JPH04202173A - Sulfonamide derivative and 5-lipoxygenase inhibitor containing the same - Google Patents
Sulfonamide derivative and 5-lipoxygenase inhibitor containing the sameInfo
- Publication number
- JPH04202173A JPH04202173A JP32972190A JP32972190A JPH04202173A JP H04202173 A JPH04202173 A JP H04202173A JP 32972190 A JP32972190 A JP 32972190A JP 32972190 A JP32972190 A JP 32972190A JP H04202173 A JPH04202173 A JP H04202173A
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydroxy
- lower alkyl
- dimethylphenyl
- sulfonamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 title claims abstract description 6
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 title claims abstract description 6
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 title claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000002252 acyl group Chemical group 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 208000026935 allergic disease Diseases 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002541 furyl group Chemical group 0.000 claims abstract description 5
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 5
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 5
- -1 thiazoyl group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000003828 azulenyl group Chemical group 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000000924 antiasthmatic agent Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000001088 anti-asthma Effects 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 18
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 4
- 238000010992 reflux Methods 0.000 abstract description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 1
- YCAHPLRLHNQQTB-UHFFFAOYSA-N n-(4-hydroxy-3,5-dimethylphenyl)methanesulfonamide Chemical compound CC1=CC(NS(C)(=O)=O)=CC(C)=C1O YCAHPLRLHNQQTB-UHFFFAOYSA-N 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 27
- 230000008018 melting Effects 0.000 description 27
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 14
- 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
- 229940124530 sulfonamide Drugs 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 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 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- MSPCOXFYKUKYLB-UHFFFAOYSA-N naphthalene-1-sulfonamide Chemical compound C1=C[C]2C(S(=O)(=O)N)=CC=CC2=C=C1 MSPCOXFYKUKYLB-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 description 5
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 5
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 3
- 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 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010033645 Pancreatitis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
- 208000019622 heart disease Diseases 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- SWBLLSQMOMPTMC-UHFFFAOYSA-N naphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)N)=CC=C21 SWBLLSQMOMPTMC-UHFFFAOYSA-N 0.000 description 3
- 201000008383 nephritis Diseases 0.000 description 3
- 208000019553 vascular disease Diseases 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BXUQULBXEVGUBW-UHFFFAOYSA-N 4-methyl-n-(3,4,5-trimethoxyphenyl)benzenesulfonamide Chemical compound COC1=C(OC)C(OC)=CC(NS(=O)(=O)C=2C=CC(C)=CC=2)=C1 BXUQULBXEVGUBW-UHFFFAOYSA-N 0.000 description 2
- KGIJOOYOSFUGPC-MSFIICATSA-N 5-Hydroxyeicosatetraenoic acid Chemical compound CCCCCC=CCC=CCC=C\C=C\[C@@H](O)CCCC(O)=O KGIJOOYOSFUGPC-MSFIICATSA-N 0.000 description 2
- KGIJOOYOSFUGPC-XRXZHELTSA-N 5-hydroxyeicosatetraenoic acid Natural products CCCCCC=CCC=CCC=C\C=C\C(O)CCCC(O)=O KGIJOOYOSFUGPC-XRXZHELTSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- 229920000084 Gum arabic Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
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- 239000002671 adjuvant Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
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- 229940125682 antidementia agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
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- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229950003102 efonidipine Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- RHBMVXBGYGIDJN-UHFFFAOYSA-N furan-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CO1 RHBMVXBGYGIDJN-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WXVZZXWTLJZRIT-UHFFFAOYSA-N n-(3,5-dimethoxy-4-oxocyclohexa-2,5-dien-1-ylidene)-4-methylbenzenesulfonamide Chemical compound C1=C(OC)C(=O)C(OC)=CC1=NS(=O)(=O)C1=CC=C(C)C=C1 WXVZZXWTLJZRIT-UHFFFAOYSA-N 0.000 description 1
- RXYMCAJJJVGOGQ-UHFFFAOYSA-N n-(3,5-dimethyl-4-oxocyclohexa-2,5-dien-1-ylidene)-4-methylbenzenesulfonamide Chemical compound C1=C(C)C(=O)C(C)=CC1=NS(=O)(=O)C1=CC=C(C)C=C1 RXYMCAJJJVGOGQ-UHFFFAOYSA-N 0.000 description 1
- JOVNOYMKMIBJSD-UHFFFAOYSA-N n-(4-hydroxy-3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide Chemical compound COC1=C(O)C(OC)=CC(NS(=O)(=O)C=2C=CC(C)=CC=2)=C1 JOVNOYMKMIBJSD-UHFFFAOYSA-N 0.000 description 1
- MULDDNZSRDGSQX-UHFFFAOYSA-N n-(4-hydroxy-3-methylphenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(O)C(C)=C1 MULDDNZSRDGSQX-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZTYZEUXZHGOXRT-UHFFFAOYSA-N quinoline-8-sulfonamide Chemical compound C1=CN=C2C(S(=O)(=O)N)=CC=CC2=C1 ZTYZEUXZHGOXRT-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、下記−形成（１）及び（ＩＩ）で表されるス
ルホンアミド誘導体及びそれを含有するりボキシゲナー
ゼ阻害剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to sulfonamide derivatives represented by the following formulas (1) and (II), and to a polyboxygenase inhibitor containing the same.
〈以下余白〉
（式中、Ａは置換基を有していてもよい炭素数Ｏ〜４の
飽和又は不飽和の炭素鎖を示し、Ｂは置換基を有してい
てもよいフェニル基、ナフタレニル基、キノリニル基、
インキノリニル基、ピロリル基、アズレニル基、フラニ
ル基、ベンゾチオフェニル基、チアゾイル基、チオフェ
ニル基またはピリジニル基もしくは低級アルキル基を示
し Ｒ１は水素原子、低級アルキル基またはアシル基を
示し、Ｒ２、Ｒ３、ＲＡ及びＲ５は同−又は異なってそ
れぞれ水素原子、ヒドロキシ基、低級アルキル基、シク
ロアルキル基、アルコキシ基、アシル基またはハロゲン
原子を示し、Ｒ６は水素原子、ヒドロキシ基、アルコキ
シ基、アシル基または低級アルキル基を示す。）
（ＩＩ）
（式中、Ａは置換基を有していてもよい炭素数０〜４の
飽和又は不飽和の炭素鎖を示し、Ｂは置換基を有してい
てもよいフェニル基、ナフタレニル基、キノリニル基、
インキノリニル基、ピロリル基、アズレニル基、フラニ
ル基、ベンゾチオフェニル基、チアゾイル基、チオフェ
ニル基またはピリジニル基もしくは低級アルキル基を示
し、Ｒ２、Ｒ３、Ｒ４及びＲ５は同−又は異なってそれ
ぞれ水素原子、ヒドロキシ基、低級アルキル基、シクロ
アルキル基、アルコキン基、アシル基またはハロゲン原
子を示す。）
［従来の技術］
リボキノゲナーゼはアラキドン酸の代謝に関与すること
が知られており、５−リボキンゲナーゼはアラキドン酸
の５位を酸化する酵素で、化学伝達物質であるＳ ＲＳ
”−Ａ （Ｓｌｏｔ Ｒｅａｃｔｉｎｇ ５ｕｂｓｔ
ａｎｃｅ ｏｆ Ａｎａｐｈｙｌａｘｉｓ）の生成経路
に関与すると考えられている（ Ｂｉｏｃｈｅｍ、 Ｂ
ｉｏｐｈｙｓ、 Ｒｅｓ、 Ｃｏｍｍｕｎ、 、 ９１
．１２６６（１９７９）、 Ｐｒｏｓｔａｇｌａｎｄｊ
’ｎｓ、１９．６４５（１９８０））。<Margin below> (In the formula, A represents a saturated or unsaturated carbon chain having 0 to 4 carbon atoms which may have a substituent, and B represents a phenyl group or naphthalenyl which may have a substituent. group, quinolinyl group,
Inquinolinyl group, pyrrolyl group, azulenyl group, furanyl group, benzothiophenyl group, thiazol group, thiophenyl group, pyridinyl group or lower alkyl group; R1 represents a hydrogen atom, lower alkyl group or acyl group; R2, R3, RA and R5 are the same or different and represent a hydrogen atom, a hydroxy group, a lower alkyl group, a cycloalkyl group, an alkoxy group, an acyl group, or a halogen atom, and R6 is a hydrogen atom, a hydroxy group, an alkoxy group, an acyl group, or a lower alkyl group. Indicates the group. ) (II) (In the formula, A represents a saturated or unsaturated carbon chain having 0 to 4 carbon atoms which may have a substituent, and B represents a phenyl group or naphthalenyl which may have a substituent. group, quinolinyl group,
It represents an inquinolinyl group, a pyrrolyl group, an azulenyl group, a furanyl group, a benzothiophenyl group, a thiazol group, a thiophenyl group, a pyridinyl group, or a lower alkyl group, and R2, R3, R4, and R5 are the same or different, and each is a hydrogen atom, a hydroxy group, lower alkyl group, cycloalkyl group, alkokene group, acyl group, or halogen atom. ) [Prior Art] Ribokinogenase is known to be involved in the metabolism of arachidonic acid, and 5-ribokinogenase is an enzyme that oxidizes the 5-position of arachidonic acid, and is a chemical mediator SRS.
”-A (Slot Reacting 5ubst
ance of Anaphylaxis) (Biochem, B
iophys, Res, Commun, , 91
．． 1266 (1979), Prostagrandj
'ns, 19.645 (1980)).
一方、スルホンアミド誘導体は血圧降下作用や抗脂血症
作用が報告（特開平２−２５５６５２号公報）されてい
るが、５−リボ牛シゲナーゼ阻害作用については知られ
ていない。On the other hand, although sulfonamide derivatives have been reported to have hypotensive and antilipidemic effects (Japanese Unexamined Patent Publication No. 2-255652), they are not known to have 5-ribocygenase inhibitory effects.
［発明が解決しようとする問題点］
５−リポキシゲナーゼによって生成される５ＲＳ−Ａは
、各種アレルギー性疾患の発現に関与する重要な因子と
考えられている。[Problems to be Solved by the Invention] 5RS-A produced by 5-lipoxygenase is considered to be an important factor involved in the expression of various allergic diseases.
従って、喘息、炎症、腎炎、肝炎、膵炎、乾癩、痴呆、
心疾患、血管障害、免疫障害、痛風等の各種アレルギー
性疾患の治療薬として有効で安全な５−リポキシゲナー
ゼ阻害剤の開発が望まれていた。Therefore, asthma, inflammation, nephritis, hepatitis, pancreatitis, psoriasis, dementia,
It has been desired to develop a 5-lipoxygenase inhibitor that is effective and safe as a therapeutic agent for various allergic diseases such as heart diseases, vascular disorders, immune disorders, and gout.
［問題点を解決するための手段］
本発明者らは、５Ｒ３−Ａに起因する上記各種アレルギ
ー性疾患に有効な５−リボ牛シゲナーゼ阻害剤を創製す
べく鋭意研究を行い、本発明を完成するに至った。[Means for Solving the Problems] The present inventors have conducted extensive research to create a 5-ribo-bovine cygenase inhibitor that is effective for the various allergic diseases mentioned above caused by 5R3-A, and have completed the present invention. I ended up doing it.
本発明における低級アルキル基としては、炭素数１〜６
の直鎖又は分枝鎖のアルキル基が挙げられ、メチル、エ
チル、プロピル、ブチル、ペンチル、ヘキシル基及びそ
の異性体が好ましい。またシクロアルキル基としてはシ
クロペンチル、シクロヘキシル基をさす。アルコキン基
としては炭素数１〜６の直鎖又は分枝鎖のものが挙げら
れ、メトキシ、エトキシ、プロポキシ、ブトキシ基及び
その異性体が好ましい。アシル基としては、炭素数２〜
４のアルカノイル基が挙げられ、アセチル、プロピオニ
ル、ブタノイル基等が好ましい。ノ１０ゲン原子として
は、塩素、臭素、フッ素またはヨウ素原子が挙げられる
。The lower alkyl group in the present invention has 1 to 6 carbon atoms.
straight-chain or branched-chain alkyl groups, with methyl, ethyl, propyl, butyl, pentyl, hexyl groups and isomers thereof being preferred. Further, the cycloalkyl group refers to cyclopentyl and cyclohexyl groups. Examples of the alcoquine group include straight or branched chains having 1 to 6 carbon atoms, with methoxy, ethoxy, propoxy, butoxy groups and isomers thereof being preferred. As an acyl group, the number of carbon atoms is 2 to
4 alkanoyl groups are mentioned, and acetyl, propionyl, butanoyl groups and the like are preferred. Examples of the hydrogen atoms include chlorine, bromine, fluorine or iodine atoms.
本発明化合物（１）は例えば以下の通り製造することが
できる。The compound (1) of the present invention can be produced, for example, as follows.
く以下余白〉
（ｍ） （ＴＶ）（式中、
Ａ、 Ｂ５Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６
は前記と同意義であり、Ｘはハロゲン原子を示す。〉 (m) (TV) (in the formula,
A, B5R1, R2, R3, R4, R5 and R6
has the same meaning as above, and X represents a halogen atom.
すなわち、一般式（ｍ）で表されるフェニル誘導体と一
般式（ＩＶ）で表される化合物を反応させることにより
、一般式（Ｉ）で表される本発明化合物が製造される。That is, the compound of the present invention represented by the general formula (I) is produced by reacting the phenyl derivative represented by the general formula (m) with the compound represented by the general formula (IV).
上記の反応は、反応に影響を及ぼさない溶媒中で行うこ
とが好ましい。溶媒としては、例えば水；酢酸メチル、
酢酸エチル等のエステル類； ジメチルホルムアミド、
ジエチルホルムアミド等のアミド類； ジエチルエーテ
ル、ジイソプロピルエーテル、テトラヒドロフラン、ジ
オキサン等のエーテル類、アセトニトリル、ジメチルス
ルホキノド等、ジクロロメタン、クロロホルム等のハロ
ゲン化炭化水素； ベンゼン、トルエン、キシレン等の
芳香族炭化水素などを単独もしくは混合して使用するこ
とができる。反応温度は使用する原料化合物に応じて変
化させればよく、通常は常圧下、ＯｏＣないし還流温度
の範囲で選ぶのが有利である。The above reaction is preferably carried out in a solvent that does not affect the reaction. As a solvent, for example, water; methyl acetate,
Esters such as ethyl acetate; dimethylformamide,
Amides such as diethylformamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as acetonitrile, dimethylsulfoquinide, dichloromethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene These can be used alone or in combination. The reaction temperature may be changed depending on the raw material compound used, and it is usually advantageous to select it under normal pressure in the range of OoC to reflux temperature.
また本反応において無機塩基または有機塩基の存在は有
利であり、例えば水酸化ナトリウム、水酸化カリウム、
水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸
水素ナトリウム、炭酸水素カリウム等の無機塩基または
トリエチルアミン、ジイソプロピルエチルアミン、ＤＢ
Ｕ（１，８−ジアザビシクロ［５，４，０］−７−ウン
デセン）、ピリジン、酢酸ナトリウム等の有機塩基を反
応に加えることが好ましい。The presence of an inorganic or organic base is also advantageous in this reaction, such as sodium hydroxide, potassium hydroxide,
Inorganic bases such as lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or triethylamine, diisopropylethylamine, DB
Preferably, an organic base such as U (1,8-diazabicyclo[5,4,0]-7-undecene), pyridine, sodium acetate, etc. is added to the reaction.
本発明化合物（ｎ）は例えば以下の通り製造することが
できる。The compound (n) of the present invention can be produced, for example, as follows.
く以下余白〉
酸化
（式中、Ａ、 Ｂ、 Ｒ２、Ｒ３、Ｒ４及びＲｓは
前記と同意義である。）
すなわち、一般式（Ｉａ）で表されるスルホンアミド誘
導体を酸化することにより、一般式（■）′で表される
本発明化合物が製造される。(space below) Oxidation (In the formula, A, B, R2, R3, R4 and Rs have the same meanings as above.) That is, by oxidizing the sulfonamide derivative represented by the general formula (Ia), the general The compound of the present invention represented by formula (■)' is produced.
上記の反応は、反応に影響を及ぼさない溶媒中で行うこ
とが好ましい。溶媒としては、例えば水；メタノール、
エタノール等のアルコール類； ジメチルホルムアミド
、ジエチルホルムアミド等のアミド類； テトラヒドロ
フラン、ジオキサン等のエーテル類； アセトニトリル
、酢酸等、ジクロロメタン、クロロホルム等のハロゲン
化炭化水素；ベンゼン、 トルエン、キンレン等の芳香
族炭化水素などを単独もしくは混合して使用することが
できる。The above reaction is preferably carried out in a solvent that does not affect the reaction. As a solvent, for example, water; methanol,
Alcohols such as ethanol; Amides such as dimethylformamide and diethylformamide; Ethers such as tetrahydrofuran and dioxane; Halogenated hydrocarbons such as acetonitrile, acetic acid, dichloromethane and chloroform; Aromatic hydrocarbons such as benzene, toluene and quinolene These can be used alone or in combination.
酸化剤としては一般的に用いられるものでよく、例えば
硝酸ニアンモニウムセリウム、四酢酸鉛、二酸化鉛、二
酸化マンガン、二酸化セレン、クロム酸類、四酸化オス
ミウム、過ヨウ素酸、酸化銀、フレミー塩、炭酸銀等を
使用することができる。Commonly used oxidizing agents may be used, such as cerium ammonium nitrate, lead tetraacetate, lead dioxide, manganese dioxide, selenium dioxide, chromic acids, osmium tetroxide, periodic acid, silver oxide, Flemy's salt, and carbonic acid. Silver etc. can be used.
反応温度は使用する原料化合物に応じて変化させればよ
く、通常は常圧下、０°Ｃないし還流温度の範囲で選ぶ
のが有利である。The reaction temperature may be changed depending on the raw material compound used, and it is usually advantageous to select it in the range of 0°C to reflux temperature under normal pressure.
かくして得られた本発明化合物（１）及び（ＩＩ）の代
表的なものとして次の化合物が挙げられる。The following compounds are representative of the compounds (1) and (II) of the present invention thus obtained.
・Ｎ−（４−ヒドロキン−３，５−ジメチルフェニル）
メタンスルホンアミド
・Ｎ−（４−ヒドロキン−３，５−ジメチルフェニル）
ペンタンスルホンアミド
・Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）
ベンゼンスルホンアミド
・Ｎ−（４−ヒドロキン−３，５−ジメチルフェニル）
ピリノンスルホンアミド
・Ｎ−（４−ヒドロキ／−３，５−ジメチルフエニル）
インキノリン−５−スルホンアミド・Ｎ−（４−ヒドロ
キシ−３，５−ジメチルフェニル）−１−メチルビロー
ル−２−スルホンアミド
・Ｎ−（４−ヒドロ牛シー３，５−ジメチルフェニル）
フラン−２−スルホンアミド
・Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）
ベンゾ［ｂｌチオフェン−４−スルホンアミド
・Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）
グアイアズレン−３−スルホンアミド・Ｎ−（４−ヒド
ロ牛シー３，５−ジメチルフェニル）チアゾール−２−
スルホンアミド・４−メチル−Ｎ−（４−ヒドロキシ−
３，５−ジメチルフェニル）ベンゼンスルホンアミド・
４−クロロ−Ｎ−（４−ヒドロキシ−３，５−ジメチル
フェニル）ベンゼンスルホンアミド・Ｎ−（４−ヒドロ
キシ−３，５−ジメチルフェニル）チオフェン−２−ス
ルホンアミド・Ｎ−（４−ヒドロキシ−３，５−ジメチ
ルフェニル）ナフタレン−１−スルホンアミド・Ｎ−（
４−ヒドロキシ−３，５−ジメチルフェニル）ナフタレ
ン−２−スルホンアミド・Ｎ−（４−ヒドロキ／−３，
５−ジメチルフェニル）キノリン−８−スルホンアミド
・３−メチル−Ｎ−（４−ヒドロキン−３，５−ジメチ
ルフェニル）チオフェン−２−スルホンアミド
・４−メチル−Ｎ−（４−ヒドロ牛シー３，５−ジメチ
ルフェニル）ナフタレン−１−スルホンアミド
・５−エチル−Ｎ−（４−ヒドロキン−３，５−ジメチ
ルフェニル）ナフタレン−１−スルホンアミド
・８−メチル−Ｎ−（４−ヒドロキシ−３，５−ジメチ
ルフェニル）ナフタレン−１−スルホンアミド
・５−メチル−Ｎ−（４−ヒドロキ／−３，５−ジメチ
ルフェニル）ナフタレン−２−スルホンアミド
・６−メチル−Ｎ−（４−ヒドロキシ−３，５−ジメチ
ルフェニル）ナフタレン−２−スルポンアミド
・Ｎ−［４−ヒドロキシ−３，５−ビス（１−メチルエ
チル）フェニルコメタンスルホンアミド・Ｎ−［４−ヒ
ドロキン−３，５−ビス（１−メチルエチル）フェニル
］ベンゼンスルホンアミド・Ｎ−［４−ヒドロキシ−３
，５−ビス（１−メチルエチル）フェニル］ナフタレン
ー１−スルホンアミド
・Ｎ−［４−ヒドロキシ−３，５−ビス（１−メチルエ
チル）フェニルコナフタレンー２−スルホンアミド
・４−メチル−Ｎ−［４−ヒドロ牛シー３．５−ビス（
，１−メチルエチル）フェニル］ベンゼンスルホンアミ
ド
・４−クロロ−Ｎ−［４−ヒドロキン−３１５＝ビス（
１−メチルエチル）フェニル］ベンゼンスルホンアミド
・Ｎ−［４−ヒドロキン−３，５−ビス（１−メチルエ
チル）フェニルコチオフェン−２−スルホンアミド
・１１−［３，５−ビス（ｌ、１−ジメチルエチル）−
４−ヒドロキンフェニル］ナフタレン−２−スルホンア
ミド
・４−メチル−Ｎ−［３，５−ビス（１，１−ジメチル
エチル）−４−ヒドロ牛ジフェニル］ベンゼンスルホン
アミド
・４−クロロ−Ｎ−［３，５−ビス（１，１−ジメチル
エチル）−ｌｌ−ヒドロ＋７フエニルＪベンゼンスルホ
ンアミド
・Ｎ−（３，４，５−トリメトキシフェニル）チオフェ
ン−２−スルホンアミド
・４−メチル−Ｎ−（３，４，５−トリメトキシフェニ
ル）ベンゼンスルホンアミド
・Ｎ−（４−ヒドロ牛シー３．５−ジメトキンフェニル
）ナフタレン−１−スルホンアミド・Ｎ−（４−ヒドロ
キシ−３，５−ジメトキシフェニル）チオフェン−２−
スルホンアミド・４−メチル−Ｎ−（４−ヒドロキシ−
３＋ ５−ジメトキシフェニル）ベンゼンスルホンアミ
ド・４−メチル−Ｎ−（４−ヒドロキシフェニル）ベン
ゼンスルホンアミド
・Ｎ−（３，５−ジメチル−４−オキソ−２，５−シク
ロへキサジエン−１−イリデン）ベンゼンスルホンアミ
ド
・Ｎ−（３，５−ジメチル−４−オキソ−２，５−シク
ロへキサジエン−１−イリデン）チオフェン−２−スル
ホンアミド
・Ｎ−（３，ｌｉ−ジメチル−４−オキソ−２，５−シ
クロへキサジエン−１−イリデン）ナフタレン−２−ス
ルホンアミド
・４−メチル−Ｎ−（３，５−ジメチル−４−オキソ−
２，５−シクロへキサジエン−１−イＩＪ テン）ベン
ゼンスルホンアミド
・Ｎ−（３，５−ジメトキシ−４−オキソ−２゜５−シ
クロへキサジエン−１−イリデン）ベンゼンスルホンア
ミド
・Ｎ−（３，５−ジメトキシ−４−オキソ−２＋５−シ
クロへキサジエン−１−イリデン）ナツタシン−ｌ−ス
ルホンアミド
・４−メチル−Ｎ−（３，５−ジメトキシ−４−オキソ
−２，５−フクロヘキサジエン−１−イリデン）ベンゼ
ンスルホンアミド
・４−メチル−Ｎ−（４−ヒドロキシ−３−メチルフェ
ニル）ベンゼンスルホンアミド
・４−メチル−Ｎ−（４−アセトキシ−３，５−ジメチ
ルフェニル）ベンゼンスルホンアミド・４−メチル−Ｎ
−メチル−Ｎ−（４−ヒドロキシ−３，５−ジメチルフ
ェニル）ベンゼンスルホンアミド
・４−クロロ−Ｎ−メトキシ−Ｎ−（４−ヒドロキシ−
３，５−ジメチルフェニル）ベンゼンスルホンアミド
・２−クロロ−Ｎ−ヒドロキン−Ｎ−（４−ヒドロキ／
−３，５−ジイソプロピルフェニル）ベンゼンスルホン
アミド
・Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）
フェニルメタンスルホンアミド
・Ｎ−（４−ヒドロキ／−３，５−ジメチルフェニル）
−２−フェニル−（Ｅ）−エテンスルホンアミド
・Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）
−２−（３−チエニル）−（Ｅ）−エテンスルホンアミ
ド
・４−メチル−Ｎ−（４−ヒドロキシ−２，３゜５−ト
リメチルフェニル）ベンゼンスルホンアミド
本発明化合物（１）及び（ＩＩ）は、後記に示すごとく
優れた５−リポキシゲナーゼ阻害作用を有し、かつ安全
性も高いので、各種アレルギー性疾患の治療剤、例えば
抗炎症剤、腎炎、肝炎及び膵炎の治療剤、痛風治療剤、
抗痴呆剤、乾廁治療剤、免疫治療剤、心疾患治療剤、血
管障害予防および／または治療剤及び抗喘息薬として有
効である。・N-(4-hydroquine-3,5-dimethylphenyl)
Methanesulfonamide/N-(4-hydroquine-3,5-dimethylphenyl)
Pentanesulfonamide/N-(4-hydroxy-3,5-dimethylphenyl)
Benzenesulfonamide N-(4-hydroquine-3,5-dimethylphenyl)
Pyrinonesulfonamide/N-(4-hydroxy/-3,5-dimethylphenyl)
Inquinoline-5-sulfonamide/N-(4-hydroxy-3,5-dimethylphenyl)-1-methylvirol-2-sulfonamide/N-(4-hydrocyto-3,5-dimethylphenyl)
Furan-2-sulfonamide/N-(4-hydroxy-3,5-dimethylphenyl)
Benzo[blthiophene-4-sulfonamide N-(4-hydroxy-3,5-dimethylphenyl)
Guaiazulene-3-sulfonamide/N-(4-hydro-3,5-dimethylphenyl)thiazole-2-
Sulfonamide 4-methyl-N-(4-hydroxy-
3,5-dimethylphenyl)benzenesulfonamide
4-chloro-N-(4-hydroxy-3,5-dimethylphenyl)benzenesulfonamide/N-(4-hydroxy-3,5-dimethylphenyl)thiophene-2-sulfonamide/N-(4-hydroxy- 3,5-dimethylphenyl)naphthalene-1-sulfonamide N-(
4-hydroxy-3,5-dimethylphenyl)naphthalene-2-sulfonamide N-(4-hydroxy/-3,
5-dimethylphenyl) quinoline-8-sulfonamide, 3-methyl-N-(4-hydroquine-3,5-dimethylphenyl)thiophene-2-sulfonamide, 4-methyl-N-(4-hydrocycetate 3 ,5-dimethylphenyl)naphthalene-1-sulfonamide・5-ethyl-N-(4-hydroquine-3,5-dimethylphenyl)naphthalene-1-sulfonamide・8-methyl-N-(4-hydroxy-3 ,5-dimethylphenyl)naphthalene-1-sulfonamide/5-methyl-N-(4-hydroxy/-3,5-dimethylphenyl)naphthalene-2-sulfonamide/6-methyl-N-(4-hydroxy- 3,5-dimethylphenyl)naphthalene-2-sulponamide/N-[4-hydroxy-3,5-bis(1-methylethyl)phenylcomethanesulfonamide/N-[4-hydroquine-3,5-bis( 1-methylethyl)phenyl]benzenesulfonamide/N-[4-hydroxy-3
,5-bis(1-methylethyl)phenyl]naphthalene-1-sulfonamide/N-[4-hydroxy-3,5-bis(1-methylethyl)phenylconaphthalene-2-sulfonamide/4-methyl-N -[4-Hydrobovine Sea 3.5-Bis(
,1-methylethyl)phenyl]benzenesulfonamide 4-chloro-N-[4-hydroquine-315=bis(
1-methylethyl)phenyl]benzenesulfonamide/N-[4-hydroquine-3,5-bis(1-methylethyl)phenylcothiophene-2-sulfonamide/11-[3,5-bis(l,1 -dimethylethyl)-
4-Hydroquinphenyl]naphthalene-2-sulfonamide 4-methyl-N-[3,5-bis(1,1-dimethylethyl)-4-hydrocydiphenyl]benzenesulfonamide 4-chloro-N- [3,5-bis(1,1-dimethylethyl)-ll-hydro+7phenylJbenzenesulfonamide/N-(3,4,5-trimethoxyphenyl)thiophene-2-sulfonamide/4-methyl-N -(3,4,5-trimethoxyphenyl)benzenesulfonamide/N-(4-hydroxy-3,5-dimethoxyphenyl)naphthalene-1-sulfonamide/N-(4-hydroxy-3,5- dimethoxyphenyl)thiophene-2-
Sulfonamide 4-methyl-N-(4-hydroxy-
3+ 5-dimethoxyphenyl)benzenesulfonamide/4-methyl-N-(4-hydroxyphenyl)benzenesulfonamide/N-(3,5-dimethyl-4-oxo-2,5-cyclohexadien-1-ylidene ) Benzenesulfonamide/N-(3,5-dimethyl-4-oxo-2,5-cyclohexadien-1-ylidene)thiophene-2-sulfonamide/N-(3,li-dimethyl-4-oxo- 2,5-cyclohexadien-1-ylidene)naphthalene-2-sulfonamide 4-methyl-N-(3,5-dimethyl-4-oxo-
2,5-cyclohexadien-1-ylidene)benzenesulfonamide N-(3,5-dimethoxy-4-oxo-2゜5-cyclohexadien-1-ylidene)benzenesulfonamide N-( 3,5-dimethoxy-4-oxo-2+5-cyclohexadien-1-ylidene) natutasin-l-sulfonamide 4-methyl-N-(3,5-dimethoxy-4-oxo-2,5-fuchlorohexadiene) -1-ylidene)benzenesulfonamide/4-methyl-N-(4-hydroxy-3-methylphenyl)benzenesulfonamide/4-methyl-N-(4-acetoxy-3,5-dimethylphenyl)benzenesulfonamide・4-methyl-N
-Methyl-N-(4-hydroxy-3,5-dimethylphenyl)benzenesulfonamide 4-chloro-N-methoxy-N-(4-hydroxy-
3,5-dimethylphenyl)benzenesulfonamide 2-chloro-N-hydroquine-N-(4-hydroxy/
-3,5-diisopropylphenyl)benzenesulfonamide/N-(4-hydroxy-3,5-dimethylphenyl)
Phenylmethanesulfonamide/N-(4-hydroxy/-3,5-dimethylphenyl)
-2-phenyl-(E)-ethenesulfonamide/N-(4-hydroxy-3,5-dimethylphenyl)
-2-(3-thienyl)-(E)-ethenesulfonamide/4-methyl-N-(4-hydroxy-2,3゜5-trimethylphenyl)benzenesulfonamide Compounds of the present invention (1) and (II) As shown below, has excellent 5-lipoxygenase inhibitory action and is highly safe, so it can be used as a therapeutic agent for various allergic diseases, such as an anti-inflammatory agent, a therapeutic agent for nephritis, hepatitis and pancreatitis, a therapeutic agent for gout,
It is effective as an anti-dementia agent, a therapeutic agent for xerosis, an immunotherapeutic agent, a therapeutic agent for heart disease, a preventive and/or therapeutic agent for vascular disorders, and an anti-asthmatic agent.
本発明化合物（１）及び（ＩＩ）は、製薬上許容される
補助剤を配合して、経口投与あるいは非経口投与用製剤
として使用することができる。Compounds (1) and (II) of the present invention can be mixed with pharmaceutically acceptable adjuvants and used as a preparation for oral or parenteral administration.
経口投与用の製剤としては、上記化合物を適当な添加剤
、たとえば乳糖、マンニット、トウモロコシデンプン、
結晶セルロース等の賦形剤、セルロース誘導体、アラビ
アゴム、ゼラチン等の結合剤、カルボキンメチルセルロ
ースカルシウム等の崩壊剤、タルク、ステアリン酸マグ
ネシウム等の滑沢剤等々と適当に組み合わせることによ
り錠剤、散剤、顆粒剤、カプセル剤とすることができる
。For formulations for oral administration, the above compounds may be combined with suitable excipients such as lactose, mannitol, corn starch,
By appropriately combining with excipients such as crystalline cellulose, binders such as cellulose derivatives, gum arabic, and gelatin, disintegrants such as carboquine methylcellulose calcium, and lubricants such as talc and magnesium stearate, tablets, powders, It can be made into granules or capsules.
また、これらの、固型製剤をヒドロキシプロピルメチル
セルロースフタレート、ヒドロキンプロピルメチルセル
ロースアセテートサクシネート、セルロースアセテート
フタレート、メタアクリレートコーポリマーなどの被覆
用基剤を用いて腸溶性製剤とすることができる。Further, these solid preparations can be made into enteric preparations by using a coating base such as hydroxypropyl methylcellulose phthalate, hydroquinepropylmethylcellulose acetate succinate, cellulose acetate phthalate, or methacrylate copolymer.
経口投与用の液剤としては、乳濁剤、溶液剤、懸濁剤、
シロップ剤、エリキシル剤等を含み、−膜内に用いられ
る不活性な希釈剤、例えば精製水、エタノールを含むこ
とができる。この組成物は不活性な希釈剤以外に湿潤剤
、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防
腐剤を含有していてもよい。その他、公知の方法により
処方されるスプレー剤とすることもできる。Liquid preparations for oral administration include emulsions, solutions, suspensions,
Includes syrups, elixirs, etc., and can include - inert diluents used within the membrane, such as purified water, ethanol. In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, and preservatives. In addition, it can also be made into a spray formulated by a known method.
非経口投与用の製剤としては、例えば水、エタノール、
グリセリン、慣用な界面活性剤等を組み合せることによ
り注射用液剤とすることができる。Preparations for parenteral administration include, for example, water, ethanol,
By combining glycerin, a commonly used surfactant, etc., it can be made into an injectable solution.
さらに、公知の方法により処方される吸入剤、外用液剤
、点眼剤、点鼻剤、軟膏のような塗布剤とすることがで
きる。Furthermore, it can be made into inhalants, external liquids, eye drops, nasal drops, and liniments such as ointments, which are prescribed by known methods.
本発明化合物（Ｉ）及び（ＩＩ）の投与量は年齢、体重
、症状、治療効果、投与方法、投与期間により異なるが
、通常、０．１〜１ｏｏｏｍｇ／日、好ましくは０．５
〜５００ｍｇ／日の投与範囲で１日１〜３回の範囲で経
口投与するか、又は０．１〜５００ｍｇの範囲で１日１
回〜数回非経口投与する。The dosage of the compounds (I) and (II) of the present invention varies depending on age, body weight, symptoms, therapeutic effects, administration method, and administration period, but is usually 0.1 to 1oomg/day, preferably 0.5
Orally at a dosage range of ~500 mg/day in a range of 1 to 3 times a day, or 0.1 to 500 mg/day once a day.
Administer parenterally one to several times.
［作用］
く５−リポキシゲナーゼ阻害活性〉
ＴＥＲＡＳＩＩＩＴＡ等の方法に準じて行った（ Ｔｈ
ｒｏｍｂｏ−ｓｉｓ ｒｅｓｅａｒｃｈ、４１，２２３
−２３７．１９８６）。[Effect] 5-lipoxygenase inhibitory activity> Performed according to the method of TERASIIITA etc. (Th
rombo-sis research, 41,223
-237.1986).
即ち、ラット好塩基球性白血病細胞（ＲＢＬ−１）を培
養液ＲＰＭ１ １６４０中で３７℃、５％Ｃ０２インキ
ユベーター中、４日間培養後、ディッンユに付着したＲ
ＢＬ−１細胞（ａｄｈｅｓｉｖｅ ＲＢＬ２Ｏ−
−１）を採取した。得られたＲＢＬ−１細胞（２，５ｘ
１０ ’ｃｅｌｌｓ／ ｍｌ）に被検化合物を加え、
さら１こアラキドン酸（０，２ｍＭ）を基質として加え
て一定時間インキニベーションした。一方、被検化合物
を加えずにアラキドン酸を加え同様に操作したものを対
照とした。インキュベーション後遠心分離して得られた
上清について、高速液体クロマトグラフィーを用い、上
記反応の生成物である５−ヒドロキシエイコサテトラエ
ン酸（５−ＨＥＴＥ）を定量した。That is, after culturing rat basophilic leukemia cells (RBL-1) in culture medium RPM1 1640 at 37°C in a 5% C02 incubator for 4 days, R
BL-1 cells (adhesive RBL2O--1) were collected. The obtained RBL-1 cells (2,5x
Add the test compound to 10' cells/ml),
Furthermore, arachidonic acid (0.2 mM) was added as a substrate and incubation was carried out for a certain period of time. On the other hand, a control was prepared in which the test compound was not added but arachidonic acid was added and the same operation was performed. The supernatant obtained by centrifugation after incubation was subjected to high performance liquid chromatography to quantify 5-hydroxyeicosatetraenoic acid (5-HETE), the product of the above reaction.
被検化合物の５−リポキシゲナーゼ阻害活性（ＩＣｓＩ
ｌ値）は、対照の酵素活性を５０％阻害する濃度（μＭ
）として求めた。結果を以下の表に示した。5-lipoxygenase inhibitory activity (ICsI) of the test compound
l value) is the concentration that inhibits the control enzyme activity by 50% (μM
). The results are shown in the table below.
〈以下余白〉
４〜５遍齢のＩＣＲ系マウス（チャールス・リバー社）
を１群１０匹として用いた。実施例１〜１５の化合物を
５％アラビアゴムに懸濁した後、それぞれａｏｏｍｇ／
ｋｇの用量にて経口投与し、７日間にわたり観察を行っ
た。その結果、本発明化合物の毒性に起因した死亡例は
認められながった。<Left below> 4-5 year old ICR mouse (Charles River)
were used with 10 animals per group. After suspending the compounds of Examples 1 to 15 in 5% gum arabic, aoomg/
It was orally administered at a dose of 1.0 kg and observed for 7 days. As a result, no cases of death due to the toxicity of the compound of the present invention were observed.
以下、実施例により本発明をさらに具体的に説明するが
、本発明はこれらにより限定されるものではない。EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.
実施例Ｉ
Ｎ−［４−ヒドロキン−３，５−ビス（１−メチルエチ
ル）フェニルコチオフェン−２−スルホンアミド
アルゴン気流下、２．６−シメチルー４−アミノフェノ
ール塩酸塩１．７３ｇ （０，０１ｍｏｌ）を酢酸エチ
ル５０ｍ１に懸濁し、水５０ｍ１及び炭酸水素ナトリウ
ム２．５２ ｇ （０，０３ｍｏ Ｉ ）を加え、室温
にて１０分間攪拌した。攪拌後、２−チオフェンスルホ
ニルクロライド１．８０ｇ（０，０１ｍｏ＋）の酢酸エ
チル溶液を徐々に滴下し、さらに３０分間攪拌した。１
０％塩酸を加え酢酸エチルで抽出した後、酢酸エチル層
を１０％塩酸、飽和食塩水の順で充分に洗浄し、無水硫
酸マグネシウムで乾燥した。溶媒を留去した後、得られ
た残香を７リカゲルカラムクロマトグラフイー（りロロ
ホルム： イソプロピルエーテル＝１： １）にて精
製した。得られた結晶物をイソプロピルエーテルから再
結晶し、Ｎ−［４−ヒドロキシ−３゜５−ビス（ｉ−メ
チルエチル）フェニルコチオフェン−２−スルホンアミ
ドを得た。収率５５％。Example I N-[4-Hydroquine-3,5-bis(1-methylethyl)phenylcothiophene-2-sulfonamide Under argon flow, 1.73 g of 2,6-dimethyl-4-aminophenol hydrochloride (0, 01 mol) was suspended in 50 ml of ethyl acetate, 50 ml of water and 2.52 g (0.03 mol) of sodium hydrogen carbonate were added, and the mixture was stirred at room temperature for 10 minutes. After stirring, an ethyl acetate solution containing 1.80 g (0.01 mo+) of 2-thiophenesulfonyl chloride was gradually added dropwise, and the mixture was further stirred for 30 minutes. 1
After adding 0% hydrochloric acid and extracting with ethyl acetate, the ethyl acetate layer was thoroughly washed with 10% hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residual aroma was purified by 7 silica gel column chromatography (liloform: isopropyl ether = 1:1). The obtained crystalline product was recrystallized from isopropyl ether to obtain N-[4-hydroxy-3°5-bis(i-methylethyl)phenylcothiophene-2-sulfonamide. Yield 55%.
融点＝ １３７〜１３９℃
ＭＳ （ｍ／ｚ） ： ３３９
ＩＲ（ｎｕｊｏｌ）ｃｍ−’： ３５１０．３２１０
．１３３８．１３０８．１１４５
ＮＭＲ（ＤＭＳＯ−ｄ６）δ：１．’０４（１２Ｈ、ｄ
）、３．０６〜３．３２ （２Ｈ，ｍ）、６．６６ （
２Ｈ，ｓ） 、７．１０ （Ｉ Ｈ，ｄ ｄ） 、７．
３７ （Ｉ Ｈ，ｄｄ）、７．８６ （ＩＨ，ｄｄ）、
７．９８ （１１（、ｓ）、９．７０ （ＩＨ，ｓ）
、実施例２
４−メチル−Ｎ−（３，５−ジメトキシ−４−オキソ−
２，５−シクロヘキサジエン−１−イリデン）ベンゼン
スルホンアミド
く以下余白〉
４−メチル−Ｎ−（３，４，５−トリメトキシフェニル
）ベンゼンスルホンアミド３．３’７ｇをアセトニトリ
ル３０ ｍｌに溶解ル、攪拌下硝酸ニアンモニウムセリ
ウムｌ１ｇの水溶液３０ｍ１を滴下した。析出した結晶
を濾取しシリカゲルカラムクロマトクラフィー（クロロ
ホルム）にて精製し、４−メチル−Ｎ−（３，’）−ジ
メトキシ−４−オキソ−２，５−シクロへキサジエン−
１−イリデン）ベンゼンスルホンアミドを２．４２ｇ得
た。収率７５％。Melting point = 137-139°C MS (m/z): 339 IR (nujol) cm-': 3510.3210
．． 1338.1308.1145 NMR (DMSO-d6) δ: 1. '04 (12H, d
), 3.06-3.32 (2H, m), 6.66 (
2H, s), 7.10 (I H, d d), 7.
37 (IH, dd), 7.86 (IH, dd),
7.98 (11(,s), 9.70 (IH,s)
, Example 2 4-Methyl-N-(3,5-dimethoxy-4-oxo-
2,5-Cyclohexadien-1-ylidene)benzenesulfonamide Dissolve 3.3'7 g of 4-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide in 30 ml of acetonitrile. Then, 30 ml of an aqueous solution containing 1 g of cerium ammonium nitrate was added dropwise while stirring. The precipitated crystals were collected by filtration and purified by silica gel column chromatography (chloroform) to give 4-methyl-N-(3,')-dimethoxy-4-oxo-2,5-cyclohexadiene-
2.42 g of 1-ylidene)benzenesulfonamide was obtained. Yield 75%.
融点・ １７２〜１７３℃
ＭＳ （ｒｎ／ｚ） ： ３２３
ＩＲ（ＫＢｒ）ｃｍ−’： １６９０．１５８５．１
３１０．１Ｊ５０．１１１Ｏ
ＮＭＲ（ＣＤＣｌ２）δ： ２．４６ （３Ｈ１，ｓ
）。Melting point: 172-173°C MS (rn/z): 323 IR (KBr) cm-': 1690.1585.1
310.1J50.111O NMR (CDCl2) δ: 2.46 (3H1,s
).
３．８１ （３Ｈ，ｓ） 、３．９４ （３Ｈ，ｓ’）
、６．０１（Ｉ Ｈ，ｄ） 、７．２ ８ （
Ｉ Ｈ，ｄ） 、７．３ ６ （２Ｈ、ｄ）、７
．９０．（２Ｈ，ｄ）
実施例３〜実施例２８
実施例１または実施例２と同様の方法で実施例３〜実施
例２８の化合物を得た。3.81 (3H,s), 3.94 (3H,s')
, 6.01 (I H, d) , 7.2 8 (
I H, d), 7.3 6 (2H, d), 7
．． 90. (2H, d) Examples 3 to 28 Compounds of Examples 3 to 28 were obtained in the same manner as in Example 1 or Example 2.
各々の化合初冬、構造式及び物理定数は以下の通りであ
る。The chemical compounds, structural formulas, and physical constants of each compound are as follows.
実施例３
Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）ナ
フタレン−２−スルホンアミド融点： 冒９〜１５０℃
Ｍ Ｓ （ｍ ／ ｚ ） ： ３２７ＩＲ（ｎｕｊ
ｏｌ）ｃｍ−’： ３４８０．３２６０，１３１８．
１３００．１１６０．１１２３
実施例４
４−クロロ−Ｎ−（４−ヒドロキ／−３，５＝ジメチル
フェニル）ベンゼンスルホンアミド融点： １４４〜１
４６℃
ＭＳ （ｍ／ｚ） ： ３１１
１Ｒ（ｎｕｊｏｌ）ｃｍ−’： ３５８０，３２７５
．１３２５．１３０８
実施例５
Ｎ二（４−ヒドロキシ−３，５−ジメチルフェニル）チ
オフェン−２−スルホンアミド融点＝ １３０〜１３２
℃
ＭＳ （ｍ／ｚ）： ２８３
ＩＲ（ｎｕｊｏｌ）ｃｍ−’： ３５４０，３２７０
，１３３８．１３１０
実施例６
Ｎ−（４−ヒドロキン−３，５−ジメチルフェニル）−
２−フェニル−（Ｅ）−エテンスルホンアミド
融点： １１０〜１１１℃
ＭＳ （ｍ／ｚ）： ａｏａ
ＩＲ（ＫＢｒ）ｃｍ−’： ３５４０．３２８０．１
３９０．１３１０．１１４０
実施例７
Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）ナ
フタレン−１−スルポンアミド −融点＝ １７８
〜１７９℃
Ｍ５ （ｍ／ｚ） ： 、３ ２ ７ＩＲ（ＫＢ
ｒ）ｃｍ−’： ３５００．３２４０，１３１０ ．
１１５５ ．１１２５
実施例８
４−メチル−Ｎ−（４−ヒドロキシ−３，５−ジメトキ
シフェニル）ベンゼンスルホンアミド融点： １４２〜
１４３℃
ＭＳ （ｍ／ｚ）： ３．２３
ＩＲ（ＫＢｒ）ｃｍ−’： ３４５０，３２６０．１
３２０．１１６０．１１１５
実施例９
４−メチル−Ｎ−（４−ヒドロ牛シー３＋ ５＝ジメチ
ルフエニル）ベンゼンスルホンアミド〈以下余白〉
一２９＝
融点： １０４〜１０６°Ｃ
ＭＳ （ｍ／ ｚ） ： ２ ９ １１Ｒ（ｎｕ
ｊｏｌ） ｃｍ−’： ３５４０．３２４０．１
３７５．１１５０
実施例１０
４−メチル−Ｎ−［４−ヒドロキシ−３，５＝ビス（１
−メチルエチル）フェニルコベンゼンスルホンアミド
融点： １６１〜１６２℃
ＭＳ （ｍ／ｚ）： ３４７
ＩＲ（ｎｕｊｏｌ）ｃｍ−’： ３５３０．３２７０
，１ ５９０．１３７０．１３１５
実施例１１
Ｎ−［４−ヒドロキン−３，５−ビス（１−メチルエチ
ル）フェニルコベンゼンスルホンアミド融点： １４６
〜１５０℃
ＭＳ （ｍ／ｚ） ： ３３３
ＩＲ（ｎｕｊｏｌ）ｃｍ−’： ３５２０．３３００
，１３７５．１３０５．１１５０
実施例１２
４−クロロ−Ｎ−［４−ヒドロキシ−３，５−ビス（１
−メチルエチル）フェニル］ベンゼンスルホンアミド
融点； １４９〜１５１℃
Ｍ５ （ｍ／ｚ）： ３６７
ＩＲ（ｎｕｊｏｌ） ａｍ−’： ３５６０．
３２６０，１３７５ ．１３１０．１２４０
実施例１３
Ｎ−［４−ヒドロキシ−３，５−ビス（１−メチルエチ
ル）フェニルコメタンスルホンアミド融点： １６５〜
１６７℃
ＭＳ （ｍ／ｚ）： ２７１
１ Ｒ（ｎｕｊｏｌ） ｃｍ−’： ３５１０，３２
４０，１３７５．１３’００，１２４５
実施例１４
４−メチル−Ｎ−［３，５−ビス（１，ｌ−ジメチルエ
チル）−４−ヒドロ牛／フェニル］ベンゼンスルホンア
ミド
〈以下余白〉
融点： １７９〜１８１℃
ＭＳ （ｍ／ ｚ） ： ３ ７ ５ＩＲ（ｎｕ
ｊｏｌ） ｃｍ−’： ３６２０，３２５０．１３
７５ ．１３２０．１２１５
実施例１５
Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）ベ
ンゼンスルホンアミド
融点＝ １５７〜１５９℃
ＭＳ （ｍ／ｚ）： ２７７
Ｉ Ｒ（ｎｕｊｏｌ） Ｃｍ−１： ３４８０，３２
４０．１３７５．１３０５．１２１０
実施例１６
＝３３−
Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）メ
タンスルホンアミド
融点： １３５〜１３６℃
ＭＳ （ｍ／ｚ） ： ２１５
ＩＲ（ｎｕｊｏｌ）ｃｍ−’： ３５３０，３２８０
，１３７０．１３００．１２４０
実施例１７
４−メチル−Ｎ−（３，４，５−）リメトキシフェニル
）ベンゼンスルホンアミド
融点＝ １４２〜１４３°Ｃ
ＭＳ （ｍ／ｚ） ： ａ ３７
Ｉ Ｒ（ｎｕｊｏｌ） ｃｍ”： ３ ２８０，
１ ３７５．１ ３２５．１２３５
実施例１８
４−メチル−Ｎ−（４−ヒドロ手ジフェニル）ベンゼン
スルホンアミド
融点： １４５〜１４７℃
ＭＳ （ｍ／ｚ） ： ２６３
ＩＲ（ｎｕｊｏｌ） ｃｍ−’： ３２４０，１５
９５．１３７５．１３３０．１２３５
実施例１９
４−クロロ−Ｎ−［３，，５−ビス（１，ｌ−ジメチル
エチル）−４−ヒドロキ／フェニルコベンゼンスルホン
アミド
融点＝ ２０３〜２０５℃
ＭＳ （ｍ／ｚ）： ３９５
ＩＲ（ｎｕｊｏｌ） ｃｍ−’： ３６２０．３２
３Ｑ、１５９ ０．１ ３ ７ ５．１ ３ ２ ０実
施例２Ｏ
Ｎ−（４−ヒドロ牛シー３，５−ジメチルフェニル）キ
ノリン−８−スルホンアミド
融点＝ ２３５〜２３８℃
ＭＳ （ｍ／ｚ）： ３２８
Ｉ Ｒ（ｎｕｊｏｌ） ｃｍ−’： １６２８．１５
９９．１３３８．１２８９，１２０５．１１４７
実施例２１
Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）ピ
リジン−３−スルホンアミド
〈以下余白〉
融点＝ １９０〜１９２℃
ＭＳ （ｍ／ｚ）： ２７８
ＩＲ（ＫＢｒ） ｃｍ−’： ３２２０，１５８０
，１４８０．１３２５．１２１０，１１６０．１０２５
実施例２２
４−メチル−Ｎ−（４−ヒドロキシ−３−メチルフェニ
ル）ベンゼンスルホンアミド
融点＝ １８０〜１８２℃
ＭＳ （ｍ／ｚ）： ２７７
ＩＲ（ＫＢｒ）ｃｍ−’： ３４４０，３２５０，１
５１５．１３８５．１３０５．．１１５５実施例２３
４−メチル−Ｎ＝（４−アセトキシ−３，５−ジメチル
フェニル）ベンゼンスルホンアミド融点＝ １６０〜ｌ
６１ ”Ｃ
ＭＳ （ｍ／ｚ）： ３３ｓ
ＩＲ（ＫＢｒ）ｃｍ−’： ３２１０．１７５５，１
３８５．１３２０，１１８５．１１５５実施例２４
４−メチル−Ｎ−メチル−Ｎ−（４−ヒドロキシ−３，
５−ジメチルフェニル）ベンゼンスルホンアミド
融点： １５６〜１５７℃
ＭＳ （ｍ／ｚ） ： １ ５ ６−１ ５ ７
℃ＩＲ（ＫＢｒ） ａｍ−１： ３４５０．１
４８５，１３２５，１２１０，１１５０．１０８０実施
例２５
Ｎ−（４−ヒドロキシ−３，５−ジメチルフェニル）フ
ェニルメタンスルホンアミド
融点・ １６０〜１６２℃
ＭＳ （ｍ／ｚ） ： ２９１
１Ｒ（ｎｕｊｏｌ） ｃｍ−’ 二 ３５０５
．３３００，１６００．１３７５，１３００．１２４０
実施例２６
Ｎ−（４−ヒドロキノ−３，５−’；メチルフェニル）
ペンタンスルホンアミド
油状物
ＭＳ （ｍ／Ｚ） ： ２７１
１Ｒ（ｎｅａｔ）ｃｍ−’： ３４８０，３２５０，
１７２０．１６１０，１４８５．１３７５
実施例２７
４−メチル−Ｎ−（４−ヒドロキシ−２，３゜５−トリ
メチルフェニル）ベンゼンスルホンアミド
融点： １６０〜１６１℃
ＭＳ （ｍ／ｚ）： ３０５
Ｉ Ｒ（ｎｕｊｏｌ） ｃｍ−’： ３ ４９
０，３ １ ７ ０，１ ６０５．１３８０，１３１０
．１２５０
実施例２８
４−メチル−Ｎ−（３，５−ジメチル−４−オキ７−２
．５−シクロへキサジエン−１−イリデン）ベンゼンス
ルホンアミド
融点＝ １０２〜１０３℃
ＭＳ （ｍ／ｚ）： ２８９
ＩＲ’（ＫＢｒ） ｃｍ−’： ３２９０，１６４
５，１６ １ ０．１ ５ ５ ５，１ ３ ７ ０．
１ ３ １ ５製剤例１
実施例１の化合物 ５０ｇ乳糖
３１５ｇトウモロコシデンプン
１２５ｇ結晶セルロース
２５ｇ上記成分を均一に混合し、７．５％ヒドロキ
シプロピルセルロース水溶液２００ｍ１を加え、押出し
造粒機により、直径０．５ｍｍスクリーンを用いて顆粒
とし、直ちにマルメライザーにより丸めた後、乾燥し顆
粒剤とした。Example 3 N-(4-hydroxy-3,5-dimethylphenyl)naphthalene-2-sulfonamide Melting point: 9~150°C M S (m/z): 327IR (nuj
ol) cm-': 3480.3260,1318.
1300.1160.1123 Example 4 4-chloro-N-(4-hydroxy/-3,5=dimethylphenyl)benzenesulfonamide Melting point: 144-1
46°C MS (m/z): 311 1R (nujol) cm-': 3580,3275
．． 1325.1308 Example 5 N2(4-hydroxy-3,5-dimethylphenyl)thiophene-2-sulfonamide Melting point = 130-132
°C MS (m/z): 283 IR (nujol) cm-': 3540,3270
, 1338.1310 Example 6 N-(4-hydroquine-3,5-dimethylphenyl)-
2-phenyl-(E)-ethenesulfonamide Melting point: 110-111°C MS (m/z): aoa IR (KBr) cm-': 3540.3280.1
390.1310.1140 Example 7 N-(4-hydroxy-3,5-dimethylphenyl)naphthalene-1-sulponamide - Melting point = 178
~179℃ M5 (m/z): , 3 2 7IR (KB
r) cm-': 3500.3240,1310.
1155. 1125 Example 8 4-Methyl-N-(4-hydroxy-3,5-dimethoxyphenyl)benzenesulfonamide Melting point: 142-
143°C MS (m/z): 3.23 IR (KBr) cm-': 3450, 3260.1
320.1160.1115 Example 9 4-Methyl-N-(4-Hydroxy3+ 5=dimethylphenyl)benzenesulfonamide (margins below) -29= Melting point: 104-106°C MS (m/z) : 2 9 11R(nu
jol) cm-': 3540.3240.1
375.1150 Example 10 4-Methyl-N-[4-hydroxy-3,5=bis(1
-Methylethyl)phenylcobenzenesulfonamide Melting point: 161-162°C MS (m/z): 347 IR (nujol) cm-': 3530.3270
,1 590.1370.1315 Example 11 N-[4-hydroquine-3,5-bis(1-methylethyl)phenylcobenzenesulfonamide Melting point: 146
~150°C MS (m/z): 333 IR (nujol) cm-': 3520.3300
, 1375.1305.1150 Example 12 4-chloro-N-[4-hydroxy-3,5-bis(1
-Methylethyl)phenyl]benzenesulfonamide Melting point; 149-151°C M5 (m/z): 367 IR (nujol) am-': 3560.
3260,1375. 1310.1240 Example 13 N-[4-hydroxy-3,5-bis(1-methylethyl)phenylcomethanesulfonamide Melting point: 165-
167°C MS (m/z): 271 1 R (nujol) cm-': 3510,32
40,1375.13'00,1245 Example 14 4-Methyl-N-[3,5-bis(1,l-dimethylethyl)-4-hydrox/phenyl]benzenesulfonamide (margin below) Melting point: 179 ~181℃ MS (m/z): 3 7 5IR (nu
jol) cm-': 3620, 3250.13
75. 1320.1215 Example 15 N-(4-hydroxy-3,5-dimethylphenyl)benzenesulfonamide Melting point = 157-159°C MS (m/z): 277 I R(nujol) Cm-1: 3480,32
40.1375.1305.1210 Example 16 =33- N-(4-hydroxy-3,5-dimethylphenyl)methanesulfonamide Melting point: 135-136°C MS (m/z): 215 IR (nujol) cm- ': 3530,3280
, 1370.1300.1240 Example 17 4-Methyl-N-(3,4,5-)rimethoxyphenyl)benzenesulfonamide Melting point = 142-143°C MS (m/z): a 37 I R(nujol ) cm”: 3 280,
1 375.1 325.1235 Example 18 4-Methyl-N-(4-hydrodiphenyl)benzenesulfonamide Melting point: 145-147°C MS (m/z): 263 IR (nujol) cm-': 3240, 15
95.1375.1330.1235 Example 19 4-chloro-N-[3,,5-bis(1,l-dimethylethyl)-4-hydroxy/phenylcobenzenesulfonamide Melting point = 203-205°C MS (m /z): 395 IR (nujol) cm-': 3620.32
3Q, 159 0.1 3 7 5.1 3 2 0 Example 2O N-(4-Hydroxy3,5-dimethylphenyl)quinoline-8-sulfonamide Melting point = 235-238°C MS (m/z) : 328 I R(nujol) cm-': 1628.15
99.1338.1289, 1205.1147 Example 21 N-(4-hydroxy-3,5-dimethylphenyl)pyridine-3-sulfonamide (blank below) Melting point = 190-192°C MS (m/z): 278 IR(KBr) cm-': 3220,1580
,1480.1325.1210,1160.1025
Example 22 4-Methyl-N-(4-hydroxy-3-methylphenyl)benzenesulfonamide Melting point = 180-182°C MS (m/z): 277 IR(KBr) cm-': 3440,3250,1
515.1385.1305. ．． 1155 Example 23 4-Methyl-N=(4-acetoxy-3,5-dimethylphenyl)benzenesulfonamide Melting point = 160~l
61 "C MS (m/z): 33s IR (KBr) cm-': 3210.1755,1
385.1320, 1185.1155 Example 24 4-Methyl-N-methyl-N-(4-hydroxy-3,
5-dimethylphenyl)benzenesulfonamide Melting point: 156-157°C MS (m/z): 1 5 6-1 5 7
°CIR(KBr) am-1: 3450.1
485,1325,1210,1150.1080 Example 25 N-(4-hydroxy-3,5-dimethylphenyl)phenylmethanesulfonamide Melting point 160-162°C MS (m/z): 291 1R (nujol) cm- '2 3505
．． 3300,1600.1375,1300.1240 Example 26 N-(4-hydroquino-3,5-'; methylphenyl)
Pentanesulfonamide oil MS (m/Z): 271 1R (neat) cm-': 3480,3250,
1720.1610, 1485.1375 Example 27 4-Methyl-N-(4-hydroxy-2,3°5-trimethylphenyl)benzenesulfonamide Melting point: 160-161°C MS (m/z): 305 I R( cm-': 3 49
0,3 1 7 0,1 605.1380,1310
．． 1250 Example 28 4-Methyl-N-(3,5-dimethyl-4-ox7-2
．． 5-Cyclohexadien-1-ylidene)benzenesulfonamide Melting point = 102-103°C MS (m/z): 289 IR'(KBr) cm-': 3290,164
5,16 1 0.1 5 5 5,1 3 7 0.
1 3 1 5 Formulation Example 1 Compound of Example 1 50g Lactose
315g corn starch 125g crystalline cellulose
Mix 25g of the above ingredients uniformly, add 200ml of 7.5% hydroxypropyl cellulose aqueous solution, make granules using an extrusion granulator using a 0.5mm diameter screen, immediately roll them with a marmerizer, and then dry to form granules. And so.
この乾燥顆粒剤に下記組成のフィルムコーティング液１
．９ｋｇを流動層造粒機を用いてコーティングし、腸溶
性顆粒剤とした。Film coating liquid 1 of the following composition is applied to this dry granule.
．． 9 kg was coated using a fluidized bed granulator to form enteric-coated granules.
コーティング液組成：
ヒドロキシプロビルメチルセルロース
フタレート ５．０ （ｗ／ｗ）％ス
テアリン酸 ０．２ ｓ （ｗ／ｗ）％塩化
メチレン ５０．０ （ｗ／ｗ）％エタノ
ール ４４．７５ 、（ｗ／ｗ）％製剤例２
実施例３の化合物 ２０ｇ乳糖
１００ｇトウモロコシデンプン
３６ｇ結晶セルロース
３０ｇカルボキシメチルセルロースカルシウム０
ｇ
ステアリン酸マグネシウム ４ｇ上記組成の
成分を均一に混合し、単発打錠機にて直径７．５ｍｍの
杵で１錠２００ｍｇの錠剤とした。Coating liquid composition: Hydroxyprobyl methylcellulose phthalate 5.0 (w/w)% Stearic acid 0.2 s (w/w)% Methylene chloride 50.0 (w/w)% Ethanol 44.75, (w/w) )% Formulation Example 2 Compound of Example 3 20g Lactose
100g corn starch 36g crystalline cellulose
30g carboxymethyl cellulose calcium 0
g Magnesium stearate 4g The ingredients of the above composition were mixed uniformly and made into tablets each weighing 200mg using a punch with a diameter of 7.5mm using a single-shot tableting machine.
次いで、この錠剤に下記組成のコーテイング液をスプレ
ーコーティングし、１錠当り１０ｍｇの被覆を施し、腸
溶性フィルムコーティング錠剤とした。Next, the tablets were spray-coated with a coating liquid having the composition shown below to give a coating of 10 mg per tablet to obtain enteric film-coated tablets.
コーティング液組成：
ヒドロキンプロピルメチルセルロース
フタレート ８．０（ｗ／ｗ）％グリ
セリン脂肪酸エステル ０．４（ｗ／ｗ）％塩化メチレ
ン ５０．０（ｗ／Ｗ）％サラシミッロウ
０．１（ｗ／ｗ）％イソプロパツール
４ ｔ、ｓ （ｗ／ｗ）％製剤例３
実施例１０の化合物 １００ｍｇ酢酸ナト
リウム ２ｍｇ酢酸（ｐＨ５，８
に調整用） 適量注射用蒸留水
適量針１０ｍｌ／バイアル
上記処方で常法により注射剤とした。Coating liquid composition: Hydroquine propyl methylcellulose phthalate 8.0 (w/w)% Glycerin fatty acid ester 0.4 (w/w)% Methylene chloride 50.0 (w/w)% Sarasimirou
0.1 (w/w)% isopropanol
4 t, s (w/w)% Formulation Example 3 Compound of Example 10 100 mg sodium acetate 2 mg acetic acid (pH 5,8
(for adjustment) Appropriate amount of distilled water for injection
Appropriate amount needle 10 ml/vial The above formulation was used to prepare an injection by a conventional method.
［発明の効果］ 。[Effect of the invention] .
上記のごとく、本発明の化合物は強い５−リポキシゲナ
ーゼ阻害作用を示し、安全性も高いことから、優れた各
種アレルギー性疾患の治療剤、例えば抗炎症剤、腎炎、
肝炎及び膵炎の治療剤、痛風治療剤、抗痴呆剤、乾癲治
療剤、免疫治療剤、心疾患治療剤、血管障害予防および
／または治療剤及び抗喘息薬として有用である。As mentioned above, the compound of the present invention exhibits a strong 5-lipoxygenase inhibitory effect and is highly safe, so it can be used as an excellent therapeutic agent for various allergic diseases, such as an anti-inflammatory agent, nephritis,
It is useful as a therapeutic agent for hepatitis and pancreatitis, a therapeutic agent for gout, an anti-dementia agent, a therapeutic agent for psoriasis, an immunotherapeutic agent, a therapeutic agent for heart disease, a preventive and/or therapeutic agent for vascular disorders, and an anti-asthmatic agent.
出願人 ゼリア新薬工業株式会社Applicant: Zeria Pharmaceutical Co., Ltd.
Claims (5)
飽和又は不飽和の炭素鎖を示し、Ｂは置換基を有してい
てもよいフェニル基、ナフタレニル基、キノリニル基、
イソキノリニル基、ピロリル基、アズレニル基、フラニ
ル基、ベンゾチオフエニル基、チアゾイル基、チオフェ
ニル基またはピリジニル基もしくは低級アルキル基を示
し、Ｒ＾１は水素原子、低級アルキル基またはアシル基
を示し、Ｒ＾２、Ｒ＾３、Ｒ＾４及びＲ＾５は同一又は
異なってそれぞれ水素原子、ヒドロキシ基、低級アルキ
ル基、シクロアルキル基、アルコキシ基、アシル基また
はハロゲン原子を示し、Ｒ＾６は水素原子、ヒドロキシ
基、アルコキシ基、アシル基または低級アルキル基を示
す。）で表されるスルホンアミド誘導体。(1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, A is a saturated or unsaturated carbon chain with 0 to 4 carbon atoms that may have a substituent. and B is a phenyl group, a naphthalenyl group, a quinolinyl group, which may have a substituent,
It represents an isoquinolinyl group, a pyrrolyl group, an azulenyl group, a furanyl group, a benzothiophenyl group, a thiazoyl group, a thiophenyl group, a pyridinyl group, or a lower alkyl group, R^1 represents a hydrogen atom, a lower alkyl group, or an acyl group, and R ^2, R^3, R^4 and R^5 are the same or different and each represents a hydrogen atom, a hydroxy group, a lower alkyl group, a cycloalkyl group, an alkoxy group, an acyl group or a halogen atom, and R^6 is hydrogen Indicates an atom, hydroxy group, alkoxy group, acyl group or lower alkyl group. ) A sulfonamide derivative represented by
飽和又は不飽和の炭素鎖を示し、Ｂは置換基を有してい
てもよいフェニル基、ナフタレニル基、キノリニル基、
イソキノリニル基、ピロリル基、アズレニル基、フラニ
ル基、ベンゾチオフエニル基、チアゾイル基、チオフェ
ニル基またはピリジニル基もしくは低級アルキル基を示
し、Ｒ＾２、Ｒ＾３、Ｒ＾４及びＲ＾５は同一又は異な
ってそれぞれ水素原子、ヒドロキシ基、低級アルキル基
、シクロアルキル基、アルコキシ基、アシル基またはハ
ロゲン原子を示す。）で表されるスルホンアミド誘導体
。(2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, A is a saturated or unsaturated carbon chain having 0 to 4 carbon atoms that may have a substituent. and B is a phenyl group, a naphthalenyl group, a quinolinyl group, which may have a substituent,
Represents an isoquinolinyl group, pyrrolyl group, azulenyl group, furanyl group, benzothiophenyl group, thiazoyl group, thiophenyl group, pyridinyl group or lower alkyl group, and R^2, R^3, R^4 and R^5 are the same Alternatively, each represents a hydrogen atom, a hydroxy group, a lower alkyl group, a cycloalkyl group, an alkoxy group, an acyl group, or a halogen atom. ) A sulfonamide derivative represented by
ルホンアミド誘導体を有効成分とする５−リポキシゲナ
ーゼ阻害剤。(3) A 5-lipoxygenase inhibitor containing the sulfonamide derivative according to claim (1) or (2) as an active ingredient.
ゲナーゼ阻害剤。(4) The 5-lipoxygenase inhibitor according to claim (3), which is an anti-asthmatic drug.
の５−リポキシゲナーゼ阻害剤。(5) The 5-lipoxygenase inhibitor according to claim (3), which is a therapeutic agent for allergic diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32972190A JPH04202173A (en) | 1990-11-30 | 1990-11-30 | Sulfonamide derivative and 5-lipoxygenase inhibitor containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32972190A JPH04202173A (en) | 1990-11-30 | 1990-11-30 | Sulfonamide derivative and 5-lipoxygenase inhibitor containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04202173A true JPH04202173A (en) | 1992-07-22 |
Family
ID=18224527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32972190A Pending JPH04202173A (en) | 1990-11-30 | 1990-11-30 | Sulfonamide derivative and 5-lipoxygenase inhibitor containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04202173A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU694696B2 (en) * | 1996-06-28 | 1998-07-23 | F. Hoffmann-La Roche Ag | Sulfonamides and their use |
| EP1379508A4 (en) * | 2001-02-28 | 2005-12-28 | Univ Temple | N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof |
| JP2006188525A (en) * | 1999-05-28 | 2006-07-20 | Abbott Lab | Cell proliferation inhibitor |
| US7161031B2 (en) | 2002-02-28 | 2007-01-09 | Temple University - Of The Commonwealth System Of Higher Education | Amino-substituted sulfonanilides and derivatives thereof for treating proliferative disorders |
| US8324190B2 (en) | 2002-02-28 | 2012-12-04 | Temple University—Of the Commonwealth System of Higher Education | Treatment of proliferative disorders with amino-substituted (E)-2,6- dialkoxystyryl 4-substituted benzylsulfones |
-
1990
- 1990-11-30 JP JP32972190A patent/JPH04202173A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU694696B2 (en) * | 1996-06-28 | 1998-07-23 | F. Hoffmann-La Roche Ag | Sulfonamides and their use |
| US5998665A (en) * | 1996-06-28 | 1999-12-07 | Hoffmann-La Roche Inc. | Use of sulfonamides |
| US6030976A (en) * | 1996-06-28 | 2000-02-29 | Hoffman-La Roche Inc. | Use of sulfonamides |
| JP2006188525A (en) * | 1999-05-28 | 2006-07-20 | Abbott Lab | Cell proliferation inhibitor |
| EP1379508A4 (en) * | 2001-02-28 | 2005-12-28 | Univ Temple | N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof |
| US7161031B2 (en) | 2002-02-28 | 2007-01-09 | Temple University - Of The Commonwealth System Of Higher Education | Amino-substituted sulfonanilides and derivatives thereof for treating proliferative disorders |
| US8324190B2 (en) | 2002-02-28 | 2012-12-04 | Temple University—Of the Commonwealth System of Higher Education | Treatment of proliferative disorders with amino-substituted (E)-2,6- dialkoxystyryl 4-substituted benzylsulfones |
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