-甲氧基嘧啶-4-基、2-甲基嘧啶-4-基等。
作为“被1-3个卤原子取代的邻苯二甲酰亚氨基”的例子,可以列举5-氯-N-邻苯二甲酰亚氨基等。
作为“被1-3个C1-6烷基取代的二氧代哌啶基”的例子,可以列举2,6-二氧代-3-乙基哌啶-3-基等。
作为“被1-3个C1-6烷基取代的苯磺酰氨基”的例子,可以列举4-甲基苯磺酰氨基等。作为“C1-6烷基氨基磺酰基C1-6烷基”的例子,可以列举甲氨基磺酰基甲基等。
作为“被1-3个选自卤原子、C1-6烷基和C1-6烷氧基的基团取代的苯基取代的噁二唑基”的例子,可以列举例如噁二唑环被有叔丁基、甲氧基、溴原子取代的苯基取代的基团。更具体说,可以列举5-(对叔丁基苯基)噁二唑-2-基、5-(间甲氧基苯基)噁二唑-2-基等。
作为“被1-3个选自卤原子、C1-6烷基和三氟甲基的基团取代的吡唑基”的例子,可以列举例如3-三氟甲基吡唑基等。
作为“被1-3个选自卤原子、C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基”的例子,可以列举被甲基、乙氧羰基等取代的呋喃基,更具体说,可以列举5-甲基-4-乙氧羰基-2-呋喃基。
作为“被1-3个C1-6烷基烷基取代的噻吩并嘧啶基硫基”,优选的是稠合环被1个甲基或乙基取代的噻吩并嘧啶基硫基,更具体说,更优选的是噻吩环被甲基取代了的该基团。
作为“被1-3个C1-6烷基取代的噻吩并吡啶基硫基”,优选的是稠合环被1个甲基或乙基取代的噻吩并吡啶基硫基,更具体说,更优选的是噻吩环被甲基取代了的该基团。
作为“被1-3个卤原子取代的苯并噻唑基硫基”,优选的是稠合环被1个卤原子取代的苯并噻唑基硫基,更具体说,更优选的是苯环被氯原子取代了的该基团。
作为“被1-3个C1-6烷基取代的异噁唑基”,优选的是被1个或2个甲基或乙基取代的异噁唑基,更具体说,更优选的是5-甲基异噁唑-3-基。
作为“被1-3个C1-6烷基取代的噻唑基”,优选的是被1个或2个甲基或乙基取代的噻唑基。
作为“被1-3个C1-6烷基取代的吡啶基”,优选的是被1个或2个甲基或乙基取代的吡啶基,特别优选的是2-甲基吡啶-6-基。
作为“被1-3个C1-6烷基取代的嘧啶基”,优选的是被1个或2个甲基或乙基取代的嘧啶基,具体说,更优选的是2,4-二甲基嘧啶-6-基。
作为“被1-3个C1-6烷氧基取代的嘧啶基”,优选的是被1个或2个甲氧基或乙氧基取代的嘧啶基,具体说,更优选的是4-甲氧基嘧啶-6-基、2,4-二甲氧基嘧啶-6-基。
作为“被1-3个C1-6烷氧基取代的哒嗪基”,优选的是被1个或2个甲氧基或乙氧基取代的哒嗪基。
术语“C2-10链烯基”是指含有双键的碳原子数2-10的直链或支化的链烯基,例如可以列举乙烯基、丙烯基、丁烯基等,更具体说,可以列举1,5-二甲基-4-己烯基等。
术语“C1-6烷硫基”是指碳原子数1-6的直链或支化的烷硫基,例如可以列举甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、异丁硫基、叔丁硫基、戊硫基、异戊硫基等,特别优选甲硫基。
术语“C2-6链烷酰氧基”是指具有C2-6链烷酰基与氧基(-O-)的复合结构的基团,例如可以列举乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基、戊酰氧基等。
作为“被1-3个选自硝基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基”的例子,可以列举4-氯苯基、4-氟苯基、2,5-二氟苯基、2,5-二氯苯基、邻苯乙基苯基、4-甲硫基苯基、间苯氧基苯基、4-甲基苯基、3-甲基苯基、2-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二甲氧基苯基、2,4-二甲氧基苯基、4-甲氧羰基苯基、对苯基苯基、间氰基苯基等。
术语“C1-6烷氧基C1-6烷氧基”是指具有C1-6烷氧基与C1-6烷氧基的复合结构的基团,其例子有甲氧甲氧基、甲氧乙氧基、乙氧乙氧基、甲氧丁氧基等。
“C1-6烷氧基C1-6烷氧基C1-6烷氧基”的例子包括CH3OCH2CH2OCH2CH2O-等。
“二(C1-6烷基)氨基”的例子包括-N(CH3)2、-N(CH2CH3)2、-N(CH2CH2CH3)2等。
“二(C1-6烷基)氨基-C1-6烷氧基”的例子包括-OCH2N(CH3)2、-OCH2CH2N(CH3)2、-OCH2CH2N(CH2CH3)2等。
术语“N-C1-6烷基甲苯氨基”是指被C1-6烷基取代的甲苯氨基(CH3-C6H4-NH-),优选的是被甲基或乙基取代的。特别优选N-乙基-间甲苯氨基。
呋喃基包括2-呋喃基、3-呋喃基。
“氧杂环丁基”是指含有1个氧原子作为杂原子的饱和四元环基团,包括2-氧杂环丁基、3-氧杂环丁基。
“氧杂环戊基”是指含有1个氧原子作为杂原子的饱和五元环基团,包括2-氧杂环戊基、3-氧杂环戊基。
“二氧戊环基”是指从含有2个氧原子作为杂原子的饱和五元环(二氧戊环),优选从1,3-二氧戊环的环上除去氢原子后衍生出来的1价基团。在二氧戊环基中,其环可以被C1-6烷基取代,其例子有2,2-二甲基-1,3-二氧戊环-4-基等。
“氧杂环己基”是指含有1个氧原子作为杂原子的饱和六元环基团,包括2-氧杂环己基、3-氧杂环己基、4-氧杂环己基。
“二噁烷基”是指从含有2个氧原子作为杂原子的饱和六元环(二噁烷),优选从1,3-二噁烷的环上除去氢原子后衍生出来的1价基团。在二噁烷基中,其环可以被C1-6烷基取代,其例子有5,5-二甲基-1,3-二噁烷-2-基等。
“苯并二噁烷基”是指从苯并二噁烷,优选从1,4-苯并二噁烷的环上除去氢原子后衍生出来的1价基团。其例子有1,4-苯并二噁烷-2-基等。
“哌啶基”包括2-哌啶基、3-哌啶基、4-哌啶基。此外,在哌啶基中,哌啶基上的氮原子可以被C1-6烷基取代,优选的是N-甲基哌啶基。
“哌啶子基”是指由哌啶的氮原子上除去氢原子后衍生的1价基团。
“吡啶基”包括2-吡啶基、3-吡啶基、4-吡啶基。此外,在吡啶基中,吡啶基环可以被C1-6烷基,优选甲基取代,作为例子,可以列举6-甲基-2-吡啶基等。
“吡啶基硫基”是指具有吡啶基与1个硫基的复合结构的基团,包括吡啶-2-硫基、吡啶-3-硫基、吡啶-4-硫基。优选吡啶-2-硫基。
“吡咯烷子基”是指由吡咯烷的氮原子上除去氢原子后衍生的1价基团。
“吡咯烷酮-1-基”包括2-吡咯烷酮-1-基、3-吡咯烷酮-1-基。
“吡咯烷基”包括2-吡咯烷基、3-吡咯烷基。此外,在吡咯烷基中,其基上的氮原子可以被C1-6烷基取代,其例子有N-甲基-2-吡咯烷基等。
“喹啉基”包括2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基,优选的是2-喹啉基。
“吡咯基”包括1-吡咯基、2-吡咯基、3-吡咯基,优选的是1-吡咯基(即N-吡咯基)。
“噻吩基”包括2-噻吩基、3-噻吩基。
“噻唑基”包括2-噻唑基、4-噻唑基、5-噻唑基。此外,在噻唑基中,噻唑基的环可以被C1-6烷基取代,其例子有4-甲基-5-噻唑基等。
“吗啉代基”是指由吗啉的氮原子上除去氢原子后衍生的1价基团。
“糠基”是指2-糠基。
“2,6-嘌呤二酮-7-基”是指由嘌呤环的2位和6位的碳原子上各自分别键合了1个氧代基(=O)的2,6-嘌呤二酮在7-位的氮原子上除去氢原子后衍生的1价基团。作为“C1-6烷基取代的2,6-嘌呤二酮-7-基“,优选的是该基团上的1个或2个氮原子被C1-6烷基,尤其甲基取代者,其例子有1,3-二甲基-2,6-嘌呤二酮-7-基等。
在通式(1)的R1-R5中,彼此相邻的任何2个基团可以与它们所连接的苯环合在一起形成上述的环结构。在这些环中,可以特别提及的是下述的环结构。
作为“被C1-6烷基取代的邻苯二甲酰亚胺环”,优选的是被甲基或乙基取代的环,具体说,例如被甲基取代的环如N-甲基-邻苯二甲酰亚胺环是更优选的。
作为“被C1-6烷氧基取代的邻苯二甲酰亚胺环”,优选的是被甲氧基或乙氧基取代的环,具体说,被1个甲氧基取代的环是更优选的。
作为“卤原子取代的芴环”,优选的是氯原子或溴原子取代的芴环,具体说,被1个溴原子取代的芴环是更优选的。
作为“被C1-6烷基取代的喹诺酮环”,优选的是该环被甲基或乙基取代者,具体说,被1个甲基取代的环是更优选的。
作为“被1-3个选自氰基、卤原子、硝基和C1-6烷基的基团取代的萘环”,优选的是被1-3个氰基、卤原子、硝基、甲基或乙基取代的萘环,具体说,被1个氰基、溴原子、氯原子、硝基或甲基取代的萘环是更优选的。
作为“被C1-6烷基取代的喹啉环”,优选的是被甲基或乙基取代的喹啉环,具体说,被1个甲基取代的喹啉环是更优选的。
作为“被1-3个选自C1-6烷基、C1-6烷氧基和C1-6烷氧基C1-6烷基的基团取代的2-氧代-α-苯并二氢吡喃环”,优选的是被甲基、乙基、甲氧基、乙氧基、甲氧甲基、甲氧乙基、乙氧甲基或乙氧乙基取代的这种基团,具体说,被1个甲基或甲氧甲基取代者更为优选。
作为“被C1-6烷基取代的肉啉环”,优选的被甲基或乙基取代者,具体说,被1个甲基取代者更为优选。
作为“被C1-6烷基取代的苯并噻唑环”,优选的是被甲基或乙基取代者,具体说,被1个甲基取代者更为优选。
此外,本发明中,术语“药物上可接受的盐”是指与碱金属、碱土金属、铵、烷基铵等形成的盐,以及与无机酸或有机酸形成的盐。作为例子,可以列举钠盐、钾盐、钙盐、铵盐、铝盐、三乙基铵盐、乙酸盐、丙酸盐、丁酸盐、甲酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡糖酸盐、葡庚糖酸盐、苯甲酸、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、十二烷基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、与半胱氨酸形成的盐、与N-乙酰基半胱氨酸形成的盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、氢碘酸盐、烟酸盐、草酸盐、苦味酸盐、硫氰酸盐、十一烷酸盐、与丙烯酸聚合物形成的盐以及与羧基乙烯基聚合物形成的盐等。
本发明的式(1)代表化合物可以通过或按照特开昭61-165360公报(并入本文作为参考)所述方法进行制备。
例如,可按下述方法合成:使下述的被R1-R5取代的苯胺衍生物:
在催化量的乙酸等有机酸、盐酸等无机酸或盐酸吡啶等胺类的无机酸盐的存在下或不存在下与原甲酸三甲酯、原甲酸三乙酯等原甲酸酯类,优选在室温-150℃,更优选在70-100℃反应2-72小时,将所得中间体分离或不分离,然后在乙醇等溶剂中用羟基胺进行处理。
要说明的是,上述苯胺衍生物例如可按以下方法合成。这里,为了说明的方便,使用其中R1、R2、R3和R5为氢原子,R3为通式-Y(CR61R62)m-(CR63R64)n-R7所示的基团的苯胺衍生物。
首先,使下式(a)代表的化合物与例如下式(b)代表的化合物在碱的存在下进行反应,得到下式(c)代表的化合物,
式中X代表卤原子,
R7(CR63R64)n-(CR61R62)mYH (b)
式中R7、Y、R61、R62、m、R63、R64和n的定义同上,
其次,用通常使芳族硝基还原成芳族氨基的方法使上式(c)代表的化合物衍生成下式(d)代表的苯胺衍生物:
本发明的20-HETE合成抑制剂含有通式(1)代表的化合物或其药物上可接受的盐作为有效成分,能有效地抑制20-HETE的合成。
此外,本发明的20-HETE合成抑制剂可用作药物,特别可用作肾脏疾病、脑血管疾病或循环器官疾病的治疗剂。
按照本发明的药物,(包括肾脏疾病、脑血管疾病或循环器官疾病的治疗剂),以及20-HETE合成抑制剂的剂量在治疗成年人的情况下优选为每日1-2000mg通式(1)代表的化合物或其药物上可接受的盐,可以1日1次或分成数次给药。该剂量可根据用途、患者的年龄、体重及症状等因素适当增减。
按照本发明的药物,(包括肾脏疾病、脑血管疾病或循环器官疾病的治疗剂),以及20-HETE合成抑制剂可以经口服或非经肠给药。给药剂型可以是片剂、胶囊剂、颗粒剂、散剂、粉剂、锭剂、软膏剂、霜剂、乳剂、悬浮剂、栓剂和注射剂等,这些剂型中的每种剂型都可以按照惯用的配制方法(例如日本药典第12次修正版规定的方法)制备。给药剂型可以根据患者的症状、年龄及治疗目的适当选择。在制造各种剂型的制剂时可以使用常用的赋形剂(例如结晶纤维素、淀粉、乳糖、甘露糖醇等)、粘结剂(例如羟丙基纤维素、聚乙烯基吡咯烷酮等)、润滑剂(例如硬脂酸镁、滑石粉等)和崩解剂(例如羧甲基纤维素钙等)等。
实施本发明的最佳方式
下面通过实施例更详细地说明本发明,但本发明不受以下实施例的限制。
实施例1
N-(4-丁基-2-甲基苯基)-N′-羟基甲脒的合成
4-丁基-2-甲基苯胺(129.18g)与原甲酸乙酯(234.66g)在100℃搅拌11小时,然后蒸去过量的原甲酸乙酯。将所得粗产物溶于甲醇(100ml)中。在0℃往盐酸羟胺(65.59g)的甲醇溶液(500ml)中滴加甲醇钠(51.02g)的甲醇溶液(350ml)使之中和。过滤除去析出的氯化钠,将滤液滴加到上述粗产物的甲醇溶液中,然后在室温下搅拌15小时。蒸出甲醇,将所得残留物溶解在800ml氯仿中,然后用水和饱和食盐水洗涤。有机层用无水硫酸镁干燥,除去溶剂,所得残留物用己烷洗涤,得到标题化合物的粗结晶63.66g。粗结晶的一部分(35.47g)用己烷∶乙酸乙酯(1∶4)进行重结晶,得到无色粉末状标题化合物(下述表1中的化合物1)29.85g。
熔点131.5-134.0℃。
实施例2
N-(4-叔丁基苯基)-N′-羟基甲脒的合成
4-叔丁基苯胺(3.9g)与原甲酸乙酯(7.9g)在100℃搅拌6.5小时,然后蒸去过量的原甲酸乙酯。将所得粗产物溶于甲醇(10ml)中。在0℃往盐酸羟胺(2.1g)的甲醇溶液(20ml)中滴加甲醇钠(1.6g)的甲醇溶液(15ml)使之中和。过滤除去析出的氯化钠,将滤液滴加到上述粗产物的甲醇溶液中,然后在室温下搅拌1.5小时。蒸出甲醇,将所得残留物溶解在50ml氯仿中,然后用水和饱和食盐水洗涤。有机层用无水硫酸镁干燥,然后浓缩,所得残留物用硅胶柱色谱法精制(己烷∶乙酸乙酯=4∶1),得到标题化合物(下述表1中的化合物2)1.65g。
熔点113.5-114.5℃。
实施例3
N-(4-甲氧羰基苯基)-N′-羟基甲脒的合成
4-氨基苯甲酸甲酯(1.98g)与原甲酸乙酯(4.07g)的混合物在100℃搅拌16小时,然后蒸去过量的原甲酸乙酯。往所得残留物中加入由盐酸羟胺(1.50g)和甲醇钠(1.10g)制备的羟胺甲醇溶液(16ml),然后在室温下搅拌6小时。蒸出溶剂后往所得残留物中加入氯仿,依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,然后蒸出溶剂,残留物用硅胶柱色谱法精制(展开溶剂∶正己烷∶乙酸乙酯),从氯仿-甲醇重结晶,得到无色粉末状标题化合物(下述表1中的化合物123)0.32g。
熔点167.0-167.5℃。
实施例4
N-(2-氨基磺酰基苯基)-N′-羟基甲脒的合成
2-氨基苯磺酰胺(3.0g)、原甲酸乙酯(5.15g)和乙酸乙酯(20ml)的混合物在100℃搅拌5小时,然后蒸去过量的原甲酸乙酯。往残留物的甲醇(30ml)溶液中加入由盐酸羟胺(1.50g)和甲醇钠(1.10g)制备的羟胺甲醇溶液(40ml),然后在室温下搅拌2天。蒸出溶剂后往所得残留物中加入氯仿,依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,然后蒸出溶剂,残留物用硅胶柱色谱法精制(展开溶剂∶乙酸乙酯),得到无色粉末状标题化合物(下述表1中的化合物236)0.73g。
熔点130.5-131.5℃。
实施例5
N-[4-(吡啶-2-基甲氧基)苯基]-N′-羟基甲脒的合成
4-(吡啶-2-基甲氧基)苯胺(1.715g)与N′-羟基甲脒的合成(2.613g)的混合物在100℃搅拌14小时,然后蒸去过量的原甲酸乙酯。往残留物的甲醇溶液(20ml)中加入1M羟胺甲醇溶液(10ml),然后在室温下搅拌2.5天。蒸出溶剂后往所得残留物中加入氯仿,依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,然后蒸出溶剂。所得残留物用乙酸乙酯进行重结晶,得到无色粉末状标题化合物(下述表1中的化合物345)0.524g。
熔点159.5-161.0℃。
实施例6
N-[4-(苄硫基)苯基]-N′-羟基甲脒的合成
4-(苄硫基)苯胺(1.18g)与原甲酸乙酯(1.78g)的混合物在100℃搅拌12小时,然后蒸去过量的原甲酸乙酯。往残留物的甲醇溶液(20ml)中加入1M羟胺甲醇溶液(10ml),然后在室温下搅拌2.5天。蒸出溶剂后往所得残留物中加入氯仿,依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,然后蒸出溶剂。所得残留物用乙酸乙酯进行重结晶,得到无色粉末状标题化合物(下述表1中的化合物441)0.43g。
熔点166℃。
实施例7
进行与实施例1同样的操作,制得了下述表1中所列出的化合物。要说明的是,上述实施例1-6中得到的化合物也与其他化合物一起列于表1中。
表1
*SiO2(NH):Merck公司预涂板 Silica gel 60 F254,SiO2(NH)(NH):TLC板NH Fuji Silysia化学公司
试验例[来源于大鼠肾脏微粒体的20-HETE合成酶的抑制作用]
关于表1所列的化合物,就其对20-HETE合成的抑制作用进行了试验。本试验按照J.Pharmacol.Exp.Ther.,第268卷,474页(1994)中所述的方法进行。
将试验化合物加入到含有50mM 3-吗啉代丙磺酸(pH 7.4)、5mM氯镁和1mM乙二胺四乙酸二钠盐(EDTA)的缓冲溶液中。
然后,加入作为酶的大鼠肾脏微粒体(由自发高血压大鼠(雄性,6周龄)的肾脏制备的微粒体级分)、作为底物的[5,6,8,9,11,12,14,15]氚代花生四烯酸(Amasham公司制造)和作为辅酶的NADPH(由Sigma公司制造),并在37℃反应1.5小时。
反应后加入甲酸使反应停止,然后再加入乙腈(最终浓度为50%),让其在室温下放置1.5小时。
用装有C18逆相柱(Biocyl C18,由Biorad公司制造)并附有放射性物质检测器的高效液体色谱仪(Gilson公司制造)测定20-HETE合成酶的活性。
以不加入试验化合物时20-HETE的生成量作为100%,加入试验化合物时20-HETE的生成量被抑制到50%时试验化合物的浓度和加入1μM试验化合物时的抑制率一起列于表1中。
由表1可以确认,本发明的化合物对20-HETE的合成具有抑制作用。
产业上利用的可能性
按照本发明的通式(1)代表的化合物或其药物上可接受的盐作为20-HETE合成抑制剂是有用的。因此,这类化合物作为药物,特别是作为人体和动物中与20-HETE有关的疾病,例如各种肾脏疾病、脑血管疾病或循环器官疾病的治疗剂是有用的。
此外,在通式(1)代表的化合物或其药物上可接受的盐中,相对于苯环上的羟基亚胺甲基氨基部分的对位上有非氢原子取代基者是特别优选的。
要说明的是,权利要求5及其后所述的化合物或其药物上可接受的盐是新化合物,且其本身是有用的,同时也显示出上述的优异效果。
Claims (7)
1.下面通式表示的羟基甲脒衍生物及其药物上可接受的盐用于制备20-羟基二十碳四烯酸合成抑制剂的用途:
式中,R1代表氢原子;卤原子;选自甲基、乙基、丙基和丁基的烷基;三氟甲基;C1-6羟烷基;C2-6烷氧羰基;3-苯基-2-丙烯氧羰基;被苯基取代的氨基甲酰基;氰基;硝基;苯环被1-5个卤原子取代的苯磺酰基C1-6烷硫基;苯基;被甲氧基取代的苯氧基;或通式-Y1-(CR161R162)m1-(CR163R164)n1-R17所示的基团,式中Y1是氧原子;R161代表氢原子或卤原子;R162代表氢原子或卤原子;R163代表氢原子;R164代表氢原子;R17代表氢原子;m1是整数1;n1是0,
其中R2代表氢原子;卤原子;选自甲基、乙基、丙基和丁基的烷基;三氟甲基;苯氧基;或通式-Y2-(CR161R262)m2-(CR263R264)n2-R37所示的基团,式中Y2代表氧原子或硫原子;R261、R262、R263和R264均代表氢原子;R27代表氢原子;m2是1-6的整数;n2是0,
R3代表氢原子;卤原子;C1-14烷基;三氟甲基;C3-8环烷基;C2-10链烷酰基;C1-6羟烷基;1,1,1,3,3,3-六氟-2-羟基丙基;C2-6烷氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氰基;硝基;苯氧基;被1-3个选自C1-6烷基和卤原子的基团取代的苯氧基;硝基苯硫基;苄基;被氰基取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;苯甲酰基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;哌啶子基;吗啉代基;被1-3个卤原子取代的邻苯二甲酰亚氨基;被1-3个C1-6烷基取代的二氧代哌啶基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;被三氟甲基取代的吡唑基;被1-3个选自C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;或通式-Y3-(CR361R362)m3-(CR363R364)n3-R37所示的基团,式中Y3是氧原子或硫原子;R361和R362各代表氢原子或卤原子,R363和R364各代表氢原子;R37代表氢原子;卤原子;C1-14烷基;C3-8环烷基;C2-10链烯基;C2-6炔基;苯基;被1-3个选自氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6羟烷基;C1-6烷氧基C1-6烷氧基;C1-6烷硫基;C2-6链烷酰氧基;苯氧基;苯硫基;N-(C1-6烷基)甲苯氨基;吡咯烷子基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基;氧杂环戊基;二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;N-(C1-6烷基)吡咯烷基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;被1-3个C1-6烷基取代的噻唑基;被C1-6烷基取代的2,6-嘌呤二酮-7-基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m3是1-6的整数;以及n3是0,
其中R4代表氢原子;卤原子;选自甲基、乙基、丙基和丁基的烷基;三氟甲基;C1-6羟烷基;C2-6烷氧羰基;或通式-Y4-(CR461R462)m4-(CR463R464)n4-R47所示的基团,其中Y4代表氧原子;R461、R462、R463和R464代表氢原子;R47代表氢原子;m4是整数1;n4是0,
其中R5代表氢原子;卤原子;C1-4烷基;甲硫基甲基;或通式-Y5-(CR561R562)m5-(CR563R564)n5-R57所示的基团,其中Y5代表氧原子;R561、R562、R563和R564代表氢原子;R57代表氢原子;m5是整数1;n5是0,
或者替代地,2个彼此相邻的基团R1和R2与它们所连接的苯环一起形成一个萘环;1,2,3,4-四氢萘环;或2个彼此相邻的基团R2和R3与它们所连接的苯环一起形成一个1,2-二氢化茚环;二苯并呋喃环;被卤原子取代的芴环;喹啉环;被C1-6烷基取代的喹啉环;或2-氧代-α-苯并吡喃环。
2.按照权利要求1的用途,其中R1、R4和R5是氢原子。
3.按照权利要求1或2的用途,其中所述的20-羟基二十碳四烯酸合成抑制剂是肾脏疾病、脑血管疾病或循环器官疾病的治疗剂。
4.下式表示的羟基甲脒衍生物或其药物上可接受的盐:
式中,R11代表氢原子;卤原子;或C1-4烷基;
R22代表氢原子;C1-4烷基;三氟甲基或卤原子;
R33代表C3-8环烷基;C1-6羟烷基;1,1,1,3,3,3-六氟-2-羟基丙基;C2-6烷氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氰基;苄基;被氰基取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;哌啶子基;吗啉代基;被1-3个卤原子取代的邻苯二甲酰亚氨基;被1-3个C1-6烷基取代的二氧代哌啶基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;被三氟甲基取代的吡唑基;被1-3个选自C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;或通式-Y6-(CR661R662)m6-(CR663R664)n6-R677所示的基团,式中Y6代表氧原子或硫原子;R661和R662各自独立地代表氢原子或卤原子,R663和R664各代表氢原子;R677代表卤原子;C3-8环烷基;C2-10链烯基;被1-3个选自氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6羟烷基;C1-6烷氧基C1-6烷氧基;C1-6烷硫基;C2-6链烷酰氧基;苯氧基;苯硫基;N-(C1-6烷基)甲苯氨基;吡咯烷-1-基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基;氧杂环戊基;二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;N-(C1-6烷基)吡咯烷基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;被1-3个C1-6烷基取代的噻唑基;被至少1个C1-6烷基取代的2,6-嘌呤二酮-7-基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m6是1-6的整数;以及n6是0,
R44代表氢原子或卤原子;
R33代表氢原子或卤原子;
或者替代地,2个彼此相邻的基团R23和R33与它们所连接的苯环一起形成一个1,2-二氢化茚环;二苯并呋喃环;被卤原子取代的芴环;喹啉环;被C1-6烷基取代的喹啉环;或2-氧代-α-苯并吡喃环。
5.权利要求4记载的羟基甲脒衍生物或其药物上可接受的盐,其中R33代表C3-8环烷基;C1-6羟烷基;1,1,1,3,3,3-六氟-2-羟基丙基;C2-6烷氧羰基;C2-6烷氧羰基C1-6烷基;二(C1-6烷基)氨基C2-6烷氧羰基;C2-10链烷酰氨基;被C1-6烷基取代的C2-6链烷酰氨基;苯甲酰氨基;氰基;苄基;被氰基取代的苯基;联苯基;α-氰基苄基;被1-5个卤原子取代的α-氰基苄基;苯乙烯基;被1-5个选自C1-6烷氧基和二(C1-6烷基)氨基烷基的基团取代的苯乙烯基;哌啶子基;吗啉代基;被1-3个卤原子取代的邻苯二甲酰亚氨基;被1-3个C1-6烷基取代的二氧代哌啶基;C1-6烷氨基磺酰基C1-6烷基;噻二唑基;被三氟甲基取代的吡唑基;被1-3个选自C1-6烷基和C2-6烷氧羰基的基团取代的呋喃基;
R55代表氢原子或卤原子。
6.权利要求4记载的羟基甲脒衍生物或其药物上可接受的盐,其中R11、R22、R44和R55代表氢原子,R33是通式-Y7-(CR761R762)m7-(CR763R764)n7-R777所示的基团,式中Y7代表氧原子或硫原子;R761和R762各自独立地代表氢原子或卤原子,R763和R764各代表氢原子;R777代表卤原子;C3-8环烷基;C2-10链烯基;被1-3个选自氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、苯基、苯氧基、苯乙基、C2-6烷氧羰基和卤原子的基团取代的苯基;氰基;羧基;C1-6烷氧基;C1-6羟烷基;C1-6烷氧基C1-6烷氧基;C1-6烷硫基;C2-6链烷酰氧基;苯氧基;苯硫基;N-(C1-6烷基)甲苯氨基;吡咯烷-1-基;哌啶子基;吗啉代基,吡啶基;被C1-6烷基取代的吡啶基;吡啶基硫基;喹啉基;呋喃基;氧杂环丁基;氧杂环戊基;二氧戊环基;被C1-6烷基取代的二氧戊环基;氧杂环己基;被C1-6烷基取代的二噁烷基;苯并二噁烷基;吡咯烷酮-1-基;N-(C1-6烷基)吡咯烷基;N-(C1-6烷基)哌啶基;吡咯基;噻吩基;被1-3个C1-6烷基取代的噻唑基;被至少1个C1-6烷基取代的2,6-嘌呤二酮-7-基;二(C1-6烷基)氨基;C2-6烷氧羰基;或二(C1-6烷基)氨基C1-6烷氧基;m7是1-6的整数;以及n7是0.
7.权利要求4-6中任何一项记载的羟基甲脒衍生物或其药物上可接受的盐用于制造治疗肾脏疾病、脑血管疾病或循环器官疾病的药物的用途。
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KR20070087044A (ko) | 2007-08-27 |
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WO2001032164A1 (fr) | 2001-05-10 |
ES2256053T3 (es) | 2006-07-16 |
DK1226819T3 (da) | 2006-05-22 |
KR20020050248A (ko) | 2002-06-26 |
HK1050141A1 (en) | 2003-06-13 |
EP1226819B1 (en) | 2006-01-18 |
AU1053301A (en) | 2001-05-14 |
US20040110830A1 (en) | 2004-06-10 |
AU759604B2 (en) | 2003-04-17 |
ATE315932T1 (de) | 2006-02-15 |
EP1226819A1 (en) | 2002-07-31 |
US7078400B2 (en) | 2006-07-18 |
US6864254B1 (en) | 2005-03-08 |
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