WO2004074240A1 - プロスタグランジン誘導体 - Google Patents
プロスタグランジン誘導体 Download PDFInfo
- Publication number
- WO2004074240A1 WO2004074240A1 PCT/JP2004/001878 JP2004001878W WO2004074240A1 WO 2004074240 A1 WO2004074240 A1 WO 2004074240A1 JP 2004001878 W JP2004001878 W JP 2004001878W WO 2004074240 A1 WO2004074240 A1 WO 2004074240A1
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- Prior art keywords
- compound
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- hydrogen
- tert
- 300mhz
- Prior art date
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- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 13
- -1 ethylene, vinylene Chemical group 0.000 claims abstract description 75
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims abstract description 5
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 5
- 201000008736 Systemic mastocytosis Diseases 0.000 claims abstract description 5
- 208000002205 allergic conjunctivitis Diseases 0.000 claims abstract description 5
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 5
- 208000006673 asthma Diseases 0.000 claims abstract description 5
- 208000024998 atopic conjunctivitis Diseases 0.000 claims abstract description 5
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 34
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 5
- 230000009885 systemic effect Effects 0.000 claims description 5
- 208000035268 Mast Cell Activation disease Diseases 0.000 claims description 4
- 206010028735 Nasal congestion Diseases 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 208000008585 mastocytosis Diseases 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 17
- 239000001257 hydrogen Substances 0.000 abstract description 16
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 abstract 1
- 206010028748 Nasal obstruction Diseases 0.000 abstract 1
- 108050000258 Prostaglandin D receptors Proteins 0.000 abstract 1
- 102000000603 Prostaglandin DP receptors Human genes 0.000 abstract 1
- 108050008032 Prostaglandin DP receptors Proteins 0.000 abstract 1
- 230000008485 antagonism Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 164
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 125000004494 ethyl ester group Chemical group 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 210000000689 upper leg Anatomy 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 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 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 11
- 229940069417 doxy Drugs 0.000 description 11
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 10
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- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
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- 238000010898 silica gel chromatography Methods 0.000 description 10
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- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 6
- 241000282376 Panthera tigris Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 108090001060 Lipase Proteins 0.000 description 5
- 239000004367 Lipase Substances 0.000 description 5
- 102000004882 Lipase Human genes 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 235000019421 lipase Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
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- 244000005700 microbiome Species 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- 241000589516 Pseudomonas Species 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000004623 platelet-rich plasma Anatomy 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 2
- JILHZKWLEAKYRC-UHFFFAOYSA-N 1-methoxy-2,2-dimethylpropane Chemical group COCC(C)(C)C JILHZKWLEAKYRC-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 2
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- 239000005051 trimethylchlorosilane Substances 0.000 description 2
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- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
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- ZKCZXVODRKOWIY-UHFFFAOYSA-N diphenylstannane Chemical compound C=1C=CC=CC=1[SnH2]C1=CC=CC=C1 ZKCZXVODRKOWIY-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- CUFKJUQMEPTUCF-UHFFFAOYSA-N ethyl 2-[3-(sulfanylmethyl)phenyl]acetate Chemical compound CCOC(=O)CC1=CC=CC(CS)=C1 CUFKJUQMEPTUCF-UHFFFAOYSA-N 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- CBCIHIVRDWLAME-UHFFFAOYSA-N hexanitrodiphenylamine Chemical class [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1NC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O CBCIHIVRDWLAME-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 108010021666 lipase II Proteins 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 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
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003761 preservation solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DEDZSLCZHWTGOR-UHFFFAOYSA-N propylcyclohexane Chemical compound CCCC1CCCCC1 DEDZSLCZHWTGOR-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 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
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003258 trimethylene group Chemical class [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- NFHRNKANAAGQOH-UHFFFAOYSA-N triphenylstannane Chemical compound C1=CC=CC=C1[SnH](C=1C=CC=CC=1)C1=CC=CC=C1 NFHRNKANAAGQOH-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to novel prostaglandin derivatives.
- PGD prostaglandin
- An object of the present invention is to provide a PG derivative having excellent DP antagonistic activity. Disclosure of the invention
- the present invention provides a compound of the formula (I)
- X represents a halogen atom
- Y represents an ethylene group, a vinylene group or an ethynylene group
- Z represents _ (CH ? 2) m — O iC HJ n — or — S ( ⁇ ) n — (CH 2 ) n — (m represents an integer of 0 to 3, n represents an integer of 0 to 2 and p represents an integer of 0 to 2)
- R 1 represents a hydrogen atom
- — indicates 5 alkyl group or a substituted alkyl group
- R 2 is C 3 _. the consequent opening alkyl groups, C substituted with an alkyl group of C i _ 4 3 _ i.
- R 3 represents a hydrogen atom, a halogen atom, an alkyl group or a substituted Ci 5 alkyl group of the formula (I), or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof. It is a hydrate.
- the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- the pinylene group is a transpinylene group or a cis-vinylene group.
- cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and the like.
- Examples of the C 3 ⁇ 0 cycloalkyl group substituted by a C i_ 4 alkyl group include a methylcyclopropyl group, a methylcyclohexyl group, an ethylcyclohexyl group, a methylcyclooctyl group, a tert-butylcyclohexyl group, and the like. I can give it.
- Examples of the C 4 — i0 cycloalkylalkyl group include, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethyl group, cycloheptylmethyl group, And 2-cyclohexyl purper 2-yl group.
- the alkyl group of C bets 5 shows a straight-chain or branched alkyl groups such as methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, ter t-butyl group, a pentyl group, Examples include an isopentyl group and a 2-methylbutyl group.
- the substituted 5 alkyl group, a halogen atom, Shiano group means a straight or branched 0 Bok 5 alkyl group substituted with one or more selected from the group consisting of alkoxy groups, eg if 2- Examples include cloethyl group, cyanomethyl group, trifluoromethyl group, and 2,2,2-trifluoroethyl group.
- Examples of pharmaceutically acceptable salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, Examples thereof include salts with piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, and tris (hydroxymethyl) aminomethane, and tetraalkylammonium salts.
- alkali metals such as sodium and potassium
- alkaline earth metals such as calcium and magnesium
- ammonia methylamine, dimethylamine, cyclopentylamine
- benzylamine examples thereof include salts with piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, and tris (hydroxymethyl) aminomethane, and tetraalkylammonium salts.
- the compounds of formula (I) can be prepared, for example, by the methods summarized in the following reaction schemes.
- R 5 and R 6 are the same or different and each represent a hydroxyl-protecting group
- X 1 represents a halogen atom other than fluorine
- Y 1 represents an ethylene group or a vinylene group
- Z 1 represents an oxygen atom or Z represents a sulfur atom
- Z 3 represents a p defined by Z Alkyl group or substitution of
- ( ⁇ _ 5 represents an alkyl group
- X, R 2, R 3 , m, n are as defined above.
- the protecting group of the hydroxyl group has generally used in the field of prostaglandin And, for example, a tert-butyldimethylsilyl group, a triethylsilyl group, a diphenylmethylsilyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a methoxymethyl group, an ethoxyxyl group, a benzyl group, etc.)
- the well-known formula (II) was obtained by the method of Sato et al. [Journal of Ob. Organic 'Chemistry, Vol. 53, p. 5590 (1988)].
- the compound represented by the formula (III) or the formula (III ') may be prepared by adding 0.8 to 2.0 equivalents of the compound represented by the formula (III) or (III') in an inert solvent at 178 to 30 ° C (for example, benzene, toluene, tetrahydrofuran, , Methylene chloride, n-hexane, etc.) to give the compound of formula (IV) stereospecifically.
- Y is an ethylene group or a compound of vinylene group one 78-0 ° C with a compound of formula (Iotaiotaganma) to obtain the (immediate Chi Y is compounds wherein Y 1), a compound of Y is Echiniren group To obtain it, the compound of the formula (III) is reacted at 0-30 ° C.
- a radical generator for example, azobisisobutyronitrile, azobiscyclohexane power liponitrile, Benzoyl peroxide, triethylporan, etc.
- a radical reducing agent eg, triptyltin hydride, triphenyltin hydride, dibutyltin hydride, diphenyltin hydride, etc.
- an organic solvent eg, benzene, toluene, xylene, n-hexane, n-pentane, acetone, etc.
- 0.5 to 4 equivalents of the compound represented by the formula (VI ′) may be added to the compound represented by the formula (IV) and, if necessary, a base (for example, an organic amine such as triethylamine, diisopropylamine, pyridine or dimethylaniline, or a polyamine).
- a base for example, an organic amine such as triethylamine, diisopropylamine, pyridine or dimethylaniline, or a polyamine.
- Base resins such as piel polypyrrolidone, diisopropylaminomethyl-polystyrene, (piperidinomethyl) polystyrene, etc.
- a divalent palladium complex or complex salt eg, dichlorobis (aceto nitrile) palladium (II) , Dichlorobis (benzonitrile) palladium (II), palladium chloride, etc. 0.01 to 0.5 equivalents, and organic solvent (for example, benzene, toluene, xylene, n-hexane, n-pentane, acetone, etc.)
- organic solvent for example, benzene, toluene, xylene, n-hexane, n-pentane, acetone, etc.
- organocopper compound of the formula (V) is represented by the formula (V ′)
- a compound of the formula (V,) is prepared by combining 0.8 to 5 equivalents of zinc activated with, for example, 1,2-dibromoethane, trimethylchlorosilane, iodine, or the like, and an inert solvent (eg, tetrahydrofuran, getyl ether, n-hexane, n-pentane, dioxane, dimethoxyethane, etc.)
- an inert solvent eg, tetrahydrofuran, getyl ether, n-hexane, n-pentane, dioxane, dimethoxyethane, etc.
- the reaction temperature is usually 0 to 150 ° C. Reacting the obtained organozinc compound with the above-mentioned inert solvent containing copper cyanide (1 to 2.5 equivalents) and lithium chloride (2 to 5 equivalents) at a temperature of 0 to 78 ° C. As a result, an organic copper compound represented by the formula (V) can be obtained. 7
- the compound of the formula (VIII) (or the formula (VI ⁇ )) can be treated with, for example, 1 to 6 equivalents of methanesulfonyl chloride or P-toluenesulfonyl chloride in a suitable solvent such as pyridine or toluene, if necessary.
- a suitable solvent such as pyridine or toluene, if necessary.
- bases such as triethylamine and 4-dimethylaminopyridine — After mesylation or tosylation at 20 to 40 ° C, 1 to 16 equivalents of tetra-n-butylammonium chloride Chlorinated, the formula (IX) (or the formula (or the formula (IX) (or the formula (or the formula (IX) (or the formula (or the formula (IX) (or the formula (or the formula (IX) (or the formula (or the formula (IX) (or the formula (or the formula (IX) (or the formula (I
- bromination and fluorination can also be performed by a usual method.
- bromination can be obtained by reacting 1 to 10 equivalents of carbon tetrabromide in acetonitrile in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of pyridine.
- Fluorination can be obtained, for example, by reacting 5 to 20 equivalents of acetylaminosulfur trifluoride (DAST) in methylene chloride.
- DAST acetylaminosulfur trifluoride
- the compound of the formula (IX) (or the formula (IX ')) is treated with methanol, ethanol, or acetonitrile using tetrabutylammonium fluoride, hydrofluoric acid, pyridinium poly (hydrogen fluoride), hydrochloric acid, or the like.
- tetrabutylammonium fluoride hydrofluoric acid
- pyridinium poly (hydrogen fluoride) hydrochloric acid, or the like.
- the protecting group for the hydroxyl group is removed under the conditions usually performed, and the formula (la) according to the present invention is removed.
- the compound of the formula (la) (or (la ')) is mixed with a solvent such as a phosphate buffer or a tris-hydrochloride buffer, if necessary, with an organic solvent (water such as acetone, methanol or ethanol).
- Enzymes include enzymes produced by microorganisms (eg, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), enzymes prepared from animal organs (eg, enzymes prepared from bush liver and pig liver) Specific examples of commercially available enzymes include lipase VII (manufactured by Sigma and derived from a microorganism of the genus Candida), lipase AY (manufactured by Amano Pharmaceutical, and derived from a microorganism of the genus Candida), and lipase PS (amano Pharmaceutical, derived from Pseudomonas spp., Lipase MF (Amano Pharmaceutical, derived from Pseudomonas spp.), PLE (Sigma, prepared from pig liver), Lipase II (Sigma, prepared from Buyu Mugen) ), Lipop mouth tin lipase (manufactured by Tokyo Chemical Industry Co., Ltd., prepared from
- the amount of the enzyme to be used may be appropriately selected depending on the enzyme titer and the amount of the substrate [compound of the formula (la)], but is usually 0.1 to 20 parts by weight of the substrate.
- the reaction temperature is from 25 to 50 ° C, preferably from 30 to 40 ° C.
- the PG derivative of the formula (Id) (or the formula (Id ')) of the present invention is obtained by hydrolyzing the compound of the formula (Ic) (or the formula (Ic')) in the same manner as in the above (6).
- the oxidation of the formula (Id) of the present invention can also be performed by oxidizing the compound using the formula (lb) (or the formula (lb ′)) in the same manner as in the above (7).
- the compounds of the present invention can be administered systemically or locally orally or parenterally, such as intravenously or intranasally. These can be orally administered, for example, in the form of tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, etc., which can be produced by conventional methods.
- aqueous or non-aqueous solutions, emulsions, suspensions, solid preparations which are dissolved in an injection solvent immediately before use, and the like can be used.
- drugs and solutions (hard capsules) containing drugs are generally used.
- the compound of the present invention can also be formulated by forming an inclusion compound with (3 ⁇ 4, / 3 or arcyclodextrin or methylated cyclodextrin, etc.
- aqueous or non-aqueous solutions, emulsions, Suspensions and the like can be administered by injection, etc. The dosage varies depending on the age, body weight, etc., but is 1 ng to 100 mg mg / day for adults, and is administered once or several times a day. Administer separately.
- Representative compounds of the formula (I) according to the present invention include the following.
- Pentyl the If)] 2 Mizu ⁇ - 5 beta-Cl CH2 shea ⁇ to 0 pentyl hydrogen 2 hydrogen - ca 6 ⁇ -Cl This emission CHS consequent hexyl 3 hydrogen one a cc 7 iS-Cl This CH2 consequent to Y.
- Hexyl m 3 Hydrogen-cc 8 ⁇ -Cl NOH CH2 ⁇ Hex 1 Hydrogen 3 hydrogen-aa 9 ⁇ -Cl NH2 CH1 NH3 1tyl 3 Hydrogen 1 a ⁇ 0 ⁇ -Gl Chicoleno CH £ Sihexyl Hydrogen 3 Hydrogen- ⁇ 1 ⁇ -Br CH2 CH 3 H-a 2 1?
- Example 1 (1) (3S) —3- (tert-butyldimethylcyclopropyl)-(3-S)-(3-tert-butyl) (Butyldimethylsiloxy) -1-cycloheptylpropane-1-in was used in substantially the same manner as in Example 1 (1) to give (3R, 4R) —2-methylene-1-(— (3S) —3— (tert-butyldimethylsiloxy) -1-cycloheptylprop-1-ynyl] -14- (tert-butyldimethylsiloxy) cyclopentane-11one was obtained.
- Example 1 (1) (3S) -3- (tert-butyldimethylcyclohexyl) -3-cyclohexylproper Instead of 1-yne, (3S) -3- (tert- (Butyldimethylsiloxy) —3-cyclopentylprop-1-yne was used in substantially the same manner as in Example 1 (1), to give (3R, 4R) -12-methylene-3 — [(3S) 13— ( tert-Butyl dimethylsiloxy) -3-cyclopentylprop-1-ynyl] -4_ (tert-butyldimethylsiloxy) cyclopentane-11-one was obtained.
- Example 7 Using the compound obtained in Example 7. (5), the title compound was obtained in substantially the same manner as in Example 2.
- Example 1 (1) in place of (3S) -3- (tert-butyldimethylcyclohexyl) -1-cyclohexylpropane-1- ⁇ f, (3S) —3— ( (3R, 4R) —2-Methylene—3 — [(3S) —3— Using tert-butyldimethylsilyloxy) -1-cyclohexyl butane 11-yne and substantially in the same manner as in Example 1 (1). (tert-butyldimethylsiloxy) -1-cyclohexylbut-1-ynyl] -4-1 (tert-butyldimethyloxy) cyclopentane-11-one was obtained.
- Example 1 (1) in place of (3S), — 3- (tert-butyldimethylcyclohexyl) -1-cyclohexylpropane-1-yne, (3S) —3- (tert Using (3-butyldimethylsiloxy) -13-cyclooctylpropane, (3R, 4R) -2-methylene-13-[(3S) 13 in substantially the same manner as in Example 1 (1). — (Tert-butyldimethylsiloxy) —3-cyclooctylprop-1-ynyl] -14- (tert-butyldimethylsiloxy) cyclopentane-11-one was obtained.
- Example 1 (2) instead of 3-force lupoethoxymethylbenzylzinc (II) bromide, 2-force lupoethoxymethylbenzylzinc (II) bromide was used, and (3R, 4R) Methylene-3-([3S) -13- (tert-butyldimethyloxy) -1-cyclohexylprop-1-ynyl] -14- (tert-butyldimethylsiloxy) cyclo 41
- Example 1 (2) (3-R, 4R) —2-— was used in place of 3-force-rupoethoxymethylbenzylzinc (II) bromide instead of 2-force-rupoethoxymethylbenzylzinc (II) bromide.
- Example 5 (1) the compound obtained in Example 5 (1) was used, and Example 1 (2 ), 3, 4, 5, 16, 17, 18, 19, 20—2,6-inter—0—phenylene-1 15—cycloheptyl-13, 14-Didehydro-PGE 1- ethyl ester 11,15-bis (tert-butyldimethylsilyl ether) was obtained.
- Example 25 Using the compound obtained in Example 25 (4), and in substantially the same manner as in Example 2, the title compound was obtained.
- Example 1 (2) was replaced with 3-force lupoethoxymethylbenzylzinc (II) bromide using 3-force lupomethoxymethyl phenethyl zinc (II) chloride.
- Example 1 2-carpomethoxymethyl phenethyl zinc (II) chloride was used in place of 3-force rupoethoxymethylbenzylzinc (II) bromide. 3,4,16,17,18,19,20-hepno-nor-2,5-inter-11-phenylene-15-cyclohexyl-13,14-dideide Raw PGEi methyl ester 11,15-bis (tert-butyldimethylsilyl ether) was obtained. ⁇ 47
- Example 1 The procedure of Example 1 was repeated, except that 3-carpomethoxymethylphenylzinc (II) chloride was used in place of 3-potuomethoxymethylbenzylzinc (II) bromide.
- Example 31 Using the compound obtained in Example 31 (4), the title compound was obtained in substantially the same manner as in Example 2.
- Example 1 3-force lipoethoxymethylbenzylzinc (II) bromide was replaced by 3-force lipoethoxymethyl-5-methylbenzylzinc (II) bromide.
- 3,4,5,16,17,18,19,20 Teatanol-1,2,6-Inter-11 m— (3-Methylphenylene) 1-15 —Cyclohexyl— 13,14-didehydro-PGEethyl ester 11, 15-bis (tert-butyldimethylsilyl ether) was obtained.
- Example 35 Using the compound obtained in Example 35 (4), the title compound was obtained in substantially the same manner as in Example 2.
- Example 37 the title compound was obtained in substantially the same manner as in Example 37, except that isopropanol was used instead of methanol.
- Example 39 (1) 3-mercaptomethyl phenyl acetic acid ethyl ester was used in place of 3-mercapto phenyl acetic acid ethyl ester, and 6-thiaone was obtained in substantially the same manner as in Example 39 (1). 3,4,16,17,18,19,20-Heptanol-2,5f-11-m-phenylene-15-cyclohexyl-PGEi ethylester 11-1,15-bis (tert-butyldimethyl Silyl ether).
- Enylene-1 15-cyclohexyl PGFi ⁇ ethyl ester 11,15-bis (tert-butyldimethylsilyl ether) was obtained.
- Example 43 (1) in place of (1E, 3S) -11-odo-3- (tert-butyldimethylsiloxy) -13-cyclohexyl-1propene, (3R) -1 — Ode— 3- (tert-butyldimethylsiloxy) — Using 3-cyclohexylpropane, in substantially the same manner as in Example 43 (1), (3R, 4R) 12-methylene— (3R) —3- (tert-butyldimethylsiloxane) —3-cyclohexyl-1-propyl] -14- (tert-butyldimethylsiloxy) cyclopentan-1-one was obtained.
- Example 1 (2) 2- (3-Rupoethoxymethylbenzylzinc (II) bromide was used instead of 3-Rupoethoxymethylbenzylzinc (II) bromide, and (3R, 4R) —Methylene— 3— [(3S) -3- (tert-butyldimethylcyclopropyl) -1-cyclohexylprop-1-ynyl] 141- (tert-butyldimethylsiloxy) cyclopentene—instead of 1-one Using the compound obtained in (1) above, 3,4,5,16,17,18,19,20-octanolou 2 was conducted in substantially the same manner as in Example 1 (2).
- Blood collected from a healthy adult person with a plastic syringe is placed in a plastic test tube containing 3.8 sodium citrate, mixed gently by inversion, and l'80Xg, 20 at room temperature. 67
- the platelet-rich plasma (PRP) of the supernatant was collected by centrifugation for minutes. PRP was further centrifuged at room temperature at 800 ⁇ g for 20 minutes to obtain platelets as a precipitate.
- the obtained platelets were homogenized in a buffer solution (150 mM aCK 5 mM KCK 5 mM glucose, 10 mM Trls / HCl (pH 7.)), and centrifuged twice at 4 ° C, 105,000 X g for 20 minutes. A platelet membrane fraction was obtained as a precipitate.
- the membrane fraction was suspended at 3 rag / ml in a preservation solution (250 mM sucrose, ImM EGTA, lOmM Trls / HCl (pH 7.4)) and stored frozen at -80 ° C until subjected to a binding experiment.
- a preservation solution 250 mM sucrose, ImM EGTA, lOmM Trls / HCl (pH 7.4)
- ⁇ Fetal trachea-derived cells EBTr [NBL-4] were seeded at 8000cels / well in a 96-well microplate, cultured in the presence of MEM medium (containing 10% Calf Serum) for 2 days, and used for experiments. The experiments were performed in a MEM medium containing 500 ⁇ m, 10 ⁇ m, and 10% Calf Serum. Contains PGD 2 and test compound 6 8
- the reaction was started by adding 100 1 of the medium, and the reaction was carried out at 37 ° C. for 15 minutes. Then, the medium was removed, and the reaction was stopped by adding ice-cold PBS. After the PBS was further removed, 200 1 of a cell lysate (Lys is reagent 1) in cAMP enzyme lynoassay system (Amersham) was added, and the cells were thawed at room temperature for 10 minutes to lyse the cells. The amount of cAMP in the cell lysate was determined according to the method described in the cAMP enzyme Immunoassay system.
- the compound of the present invention Since the compound of the present invention has excellent DP antagonistic activity, it is useful for diseases such as allergic rhinitis, nasal congestion, asthma, allergic conjunctivitis, systemic mastocytosis, and systemic mast cell activation disorder. is there.
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Description
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JP2005502762A JPWO2004074240A1 (ja) | 2003-02-20 | 2004-02-19 | プロスタグランジン誘導体 |
EP04712705A EP1598335A4 (en) | 2003-02-20 | 2004-02-19 | PROSTAGLANDINE DERIVATIVES |
US10/545,785 US20060270740A1 (en) | 2003-02-20 | 2004-02-19 | Prostaglandin derivatives |
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US (1) | US20060270740A1 (ja) |
EP (1) | EP1598335A4 (ja) |
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US7714132B2 (en) | 2004-03-11 | 2010-05-11 | Actelion Pharmaceuticals, Ltd. | Tetrahydropyridoindole derivatives |
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WO2008073748A1 (en) | 2006-12-08 | 2008-06-19 | University Of Rochester | Expansion of hematopoietic stem cells |
Citations (2)
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WO2000015608A1 (en) * | 1998-09-14 | 2000-03-23 | Ono Pharmaceutical Co., Ltd. | φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT |
WO2001012596A1 (fr) * | 1999-08-13 | 2001-02-22 | Taisho Pharmaceutical Co., Ltd. | Derives de prostaglandine |
Family Cites Families (4)
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US4013695A (en) * | 1975-10-02 | 1977-03-22 | The Upjohn Company | 4,4,5,5-Tetradehydro-PGE1 analogs |
US4029681A (en) * | 1976-02-13 | 1977-06-14 | The Upjohn Company | 13,14-Didehydro-PG analogs |
JP3573480B2 (ja) * | 1994-02-21 | 2004-10-06 | 大正製薬株式会社 | プロスタグランジン誘導体およびその使用 |
DE69912277T2 (de) * | 1998-05-25 | 2004-07-15 | Taisho Pharmaceutical Co., Ltd. | Prostaglandinderivate |
-
2004
- 2004-02-19 US US10/545,785 patent/US20060270740A1/en not_active Abandoned
- 2004-02-19 WO PCT/JP2004/001878 patent/WO2004074240A1/ja not_active Application Discontinuation
- 2004-02-19 JP JP2005502762A patent/JPWO2004074240A1/ja active Pending
- 2004-02-19 EP EP04712705A patent/EP1598335A4/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000015608A1 (en) * | 1998-09-14 | 2000-03-23 | Ono Pharmaceutical Co., Ltd. | φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT |
WO2001012596A1 (fr) * | 1999-08-13 | 2001-02-22 | Taisho Pharmaceutical Co., Ltd. | Derives de prostaglandine |
Non-Patent Citations (1)
Title |
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See also references of EP1598335A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7714132B2 (en) | 2004-03-11 | 2010-05-11 | Actelion Pharmaceuticals, Ltd. | Tetrahydropyridoindole derivatives |
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EP1598335A1 (en) | 2005-11-23 |
US20060270740A1 (en) | 2006-11-30 |
EP1598335A4 (en) | 2006-04-12 |
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