JPH0233704B2 - CHIKANBINIRUKARUBONSANJUDOTAI - Google Patents
CHIKANBINIRUKARUBONSANJUDOTAIInfo
- Publication number
- JPH0233704B2 JPH0233704B2 JP17691882A JP17691882A JPH0233704B2 JP H0233704 B2 JPH0233704 B2 JP H0233704B2 JP 17691882 A JP17691882 A JP 17691882A JP 17691882 A JP17691882 A JP 17691882A JP H0233704 B2 JPH0233704 B2 JP H0233704B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- pyridyl
- phenyl
- reaction
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 methylenedioxy group Chemical group 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000001931 aliphatic group Chemical group 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002723 alicyclic group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 238000006243 chemical reaction Methods 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 150000001875 compounds Chemical class 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000004519 manufacturing process Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000012300 argon atmosphere Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 102000003960 Ligases Human genes 0.000 description 5
- 108090000364 Ligases Proteins 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 229940043279 diisopropylamine Drugs 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 4
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- BVYXDHVFMIFWEZ-UHFFFAOYSA-N (5-carboxy-5-methylhexyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(C)(C)C(O)=O)C1=CC=CC=C1 BVYXDHVFMIFWEZ-UHFFFAOYSA-N 0.000 description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- AVRIVCUNRSJYAU-UHFFFAOYSA-N (5-carboxy-5-phenylpentyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C(=O)O)CCCC[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 AVRIVCUNRSJYAU-UHFFFAOYSA-N 0.000 description 2
- FGSUUFDRDVJCLT-UHFFFAOYSA-N 3-methylazepan-2-one Chemical compound CC1CCCCNC1=O FGSUUFDRDVJCLT-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XUUQFBORVUCWIT-BKUYFWCQSA-N C=1C=CC=CC=1C(C(=O)OCC)CCC\C=C(C=1C=NC=CC=1)/C1=CC=CS1 Chemical compound C=1C=CC=CC=1C(C(=O)OCC)CCC\C=C(C=1C=NC=CC=1)/C1=CC=CS1 XUUQFBORVUCWIT-BKUYFWCQSA-N 0.000 description 2
- XUUQFBORVUCWIT-FYJGNVAPSA-N C=1C=CC=CC=1C(C(=O)OCC)CCC\C=C(C=1C=NC=CC=1)\C1=CC=CS1 Chemical compound C=1C=CC=CC=1C(C(=O)OCC)CCC\C=C(C=1C=NC=CC=1)\C1=CC=CS1 XUUQFBORVUCWIT-FYJGNVAPSA-N 0.000 description 2
- CENHVAWYQQJVTI-KOEQRZSOSA-N C=1C=CC=CC=1COC(=O)C(C)(C)CCC\C=C(C=1C=NC=CC=1)/C1=CC=CC=C1 Chemical compound C=1C=CC=CC=1COC(=O)C(C)(C)CCC\C=C(C=1C=NC=CC=1)/C1=CC=CC=C1 CENHVAWYQQJVTI-KOEQRZSOSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 206010047163 Vasospasm Diseases 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 2
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- XDKDNKJMIHZLFJ-KGENOOAVSA-N methyl (e)-7-phenyl-2-prop-1-en-2-yl-7-pyridin-3-ylhept-6-enoate Chemical compound C=1C=CN=CC=1C(=C/CCCC(C(=O)OC)C(C)=C)/C1=CC=CC=C1 XDKDNKJMIHZLFJ-KGENOOAVSA-N 0.000 description 2
- HXCYYOOGOVGGIJ-LDADJPATSA-N methyl (e)-7-phenyl-7-pyridin-3-ylhept-6-enoate Chemical compound C=1C=CN=CC=1C(=C/CCCCC(=O)OC)/C1=CC=CC=C1 HXCYYOOGOVGGIJ-LDADJPATSA-N 0.000 description 2
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- RYMBAPVTUHZCNF-UHFFFAOYSA-N phenyl(pyridin-3-yl)methanone Chemical compound C=1C=CN=CC=1C(=O)C1=CC=CC=C1 RYMBAPVTUHZCNF-UHFFFAOYSA-N 0.000 description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- FMNQRUKVXAQEAZ-JNRFBPFXSA-N (5z,8s,9r,10e,12s)-9,12-dihydroxy-8-[(1s)-1-hydroxy-3-oxopropyl]heptadeca-5,10-dienoic acid Chemical compound CCCCC[C@H](O)\C=C\[C@@H](O)[C@H]([C@@H](O)CC=O)C\C=C/CCCC(O)=O FMNQRUKVXAQEAZ-JNRFBPFXSA-N 0.000 description 1
- VORHMCUVEZJITN-PDGQHHTCSA-N (z)-2,2-dimethyl-7-phenyl-7-pyridin-3-ylhept-6-enoic acid Chemical compound C=1C=CN=CC=1C(=C/CCCC(C)(C)C(O)=O)\C1=CC=CC=C1 VORHMCUVEZJITN-PDGQHHTCSA-N 0.000 description 1
- JLIDRDJNLAWIKT-UHFFFAOYSA-N 1,2-dimethyl-3h-benzo[e]indole Chemical compound C1=CC=CC2=C(C(=C(C)N3)C)C3=CC=C21 JLIDRDJNLAWIKT-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- VORHMCUVEZJITN-UHFFFAOYSA-N 2,2-dimethyl-7-phenyl-7-pyridin-3-ylhept-6-enoic acid Chemical compound C=1C=CN=CC=1C(=CCCCC(C)(C)C(O)=O)C1=CC=CC=C1 VORHMCUVEZJITN-UHFFFAOYSA-N 0.000 description 1
- GHLGYKHZQGQNMQ-UHFFFAOYSA-N 2,2-dimethyl-7-pyridin-3-yl-7-thiophen-2-ylhept-6-enoic acid Chemical compound C=1C=CN=CC=1C(=CCCCC(C)(C)C(O)=O)C1=CC=CS1 GHLGYKHZQGQNMQ-UHFFFAOYSA-N 0.000 description 1
- COXWJDIIGQLOLY-UHFFFAOYSA-N 2,2-dimethyl-8-phenyl-8-pyridin-3-yloct-7-enoic acid Chemical compound C=1C=CN=CC=1C(=CCCCCC(C)(C)C(O)=O)C1=CC=CC=C1 COXWJDIIGQLOLY-UHFFFAOYSA-N 0.000 description 1
- OIDZFKHFAZUXHF-UHFFFAOYSA-N 2,2-dimethyl-8-pyridin-3-yl-8-thiophen-2-yloct-7-enoic acid Chemical compound C=1C=CN=CC=1C(=CCCCCC(C)(C)C(O)=O)C1=CC=CS1 OIDZFKHFAZUXHF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WOBLAPNMOCBBFG-BOPFTXTBSA-N 3-[(z)-6-iodo-1-phenylhex-1-enyl]pyridine Chemical compound C=1C=CN=CC=1C(=C/CCCCI)\C1=CC=CC=C1 WOBLAPNMOCBBFG-BOPFTXTBSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- NQPXQJXVGAHQJI-UHFFFAOYSA-M 4-hydroxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCO)C1=CC=CC=C1 NQPXQJXVGAHQJI-UHFFFAOYSA-M 0.000 description 1
- FLPVVTDEKLGZDZ-UHFFFAOYSA-N 4-iodobutyl acetate Chemical compound CC(=O)OCCCCI FLPVVTDEKLGZDZ-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HGSHYXNIDCWDJD-UHFFFAOYSA-N 5-carboxyhexyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(C)C(O)=O)C1=CC=CC=C1 HGSHYXNIDCWDJD-UHFFFAOYSA-N 0.000 description 1
- AFSUUOKFJZJTQL-UHFFFAOYSA-N 5-iodopentan-2-yl acetate Chemical compound CC(=O)OC(C)CCCI AFSUUOKFJZJTQL-UHFFFAOYSA-N 0.000 description 1
- PGMAZFHBCMIDBD-UHFFFAOYSA-N 6-acetyloxy-2,2-dimethylhexanoic acid Chemical compound CC(=O)OCCCCC(C)(C)C(O)=O PGMAZFHBCMIDBD-UHFFFAOYSA-N 0.000 description 1
- XBLBTILEUDNPQJ-UHFFFAOYSA-N 6-bromo-2,2-dimethylhexanoic acid Chemical compound OC(=O)C(C)(C)CCCCBr XBLBTILEUDNPQJ-UHFFFAOYSA-N 0.000 description 1
- IPKFFYBHMDNBSC-UHFFFAOYSA-N 6-bromo-2-methylhexanoic acid Chemical compound OC(=O)C(C)CCCCBr IPKFFYBHMDNBSC-UHFFFAOYSA-N 0.000 description 1
- UXMYJBLCCDAZQR-UHFFFAOYSA-N 6-bromo-2-phenylhexanoic acid Chemical compound BrCCCCC(C(=O)O)C1=CC=CC=C1 UXMYJBLCCDAZQR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- QCMMKUKDBUYBBL-UHFFFAOYSA-N C(C)(C)(C)O[Na].[K] Chemical compound C(C)(C)(C)O[Na].[K] QCMMKUKDBUYBBL-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
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- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229940090012 bentyl Drugs 0.000 description 1
- DULCUDSUACXJJC-UHFFFAOYSA-N benzeneacetic acid ethyl ester Natural products CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- TXKMVPPZCYKFAC-UHFFFAOYSA-N disulfur monoxide Chemical compound O=S=S TXKMVPPZCYKFAC-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- GMVFLDZZYNKAQQ-UHFFFAOYSA-N ethyl 6-acetyloxy-2,2-dimethylhexanoate Chemical compound CCOC(=O)C(C)(C)CCCCOC(C)=O GMVFLDZZYNKAQQ-UHFFFAOYSA-N 0.000 description 1
- GVPQPKKHAHPDRA-UHFFFAOYSA-N ethyl 6-acetyloxy-2-phenylhexanoate Chemical compound CC(=O)OCCCCC(C(=O)OCC)C1=CC=CC=C1 GVPQPKKHAHPDRA-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 208000023589 ischemic disease Diseases 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
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- VLASUHAEHVUSKV-CPNJWEJPSA-N methyl (E)-2-methyl-7-phenyl-7-pyridin-3-ylhept-6-enoate Chemical compound C=1C=CN=CC=1C(=C/CCCC(C)C(=O)OC)/C1=CC=CC=C1 VLASUHAEHVUSKV-CPNJWEJPSA-N 0.000 description 1
- JMUZMDKWJWSBCU-UHFFFAOYSA-N methyl 2-(4-methylphenyl)sulfonylacetate Chemical compound COC(=O)CS(=O)(=O)C1=CC=C(C)C=C1 JMUZMDKWJWSBCU-UHFFFAOYSA-N 0.000 description 1
- PDJMIZHFWZAEOE-UHFFFAOYSA-N methyl 7-pyridin-3-ylhept-6-enoate Chemical compound COC(=O)CCCCC=CC1=CC=CN=C1 PDJMIZHFWZAEOE-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- SGUKUZOVHSFKPH-YNNPMVKQSA-N prostaglandin G2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](OO)CCCCC)[C@H]2C\C=C/CCCC(O)=O SGUKUZOVHSFKPH-YNNPMVKQSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003826 tablet Substances 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本発明は、トロンボキサンA2（TXA2）合成酵
素を特異的に阻害する作用を有する新規置換ビニ
ルカルボン酸誘導体に関する。
TXA2はアラキドン酸の代謝産物の一つであつ
て血小板凝集作用を有している。したがつてそれ
が体内で過剰に産生された場合血管閉塞、血管れ
ん縮による虚血性心・腎・脳の諸疾患をひき起す
ことが知られている。本発明者らはTXA2合成酵
素阻害作用を有する物質の合成、探索研究を行つ
た結果、優れたTXA2合成酵素阻害作用を有する
一群の新規化合物を見つけた。
すなわち本発明は、一般式
〔式中、R1はピルジル基を、R2は低級アルコキ
シ基，低級アルキル基，ハロゲン原子，トリフル
オロメチル基，低級アルケニル基またはメチレン
ジオキシ基を置換基として有していてもよいフエ
ニル基，チエニル基，フリール基，ナフチル基，
ベンゾチエニル基またはピリジル基を、R3は水
素原子，ベンジル基または低級アルキル基を示
す。R4およびR5はいずれか一方が水素原子また
は低級アルキル基で他方はアリールオキシ基また
は置換基を有していてもよい低級脂肪族炭化水素
基，炭素数６以下の脂肪族炭化水素基，芳香族基
または式―Ｓ（Ｏ）n――R6（ただし、R6はフエニル
基または低級アルキル基を、ｍは０〜２の整数を
示す。）で示される基を示すか、またはR4とR5が
互いに結合してR4とR5で一個のアルキレン基を
示す。ｎは２〜６の整数を示す。〕で表わされる
置換ビニルカルボン酸誘導体である。
前記一般式（）中、R1，R2で示されるピリ
ジル基としては、２―ピリジル，３―ピリジル，
４―ピリジルがあげられるが、中でも３―ピリジ
ル基が好ましい。またR2で示されるチエニルは
２―チエニル，３―チエニル，フリルは２―フリ
ル，３―フリル、ナフチルはα―ナフチル，β―
ナフチル，ベンゾチエニルは２―ベンゾチエニ
ル，３―ベンゾチエニル，４―ベンゾチエニル，
５―ベンゾチエニル，６―ベンゾチエニル，７―
ベンゾチエニルのいずれでもよい。R2で示され
るフエニル，チエニル，フリル，ナフチル，ベン
ゾチエニル，ピリジンの置換基である低級アルコ
キシ基としては、たとえばメトキシ，エトキシ，
ｎ―プロポキシ，ｉ―プロポキシ，ｎ―ブトキ
シ，ｉ―ブトキシ，ｔ―ブトキシなど炭素数１〜
４のものが、低級アルキル基としては、たとえば
メチル，エチル，ｎ―プロピル，ｉ―プロピル，
ｎ―ブチル，ｉ―ブチル，ｔ―ブチル，ｎ―ペン
チル，ｉ―ペンチルなど炭素数１〜５のものが、
ハロゲン原子としては、たとえばフツ素，塩素，
臭素などが、低級アルケニル基としては、たとえ
ばビニル，アリール，ペンテニルなどの炭素数２
〜５のものがそれぞれあげられる。R2で示され
るフエニル，チエニル，フリル，ナフチル，ベン
ゾチエニル，ビリジルが置換基を有するとき、こ
れらの置換基は環上の任意の位置に置換しうる。
またR3，R4，R5で示される低級アルキル基とし
ては、たとえばメチル，エチル，ｎ―プロピル，
ｎ―ブチルなど炭素数１〜４のものがあげられ
る。R4またはR5で示されるアリールオキシ基と
してはたとえばフエニルオキシ，１―ナフトキ
シ，２―ナフトキシなどがあげられる。R4また
はR5で示される低級脂肪族炭化水素基としては、
たとえばメチル，エチル，ｎ―プロプル，ｎ―ブ
チル，ｎ―ベンチル，ｎ―ヘキシル，ｎ―ヘプチ
ルなど炭素数１〜８の低級アルキル基、たとえば
ビニル，アリル，１―メチルビニル，３―メチル
―２―ブテニル，２―ペンテニル，２―ヘキセニ
ル，２―ヘプテニルなど炭素数２〜８の低級アル
ケニル、たとえばエチニル，２―プロピニル，２
―ブチニル，２―ヘキシニル，２―オクチニルな
ど炭素数２〜８のアルキニル基など炭素数８以下
のものがあげられるが、なかでも炭素数１〜４の
アルキル基，炭素数２〜５のアルケニル基，炭素
数２〜８のアルキニル基が好ましい。またR4ま
たはR5で示される炭素数６以下の脂環族炭化水
素基としてはたとえばシクロプロピル，シクロブ
チル，シクロペンチル，シクロヘキシルなど炭素
数３〜６のシクロアルキル基、たとえばシクロ―
１―ペンテニル，シクロ―１―ヘキセニルなど炭
素数５〜６のシクロアルケニルなど炭素数６以下
のものがあげられる。またR4またはR5で示され
る芳香族基としてはたとえばフエニル，ナフチ
ル，２―チエニル，３―チエニル，３―ピリジル
などがあげられる。上記R4またはR5で示される
低級脂肪族炭化水素，炭素数６以下の脂環族炭化
性素基および芳香族はたとえば水酸基，シアノ
基，低級アルキル基（たとえばメチル，エチルな
ど炭素数１〜３のもの），低級アルコキシ基（た
とえばメトキシ，エトキシなど炭素数１〜３のも
の），ハロゲン原子（たとえばフツ素，塩素，臭
素など），フエニル基，シアノ置換フエニル基な
どの置換基を有していてもよい。R4またはR5で
示される式―Ｓ（Ｏ）nR6で示される基としてはた
とえばメチルチオ，エチルチオ，イソプロピルチ
オ，メチルスルフエニル，エチルスルフエニル，
メチルスルホニル，エチルスルホニル，フエニル
チオ，フエニルスルフエニル，フエニルスルホニ
ル，ｐ―トルエンスルホニルなどがあげられる。
R4とR5が結合してR4とR5で一個のアルキレン基
を示すときこのアルキレン基はメチレン基が１〜
６個連なつたものであり、R4とR5で１個のメチ
レン基を示すときはR4およびR5が結合する炭素
とメチレン基が二重結合を介して結合しているこ
とを意味し、R4とR5で炭素２〜６個のポリメチ
レン基を示すときはR4およびR5が結合する炭素
と共に環を形成していることを意味する。またこ
のアルキレン基は任意の位置に置換基を有してい
てもよい。この置換基としてはたとえばメチル，
エチルなどの低級アルキル基、フエニル基，ピリ
ジル基，チエニル基などがあげられ、これらは１
〜２個置換していてもよい。
一般式（）で表わされる化合物は薬理学的に
許容される有機酸または無機酸の付加塩であつて
もよく、このような付加塩としては、たとえば塩
酸，臭化水素酸，リン酸，硫酸，クエン酸，コハ
ク酸，マレイン酸，フマール酸，メタンスルホン
酸，ベンゼンスルホン酸などとの塩があげられ
る。また化合物（）のR3が水素原子であると
きは、ナトリウム塩，カリウム塩などのアルカリ
金属塩，アルシウム塩などのアルカリ土類金属塩
であつてもよい。
化合物（）の代表例としては、たとえば２，
２―ジメチル―７―フエニル―７―（３―ピリジ
ル）―６―ヘプテン酸，２，２―ジメチル―８―
フエニル―８―（３―ピリジル）―７―オクテン
酸，２，２―ジメチル―７―（２―チエニル）―
７―（３―ピリジル）―６―ヘプテン酸，２，２
―ジメチル―８―（２―チエニル）―８―（３―
ピリジル）―７―オクテン酸，２，２―ジメチル
―７―（２―ナフチル）―７―（３―ピリジル）
―６―ヘプテン酸などがあげられる。
本発明の前記一般式（）で表わされる置換ビ
ニルカルボン酸誘導体およびその塩はヒト，馬な
どの血小板ミクロゾーンより可溶化分画したトロ
ンボキサン合成酵素に対し強力な阻害作用を有
し、ヒトを含む哺乳動物において、強力なトロン
ボキサンA2（TXA2）の生合成阻害作用を示す。
また、本発明の化合物（）は、動脈平滑筋弛
緩作用，血小板凝集阻害作用あるいは凝集した血
小板の再解離作用などを示すプロスタグランジン
I2（PGI2）の産生効率を高める効果を示す。すな
わち、プロスタグランジンG2（PGG2）またはプ
ロスタグランジンH2（PGH2）はトロンボキサン
A2，プロスタグランジンI2およびその他のプロス
タグランジン類の重要な中間体であり、本発明化
合物（）はPGH2またはPGG2からトロンボキ
サンA2への変換酵素（トロンボキサンA2合成酵
素）を極めて低濃度（３×10-8モル以下）で阻害
作用を示すが、一方、生理的に極めて有用なプロ
スタグランジンI2（PGI2）およびその他のプロス
タグランジン類への変換酵素、例えばPGI2合成
酵素およびプロスタグランジン合成酵素に対して
は殆んど阻害作用を示さず、むしろPGH2あるい
はPGG2の生体内での利用効率を高め、例えば血
小板においてはPGD2を、また、血管内皮細胞の
存在下にはPGI2の産生増強作用がみられる。
このように、一般式（）で表わされる置換ビ
ニルカルボン酸誘導体は、プロスタグランジンI2
（PGI2）合成酵素，プロスタグランジン合成酵素
（シクロオキシゲナーゼ）および種々のプロスタ
グランジン類の合成酵素に対し抑制作用を示さ
ず、トロンボキサンA2（TXA2）合成酵素を選択
的に阻害する。
また本発明化合物はラツト，イヌなどに対して
毒性作用が極めて低く、毒性と薬効有効量との巾
が広いのが特徴的である。また、本発明化合物
は、カルボン酸側からの代謝分解による減炭反応
が起りにくゝ、生体内における薬効持続がなが
く、長時間安定したTXA2合成酵素阻害作用が期
待される。したがつて、本発明による化合物は、
使用投与量が少なく、長期間連用による副作用も
少なく、血小板凝集に基づく血栓症あるいは心
臓、脳および末梢，循環器系における血管攣縮に
因る虚血性疾患（例えば心筋梗塞，脳卒中，腎，
肺などの血管梗塞，消化管系潰瘍など）および
TXA2／PGI2不均衡に基づく諸疾患（例えば動
脈硬化症，高血圧症など）の予防あるいは治療の
ために人を含む哺乳動物に使用される。投与方法
は、たとえば錠剤，カプセル剤，散剤，顆粒剤な
どとして経口的に用いられるほか、注射剤，ペレ
ツトとして非経口的に投与することができる。投
与量は成人１人につき通常１日20〜200mgを経口
的に、10〜100mgを非経口的に１〜３回に分けて
投与される。
本発明の化合物（）はたとえば以下に記載の
方法のいずれかによつて製造することができる。
〔製造法 １〕
一般式
（式中R1，R2およびｎは前記と同意義であり、
Ｘはハロゲン原子を示す。）で表わされる化合物
と一般式
（式中、R3，R4およびR5は前記と同意義であ
る。）で表わされる化合物とを反応させることに
よつて一般式（）で表わされる化合物を得るこ
とができる。
前記一般式（）中Ｘで示されるハロゲン原子
としてはたとえば臭素，ヨウ素などがあげられ
る。
この反応は、通常無水溶媒中不活性ガス存在下
に強塩基化合物の存在下に行なわれる。本反応で
用いられる溶媒としては、ジメチルスルホキサイ
ド，ジメチルホルムアミド，ヘキサメチルホスホ
ルトリアミド，テトラヒドロフラン，ジエチルエ
ーテル，１，２―ジメトキシエタンおよびこれら
から選らばれる混合溶媒が挙げられる。不活性ガ
スとしては、アルゴン，ヘリウム，窒素などが用
いられる。反応温度は、置換基R4およびR5，反
応溶媒の種類および用いる強塩基化合物の種類な
どによつて異なるが通常−70℃から30℃の範囲で
ある。
強塩基化合物としては、例えばリチウムジイソ
プロピルアミド，水素化カリウム，水素化ナトリ
ウム，ナトリウムアミド，第３級ブトキシカリウ
ム，リチウムイソプロピルシクロヘキシルアミド
などから適宜選ばれ使用される。
反応は通常30分から３時間以内に終了する。
〔製造法 ２〕
一般式
（式中、R1およびR2は前記と同意義である。）で
表わされる化合物と一般式
（式中、R7およびR8は一方が水素原子または低
級アルキル基を示し、他方が低級脂肪族炭化水素
基，炭素数６以下の脂環族炭化水素基または芳香
族基を示す。X-はハロゲンイオンを示す。R3お
よびｎは前記と同意義である。）で表わされる化
合物とを反応させることにより一般式
（式中の各記号は前記と同意義である。）で表わ
される化合物を得ることができる。
前記一般式（―１）および（）中、R7お
よびR8で示される低級脂肪族炭化水素基，炭素
数６以下の脂肪族炭化水素基および芳香族基は
R4，R5で示されるそれらの定義と同じである。
X-で示されるハロゲンイオンはたとえば塩素イ
オン，臭素イオン，ヨウ素イオンなどがあげられ
る。
この反応は通常、有機溶媒中塩基の存在下に行
なわれる。塩基としては、たとえばｎ―ブチルリ
チウム，リチウムジイソプロピルアミド，水素化
ナトリウム，水素化カリウム，第３級ブトキシカ
リウム，ナトリウムアミドなどがあげられるが、
なかでもリチウムジイソプロピルアミド，水素化
ナトリウム，ナトリウムアミドが好ましく用いら
れる。溶媒としては、たとえばエーテル，テトラ
ヒドロフラン，ジメチルホルムアミド，ジメチル
スルホキシドまたはこれらの溶媒から選ばれた２
種以上の混合溶媒があげられる。この反応は乾燥
不活性ガス（たとえば窒素ガス，アルゴンガス，
ヘリウムガスなど）雰囲気下に行なうのがよい。
反応温度は−20℃〜50℃、好ましくは０℃〜30℃
である。本反応はホスホランの特有な色の消失を
観察することによつてその反応の進行度合を知る
ことができ、通常１〜６時間程度で反応が終了す
る。
〔製造法 ３〕
一般式
（式中R1，R2，R3およびｎは前記と同意義であ
り、R9は水素原子，低級アルキル基またはアリ
ールチオ基を示す。）で表わされる化合物と一般
式
R10―Ｘ （）
（式中、Ｘは前記と同意義であり、R10は低級脂
肪族炭化水素基を示す。）で表わされる化合物と
を反応させることによつて一般式
（式中、各記号は前記と同意義である。）で表わ
される化合物を製造することができる。
前記一般式（）および（―２）中R9で表
わされる低級アルキル基としては、R4またはR5
で示される低級アルキル基の定義と同じであり、
R9で示されるアリールチオ基としては、たとえ
ばフエニルチオ，ナフチルチオなどがあげられ
る。また前記一般式（）および（―２）中、
R10で示される低級脂肪族炭化水素基としてはR4
またはR5で示される低級脂肪族炭化水素の定義
と同じである。
この反応は通常溶媒中塩基の存在下に行なわれ
る。塩基としては、たとえば、ｎ―ブチルリチウ
ム，リチウムジイソプロピルアミド，リチウムイ
ソプロピルシクロヘキシルアミド，水素化ナトリ
ウム，第３級ブトキシカリウムなどが挙げられ
る。溶媒としては、たとえば、エーテル，テトラ
ヒドロフラン，ジメチルスルホキサイド，ヘキサ
メチルホスホルトリアミドまたはこれらの溶媒か
ら選ばれた２種以上の混合溶媒が使用される。反
応温度は通常好ましくは−78℃〜０℃であり、反
応は通常１〜３時間である。
〔製造法 ４〕
一般式
（式中、R1，R2，R3およびｎは前記と同意義で
あり、R11は水素原子または低級アルキル基を示
す。）で表わされる化合物と一般式
（R12―Ｓ―）2 （）
（式中R12は低級アルキル基またはアリール基を
示す。）で表わされる化合物とを反応させること
により一般式
（式中、各記号は前記と同意義である。）で表わ
される化合物を得ることができる。
前記一般式（）および（―３）中R11で示
される低級アルキル基は、R4またはR5で示され
る低級アルキル基の定義と同じであり、R12で示
される低級アルキル基としてはたとえばメチル，
エチル，ｎ―プロピル，イソプロプル，ｎ―ブチ
ル，ｎ―ペンチル，ｎ―ヘキシル，ｎ―ヘプチル
など炭素数１〜８のものがあげられる。
この反応は、通常テトラヒドロフラン，ジエチ
ルエーテル，１，２―ジメトキシエタンなどの溶
媒中、−70℃から０℃までの反応温度で、不活性
ガス雰囲気下にリチウムジイソプロピルアミドあ
るいはリチウムイソプロピルシクロヘキシルアミ
ドなどの存在下に行われる。反応は１〜３時間で
ある。
〔製造法 ５〕
一般式
（式中、R1，R2，R3およびｎは前記と同意義で
あり、R13は水素原子または低級アルキル基を示
す。）で表わされる化合物と一般式
（式中R14，R15はそれぞれ低級アルキル基およ
び芳香族基を示すか、またはR14とR15が互いに
結合してR14，R15で一個のアルキレン基を示
す。）で表わされる化合物とを反応させることに
よつて一般式
（式中、各記号は前記と同意義である。）で表わ
される化合物を得ることができる。
前記式（Ｘ）および（―４）中、R13で示さ
れる低級アルキル基は、R4またはR5で示される
低級アルキル基の定義と同じであり、R14，R15
で示される低級アルキルとしてはたとえばメチ
ル，エチル，ｎ―プロピル，ｎ―ブチル，ｎ―ペ
ンチル，ｎ―ヘキシル，ｎ―ヘプチルなど炭素数
１〜８のものがあげられる。また、芳香族基とし
てフエニルおよびナフチルが挙げられる。R14と
R15が同一の炭素に結合してR4とR5で１個のアル
キレン基を示すとき、このアルキレン基はメチレ
ン基が２〜６個連なつたものであり、このアルキ
レン基はR4およびR5の結合する炭素原子と共に
環を形成している。
この反応は、前記製造法４において用いられる
塩基，溶媒，反応温度，不活性ガスなどと同じ諸
条件に準じて行なうことができる。
〔製造法 ６〕
一般式
（式中、各記号は前記と同意義である。）で表わ
される化合物を脱水反応に付すことによつて一般
式
または一般式
（式中、R1，R2，R3，ｎ，R13，R14およびR15は
前記と同意義を、またR16，R17は一方が水素原
子または低級アルキル基で他方が低級アルキル基
を示すか、またはR16とR17が結合し、R16とR17
で一個の炭素数１〜５のアルキレン基を示す。）
で表わされる化合物を得ることができる。
この反応は、メチレンクロライド，クロロホル
ム，酢酸エチル，トルエン，エーテル，テトラヒ
ドロフランなどの不活性溶媒中、ピリジン，トリ
エチルアミンなどの有機塩基の存在下にチオニル
クロライド，オキシ塩化リンなどの脱水剤を用い
て行われる。
このようにして製造される置換ビニルカルボン
酸誘導体（）は、たとえば抽出，濃縮，結晶化
法，液体クロマトグラフイーなど通常の手段によ
り分離，精製することができる。また化合物
（）は３置換オレフイン化合物に属し、２種の
幾何学的異性体が存在する場合があり、異性体の
分離は、必要により、分別結晶化法，クロマトグ
ラフイーあるいはこれらの組み合せなどによつて
行なうことができる。
一般式（）で表わされる化合物がカルボン酸
〔式（）中R3が水素原子〕であるときは必要に
よりこれをエステル化することによりエステル体
〔式（）中R3が低級アルキル基〕に導びくこと
ができ、また逆にエステル体であるときは必要に
よりこれを遊離のカルボン酸に導びくこともでき
る。
前記一般式（）で表わされる化合物は、たと
えば下に示されるように、有機リチウム化合物と
アルデヒド化合物を反応させることによつて化合
物（XI）を得、ついでこれに二酸化マンガンま
たはジメチルスルホキサイド―修酸クロライドを
反応させることによつて製造することができる。
前記一般式（）で表わされる化合物は、たと
えば一般式
（式中、R1，R2，R3およびｎは前記と同意義で
ある。）を水素化リチウムアルミニウムなどで還
元し、相当するアルコール体に変換し、ついでハ
ロゲン化反応を行うことによつて製造することが
できる。
また、前記一般式（）で表わされるトリフエ
ニルホスホニウム塩は、たとえば下記に示される
反応によつて製造することができる。
（R3，R7，R8nおよびＸは前記と同意義である。）
以下に参考例，実施例および実験例を記載して
本発明をより具体的に説明する。
なお、異性体表示は、３―ピリジル基の置換す
る二重結合において３―ピリジル基とオレフイン
プロトンが同方向にあるものを(E)―異性体とし、
３―ピリジル基とオレフインプロトンが逆方向に
あるものを（Ｚ）―異性体とした。
以下の表中、略号とそれが示す基との対応関係
はつぎのとおりである。
３―Py：３―ピリジル基；２―Th，３―Th：
２―チエニル基，３―チエニル基；Ph：フエニ
ル基；Me：メチル基；Et：エチル基；PhCH2：
ベンジル基；PhO：フエノキシ基；ｉ―Pr―
Ｓ：イソプロピルチオ；MeS―：メチルチオ；
PhS：フエニルチオ基
核磁気共鳴スペクトルは、重クロロホルム中、
EM―390（バリアン社製）装置を用いて測定し
た。
参考例 １
（Ｅ＋Ｚ）―６―フエニル―６―（３―ピリジ
ル）―５―ヘキセン酸メチル（23ｇ）を無水テト
ラヒドロフラン（100ml）に溶解し、５℃に氷冷
した。これに水素化リチウムアルミニウム（４
ｇ）を徐々に加え、室温で３時間かきまぜた。反
応後、飽和酒石酸カリウムナトリウム水を加え過
剰の試薬を分解して、無機物を固化させた。有機
層を分離し、残つた無機物を酢酸エチルで洗浄
し、有機層と酢酸エチル層を合併して減圧濃縮し
た。残渣をシリカゲルクロマトグラフイーに付
し、酢酸エチルで溶出すると（Ｅ＋Ｚ）―６―フ
エニル―６―（３―ピリジル）―５―ヘプテン―
１―オール（16ｇ）が得られた。このアルコール
体（15ｇ）を47％臭化水素酸水（100ml）に溶解
し、100℃で18時間加熱反応した。冷却後、炭酸
水素ナトリウムを加えてPH８とし、生成物を酢酸
エチルで抽出した。有機層を常法に従つて処理
し、酢酸エチルを減圧で濃縮し、残渣をシリカゲ
ルクロマトグラフイーに付し、酢酸エチル：イソ
プロピルエーテル（１：１）で展開すると（Ｅ＋
Ｚ）―１―ブロム―６―フエニル―６―（３―ピ
リジル）―５―ヘキセン（15ｇ）が得られた。
NMR（δ値）：8.50（2H，ｍ），7.30（7H，ｍ），
6.16（1/2Ｈ），ｔ，７Hz），6.08（1/2Ｈ，ｔ，７
Hz），3.34（2H，ｔ，６Hz），2.05（3H，ｍ），1.80
（3H，ｍ）。
上記で得られたプロム体（15ｇ）をアセトン
（100ml）に溶解し、ヨウ化ナトリウム（25ｇ）を
加えて室温で１時間かきまぜる。反応後水（50
ml）を加え酢酸エチルで抽出し、有機層を水洗，
乾燥後減圧で濃縮し、残渣をシリカゲルクロマト
グラフイーに付し酢酸エチル：イソプロプルエー
テル（１：１）で展開するとまずＺ体が溶出しつ
いでＥ体が溶出した〔（Ｅ）―１―ヨウド―６―
フエニル―６―（３―ピリジル）―５―ヘキセ
ン：NMR（δ値）8.50（2H，ｍ），7.30（7H，ｍ），
6.08（1H，ｔ，７Hz），3.15（2H，ｔ，６Hz），
2.02（2H，ｍ），1.80（2H，ｍ）；（Ｚ）―１―ヨウ
ド―６―フエニル―６―（３―ピリジル）―５―
ヘキセン：NMR（δ値）8.50（2H，ｍ），7.31
（7H，ｍ），6.16（1H，ｔ，７Hz），3.18（2H，ｔ，
６Hz），2.00（2H，ｍ），1.78（2H，ｍ）〕。
参考例 ２
（Ｅ＋Ｚ）―５―フエニル―５―（３―ピリジ
ル）―４―ペンテン―１―オール（３―ベンゾイ
ルピリジンと４―ヒドロキシブチルトリフエニル
ホスホニウムブロマイドからウイテツヒ反応によ
つて調整）〔NMR（δ値）：8.34〜8.60（2H，ｍ），
7.1〜7.6（7H，ｍ），6.0〜6.3（1H，ｍ），3.40（2H，
ｔ），2.0〜2.4（2H，ｍ），1.5〜1.9（2H，ｍ）〕（12
ｇ）をジクロルメタン（100ml）に溶解し、０℃
に冷却した。これにトリエチルアミン（6.0ｇ）
を加え同条件下にかきまぜた。この溶液にメタン
スルホニルクロライド（6.2ｇ）のジクロルメタ
ン（20ml）溶液を加えた。反応終了後水（100ml）
を加えよく振りまぜたのち、有機層を分離し、さ
らに有機層を水洗後、乾燥し、溶媒を減圧下に濃
縮した。残渣にアセトン（100ml）とヨウ化ナト
リウム（８ｇ）を加えて室温で３時間反応させ
た。反応終了後、アセトンを減圧で除去し、酢酸
エチル（100ml）と水（50ml）を加えて生成物を
抽出した。有機層を水洗，乾燥後、溶媒を減圧濃
縮し、残渣をシリカゲルクロマトグラフイーに付
し、イソプロピルエーテル：酢酸エチル（１：
１）で展開するとまずＺ体が溶出しついでＥ体が
溶出した〔（Ｅ）―１―ヨウド―５―フエニル―
５―（３―ピリジル）―４―ペンテン：NMR
（δ値）8.35〜8.60（2H，ｍ），7.1〜7.6（7H，ｍ），
6.07（1H，ｔ，７Hz），3.42（2H，ｔ），3.27（2H，
ｔ），2.35（2H，ｍ）；（Ｚ）―１―ヨウド―５―
フエニル―５―（３―ピリジル―４―ペンテン：
NMR（δ値）8.35〜8.60（2H，ｍ），7.1〜7.6（7H，
ｍ），6.20（1H，ｔ，７Hz），3.43（2H，ｔ），3.28
（2H，ｔ），2.36（2H，ｍ）〕。
参考例 ３
５―カルボキシ―５，５―ジメチルペンチルト
リフエニルホスホニウムブロマイドの製造
ａ ６―アセトキシ―２，２―ジメチルヘキサン
酸エチル
アルゴン雰囲気下にジイソプロピルアミン
（8.25ml）を無水テトラヒドロフラン（100ml）
に溶かし−70℃に冷却した。これに1.6Mのｎ
―ブチルリチウムヘキサン溶液（37ml，
60mmole）を滴下した。ついで反応温度を−
60℃以下に保ちながらイソ酪酸エチル（5.6ｇ，
48mmole）の無水テトラヒドロフラン（５ml）
溶液を加えた。同反応条件下で30分間かきまぜ
たのち４―アセトキシブチルヨウド（12ｇ，
50mmole）のヘキサメチルホスホルトリアミ
ド（５ml）溶液を滴下し、室温になるまで反応
を行つた。反応終了後、２規定塩酸（10ml）を
加え、減圧濃縮し、生成物を酢酸エチル（100
ml）に溶解し、有機層を水洗，乾燥・減圧濃縮
した。残渣をシリカゲルカラムクロマトグラフ
イーに付し、イソプロピルエーテルで展開して
６―アセトキシ―２，２―ジメチルヘキサン酸
エチル（5.6ｇ，50％）を得た。
ｂ ６―プロム―２，２―ジメチルヘキサン酸
６―アセトキシ―２，２―ジメチルヘキサン
酸（4.5ｇ）を47％臭化水素酸水（25ml）に溶
かし130℃で４時間加熱した。反応後冷却し、
水（100ml）を加え、エーテルで生成物を抽出
した。有機層を水洗，乾燥後減圧濃縮し、残渣
をシリカゲルカラムクロマトグラフイーに付
し、イソプロピルエーテルで展開すると６―ブ
ロム―２，２―ジメチルヘキサン酸（４ｇ，91
％）が得られた。
ｃ ５―カルボキシ―５，５―ジメチルペンチル
トリフエニルホスホニウムブロマイド
６―ブロム―２，２―ジメチルヘキサン酸
（3.8ｇ，17mmole）とトリフエニルホスフイン
（4.9ｇ，18.7mmole）をアセトニトリル（30
ml）に溶解し、20時間加熱還流を行つた。反応
終了後、溶媒を減圧で除去し、残渣にトルエン
（100ml）を加えよくかきまぜたのち、不溶物と
トルエン溶液を分離した。不溶物を酢酸エチル
で結晶化すると５―カルボキシ―５，５―ジメ
チルペンチルトルフエニルホスホニウムブロマ
イド（4.8ｇ，58％）が得られた〔NMR（δ
値）：1.10（6H，ｓ），1.4〜1.6（6H），3.4〜3.8
（2H）〕。
参考例 ４
５―カルボキシ―５―メチルペンチルトリフエ
ニルホスホニウムブロマイドの製造
ａ ２―メチルカプロラクタム
アルゴン雰囲気下にジイソプロピルアミン
（6.5ml，46.4mmole）のテトラヒドロフラン
（50ml）溶液に、−60゜で1.6Mのｎ―ブチルリチ
ウムヘキサン溶液（28.9ml，46.2mmole）をか
きまぜながら滴下した。10分後、カプロラクト
ン（5.0ｇ，43.8mmole）のテトラヒドロフラ
ン（10ml）溶液を−60℃以下で滴下した。同条
件下で20分間反応後、ヨウ化メチル（7.5ｇ，
52.8mmole）のヘキサメチルホスホルトリアミ
ド（9.2ml）溶液を徐々に加え、滴下終了後−
40゜〜−45℃に保ち１時間かきまぜた。反応液
に飽和塩化アンモニウム水（20ml）を加えて反
応を停止し、水（100ml）を加え、生成物を酢
酸エチルで抽出した。有機層を水洗，乾燥後、
濃縮し、残渣をシリカゲルカラムクロマトグラ
フイーに付し、イソプロピルエーテルで展開す
ると２―メチルカプロラクタム（3.7ｇ，66％）
が得られた〔NMR（δ値）：1.18（3H，ｄ，６
Hz），2.5―2.9（1H，ｍ），4.18〜4.34（2H，
ｍ）〕。
ｂ ６―ブロム―２―メチルヘキサン酸
２―メチルカプロラクトン（1.8ｇ，
14mmole）に47％臭化水素酸水（10.5ml）と濃
硫酸（2.6ml）の混液を加え、130℃で３時間加
熱反応を行つた。反応液を冷却後、水を加え、
エーテルで生成物を抽出した。有機層を水洗，
乾燥後、溶媒を減圧濃縮した。残渣を常法に従
つてシリカゲルカラムクロマトグラフイーに付
し、イソプロピルエーテルで展開すると６―ブ
ロム―２―メチルヘキサン酸（1.56ｇ，53.3
％）が得られた〔NMR（δ値）：1.18（3H，ｄ，
６Hz），2.25―2.8（1H，ｍ），3.40（2H，ｔ，６
Hz），11.56（1H，COOH）〕。
ｃ ５―カルボキシ―５―メチルペンチルトリフ
エニルホスホニウムブロマイド
６―ブロム―２―メチルヘキサン酸（1.08
ｇ，5.17mmole）とトリフエニルホスフイン
（1.42ｇ，5.4mmole）のトルエン（５ml）溶液
を18時間加熱還流した。冷後、析出した結晶を
取し、トルエン，酢酸エチルで洗浄すると５
―カルボキシ―５―メチルペンチルトリフエニ
ルホスホニウムブロマイド（1.6ｇ，64％）が
得られた。
参考例 ５
５―カルボキシ―５―フエニルペンチルトリフ
エニルホスホニウムブロマイドの製造
ａ ６―アセトキシ―２―フエニルヘキサン酸エ
チル
アルゴン雰囲気下にジイソプロピルアミン
（2.4ｇ，23.8mmole）を無水テトラヒドロフラ
ン（50ml）にとかし、−70℃に冷却した。これ
に1.6Mのｎ―ブチルリチウムヘキサン溶液
（14.8ml，23.7mmole）を滴下し−70℃で10分
間かきまぜた。ついでフエニル酢酸エチル
（3.24ｇ，20mmole）を含むテトラヒドロフラ
ン（10ml）溶液を−60℃以下に保ちながら加え
た。同条件下に30分かきまぜたのち、４―アセ
トキシペンチルヨウド（4.8ｇ，20mmole）を
ヘキサメチルホスホルトリアミド（４ml）に溶
かして滴下した。滴下終了後、−70℃でさらに
１時間かきまぜたのち、室温まで反応温度を上
昇させ、２規定塩酸（30ml）を加え、生成物を
イソピロピルエーテルで抽出した。有機層を水
洗，乾燥後、減圧濃縮し、残渣をシリカゲルク
ロマトグラフイーに付し、イソプロピルエーテ
ル：ヘキサン（１：１）で展開すると６―アセ
トキシ―２―フエニルヘキサン酸エチル（５
ｇ，90％）が得られた。
ｂ ６―ブロム―２―フエニルヘキサン酸
６―アセトキシ―２―フエニルヘキサン酸エ
チル（22ｇ）を47％臭化水素酸水（100ml）に
とかし、130℃で４時間加熱した。反応後冷却
し、食塩水（300ml）を加え、イソプロピルエ
ーテルで生成物を抽出した。有機層を水洗，乾
燥後、減圧濃縮し、残渣をシリカゲルカラムク
ロマトグラフイーに付し、イソプロピルエーテ
ルで展開すると６―ブロム―２―フエニルヘキ
サン酸（16ｇ，75％）が得られた。
ｃ ５―カルボキシ―５―フエニルベンチルトリ
フエニルホスホニウムブロマイド
６―ブロム―２―フエニルヘキサン酸（16
ｇ，59mmole）とトリフエニルホスフイン
（20ｇ，76mmole）をアセトニトリル（100ml）
にとかし、100℃で18時間加熱した。反応後冷
却し、溶媒を減圧濃縮し、残渣にトルエンを加
え３回洗浄すると結晶が析出した。これを酢酸
エチルより結晶化すると５―カルボキシ―５―
フエニルペンチルトリフエニルホスホニウムブ
ロマイド（21ｇ，67％，mp210―215℃）が得
られた。
実施例 １
（製造法１）
Ａ法：
アルゴン雰囲気下にジイソプロピルアミン
（0.6ｇ，6mmole）をテトラヒドロフラン（20ml）
に溶かし−70℃に冷却した。これに1.6Mのｎ―
ブチルリチウムヘキサン溶液（４ml）を滴下し、
同反応条件下で10分間かきまぜた。この溶液にシ
クロヘキサンカルボン酸メチル（0.86ｇ，
5.5mmole）のテトラヒドロフラン（２ml）溶液
を加え、−70℃で15分間かきまぜた。ついで(E)―
６―フエニル−６−（３―ピリジル）―１―ヨウ
ド―５―ヘキセン（1.8ｇ，5mmole）のヘキサメ
チルホスホルアミド（３ml）溶液を滴下した。反
応温度を徐々に室温にまで上昇させ、同条件下で
30分かきまぜた。反応終了後、水を加え生成物を
酢酸エチルで抽出した。有機層を常法に従つて処
理したのち、粗生成物をシリカゲルクロマトグラ
フイーに付し、イソプロピルエーテル：酢酸エチ
ル（２：１）で展開して目的とする(E)―２，２―
（１，５―ペンタメチレン）―８―フエニル―８
―（３―ピリジル）―７―オクテン酸メチル（１
―ｈ）（1.2ｇ）を得た。
Ｂ法：
ｐ―メチルフエニルスルホニル酢酸メチル
（0.43ｇ，2mmole）をジメチルホルムアミドに溶
解し、アルゴン雰囲気下に０℃に冷却したのち、
水素化ナトリウム（0.1ｇ）を加え10分間かきま
ぜた。この反応液に（Ｚ）―６―フエニル―６―
（３―ピリジル）―１―ヨウド―５―ヘキセン
（0.8ｇ）のジメチルホルムアミド（４ml）溶液を
加え３時間室温で反応を行つた。反応後、水（30
ml）を加え、生成物を酢酸エチルで抽出した。有
機層を常法に従つて処理したのち、粗生成物をシ
リカゲルクロマトグラフイーに付し、イソプロピ
ルエーテル：酢酸エチル（１：１）で展開して目
的とする（Ｚ）―８―フエニル―８―（３―ピリ
ジル）―２―（ｐ―メチルフエニルスルホニル）
―７―オクテエン酸メチル（１―ｃ）（0.6ｇ，61
％）を得た。
Ｃ法：
(E)―２，２―（１，５―ペンタメチレン）―８
―フエニル―８―（３―ピリジル）―７―オクテ
エン酸メチル（１―ｈ）（0.2ｇ）を含水メタノー
ル（40ml）と溶かし、水酸化リチウム（0.3ｇ）
を加えて48時間加熱還流した。反応後、溶媒を減
圧濃縮し、２規定塩酸でPHを６とし、生成物を酢
酸エチルで抽出した。抽出液を水洗，乾燥後、減
圧濃縮し、残渣をシリカゲルクロマトグラフイー
に付し、酢酸エチルで展開し、初流出部を除いた
のち、ついで溶出する画部より(E)―２，２―
（１，５―ペンタメチレン）―８―フエニル―８
―（３―ピリジル）―７―オクテエン酸（１―
ｆ）（0.18ｇ）を得た。
上記実施例に準じて表に示す化合物（―ａ
〜―ｕ）を製造した。
The present invention relates to novel substituted vinylcarboxylic acid derivatives that have the ability to specifically inhibit thromboxane A 2 (TXA 2 ) synthetase. TXA 2 is one of the metabolites of arachidonic acid and has a platelet aggregation effect. Therefore, if it is produced in excess in the body, it is known to cause various ischemic heart, kidney, and brain diseases due to vascular occlusion and vasospasm. The present inventors conducted synthetic and exploratory research on substances that have a TXA 2 synthetase inhibitory effect, and as a result, discovered a group of new compounds that have an excellent TXA 2 synthetase inhibitory effect. That is, the present invention is based on the general formula [In the formula, R 1 is a pyridyl group, and R 2 is a phenyl group which may have a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylenedioxy group as a substituent. , thienyl group, furyl group, naphthyl group,
R 3 represents a benzothienyl group or a pyridyl group, and R 3 represents a hydrogen atom, a benzyl group or a lower alkyl group. One of R 4 and R 5 is a hydrogen atom or a lower alkyl group, and the other is an aryloxy group or a lower aliphatic hydrocarbon group which may have a substituent, an aliphatic hydrocarbon group having 6 or less carbon atoms, represents an aromatic group or a group represented by the formula -S(O) n --R 6 (wherein, R 6 represents a phenyl group or a lower alkyl group, and m represents an integer of 0 to 2), or R 4 and R 5 are bonded to each other and R 4 and R 5 represent one alkylene group. n represents an integer of 2 to 6. ] is a substituted vinyl carboxylic acid derivative represented by In the general formula (), the pyridyl groups represented by R 1 and R 2 include 2-pyridyl, 3-pyridyl,
Examples include 4-pyridyl, of which 3-pyridyl is preferred. Also, thienyl represented by R 2 is 2-thienyl, 3-thienyl, furyl is 2-furyl, 3-furyl, naphthyl is α-naphthyl, β-
Naphthyl, benzothienyl is 2-benzothienyl, 3-benzothienyl, 4-benzothienyl,
5-benzothienyl, 6-benzothienyl, 7-
Any benzothienyl may be used. Examples of the lower alkoxy group as a substituent for phenyl, thienyl, furyl, naphthyl, benzothienyl, and pyridine represented by R2 include methoxy, ethoxy,
1 or more carbon atoms, such as n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, etc.
Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl,
Those with 1 to 5 carbon atoms, such as n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl,
Examples of halogen atoms include fluorine, chlorine,
Examples of lower alkenyl groups include bromine, etc., which have 2 carbon atoms, such as vinyl, aryl, and pentenyl.
~5 things can be listed. When phenyl, thienyl, furyl, naphthyl, benzothienyl, or biridyl represented by R 2 has a substituent, these substituents can be substituted at any position on the ring.
Examples of lower alkyl groups represented by R 3 , R 4 and R 5 include methyl, ethyl, n-propyl,
Examples include those having 1 to 4 carbon atoms such as n-butyl. Examples of the aryloxy group represented by R 4 or R 5 include phenyloxy, 1-naphthoxy, and 2-naphthoxy. The lower aliphatic hydrocarbon group represented by R 4 or R 5 is
For example, lower alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-bentyl, n-hexyl, n-heptyl, etc., such as vinyl, allyl, 1-methylvinyl, 3-methyl-2 -Lower alkenyl having 2 to 8 carbon atoms such as butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, such as ethynyl, 2-propynyl, 2
-Alkynyl groups with 2 to 8 carbon atoms, such as butynyl, 2-hexynyl, 2-octynyl, and those with 8 or less carbon atoms, especially alkyl groups with 1 to 4 carbon atoms, and alkenyl groups with 2 to 5 carbon atoms. , an alkynyl group having 2 to 8 carbon atoms is preferred. Examples of the alicyclic hydrocarbon group having 6 or less carbon atoms represented by R 4 or R 5 include cycloalkyl groups having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, such as cyclo-
Examples include those having 6 or less carbon atoms, such as cycloalkenyl having 5 to 6 carbon atoms, such as 1-pentenyl and cyclo-1-hexenyl. Examples of the aromatic group represented by R 4 or R 5 include phenyl, naphthyl, 2-thienyl, 3-thienyl, and 3-pyridyl. The lower aliphatic hydrocarbons, alicyclic carbon groups having 6 or less carbon atoms, and aromatic groups represented by R 4 or R 5 above are, for example, hydroxyl groups, cyano groups, and lower alkyl groups (for example, methyl, ethyl, etc. having 1 to 1 carbon atoms). 3), lower alkoxy groups (for example, those with 1 to 3 carbon atoms such as methoxy and ethoxy), halogen atoms (for example, fluorine, chlorine, bromine, etc.), phenyl groups, and cyano-substituted phenyl groups. You can leave it there. Examples of the group represented by the formula - S(O) n R 6 represented by R 4 or R 5 include methylthio, ethylthio, isopropylthio, methylsulfenyl, ethylsulfenyl,
Examples include methylsulfonyl, ethylsulfonyl, phenylthio, phenylsulfenyl, phenylsulfonyl, p-toluenesulfonyl, and the like.
When R 4 and R 5 combine to form an alkylene group, this alkylene group has 1 to 1 methylene group.
When R 4 and R 5 represent one methylene group, it means that the carbon to which R 4 and R 5 are bonded and the methylene group are bonded via a double bond. However, when R 4 and R 5 represent a polymethylene group having 2 to 6 carbon atoms, it means that R 4 and R 5 form a ring together with the carbon to which they are bonded. Further, this alkylene group may have a substituent at any position. Examples of this substituent include methyl,
Examples include lower alkyl groups such as ethyl, phenyl groups, pyridyl groups, thienyl groups, etc.
~2 pieces may be substituted. The compound represented by the general formula () may be an addition salt of a pharmacologically acceptable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc. , citric acid, succinic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, etc. Further, when R 3 of the compound () is a hydrogen atom, it may be an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth metal salt such as an aluminum salt. Representative examples of the compound () include 2,
2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid, 2,2-dimethyl-8-
Phenyl-8-(3-pyridyl)-7-octenoic acid, 2,2-dimethyl-7-(2-thienyl)-
7-(3-pyridyl)-6-heptenoic acid, 2,2
-dimethyl-8-(2-thienyl)-8-(3-
pyridyl)-7-octenoic acid, 2,2-dimethyl-7-(2-naphthyl)-7-(3-pyridyl)
Examples include -6-heptenoic acid. The substituted vinyl carboxylic acid derivatives of the present invention represented by the general formula () and their salts have a strong inhibitory effect on thromboxane synthase, which is solubilized and fractionated from platelet microzones of humans, horses, etc. It exhibits a strong inhibitory effect on the biosynthesis of thromboxane A 2 (TXA 2 ) in mammals that contain it. In addition, the compound () of the present invention is a prostaglandin that exhibits an arterial smooth muscle relaxing effect, a platelet aggregation inhibiting effect, or an aggregated platelet re-dissociation effect.
Shows the effect of increasing the production efficiency of I 2 (PGI 2 ). That is, prostaglandin G 2 (PGG 2 ) or prostaglandin H 2 (PGH 2 ) is thromboxane.
A 2 , prostaglandin I 2 and other prostaglandins . ), which exhibits an inhibitory effect at extremely low concentrations (3×10 -8 mol or less), while converting enzymes into physiologically extremely useful prostaglandin I 2 (PGI 2 ) and other prostaglandins; For example, it shows almost no inhibitory effect on PGI 2 synthetase and prostaglandin synthase, but rather increases the in vivo utilization efficiency of PGH 2 or PGG 2 , for example, in platelets, PGD 2 , and In the presence of vascular endothelial cells, PGI 2 production is enhanced. Thus, the substituted vinylcarboxylic acid derivative represented by the general formula () is prostaglandin I 2
(PGI 2 ) synthetase, prostaglandin synthase (cyclooxygenase), and various prostaglandin synthases, but selectively inhibits thromboxane A 2 (TXA 2 ) synthase. Furthermore, the compounds of the present invention are characterized by having extremely low toxic effects on rats, dogs, etc., and having a wide range of toxicity and medicinally effective doses. In addition, the compounds of the present invention are expected to have a long-lasting efficacy in vivo and stable TXA 2 synthetase inhibitory action because carbon reduction reactions due to metabolic decomposition from the carboxylic acid side are unlikely to occur. The compounds according to the invention therefore:
The dosage used is small and there are few side effects due to long-term use, and it is effective against thrombosis caused by platelet aggregation or ischemic diseases caused by vasospasm in the heart, brain, peripherals, and circulatory system (e.g. myocardial infarction, stroke, kidney disease, etc.).
vascular infarction in the lungs, gastrointestinal ulcer, etc.) and
It is used in mammals including humans for the prevention or treatment of various diseases based on TXA 2 /PGI 2 imbalance (eg arteriosclerosis, hypertension, etc.). For example, the drug can be administered orally in the form of tablets, capsules, powders, granules, etc., or parenterally in the form of injections or pellets. The dosage for each adult is usually 20 to 200 mg per day orally and 10 to 100 mg parenterally in 1 to 3 divided doses. The compound () of the present invention can be produced, for example, by any of the methods described below. [Manufacturing method 1] General formula (In the formula, R 1 , R 2 and n have the same meanings as above,
X represents a halogen atom. ) Compounds and general formulas represented by (In the formula, R 3 , R 4 and R 5 have the same meanings as above.) A compound represented by the general formula () can be obtained. Examples of the halogen atom represented by X in the general formula () include bromine and iodine. This reaction is usually carried out in an anhydrous solvent in the presence of an inert gas and in the presence of a strong basic compound. Examples of the solvent used in this reaction include dimethylsulfoxide, dimethylformamide, hexamethylphosphortriamide, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and a mixed solvent selected from these. Argon, helium, nitrogen, etc. are used as the inert gas. The reaction temperature varies depending on the substituents R 4 and R 5 , the type of reaction solvent, the type of strong base compound used, etc., but is usually in the range of -70°C to 30°C. The strong base compound is appropriately selected from, for example, lithium diisopropylamide, potassium hydride, sodium hydride, sodium amide, tertiary butoxypotassium, lithium isopropylcyclohexylamide, and the like. The reaction usually completes within 30 minutes to 3 hours. [Manufacturing method 2] General formula (In the formula, R 1 and R 2 have the same meanings as above.) and the general formula (In the formula, one of R 7 and R 8 represents a hydrogen atom or a lower alkyl group, and the other represents a lower aliphatic hydrocarbon group, an alicyclic hydrocarbon group having 6 or less carbon atoms, or an aromatic group . represents a halogen ion. R 3 and n have the same meanings as above.) By reacting with a compound represented by the general formula (Each symbol in the formula has the same meaning as above.) A compound represented by the following can be obtained. In the general formulas (-1) and (), the lower aliphatic hydrocarbon group, the aliphatic hydrocarbon group having 6 or less carbon atoms, and the aromatic group represented by R 7 and R 8 are
The definitions are the same as those shown in R 4 and R 5 .
Examples of the halogen ions represented by X - include chlorine ions, bromide ions, and iodine ions. This reaction is usually carried out in an organic solvent in the presence of a base. Examples of the base include n-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, potassium tertiary butoxy, sodium amide, etc.
Among them, lithium diisopropylamide, sodium hydride, and sodium amide are preferably used. Examples of the solvent include ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or two selected from these solvents.
Examples include mixed solvents of more than one species. This reaction is carried out using a dry inert gas (e.g. nitrogen gas, argon gas,
It is best to perform this under an atmosphere (such as helium gas).
The reaction temperature is -20℃~50℃, preferably 0℃~30℃
It is. The progress of this reaction can be determined by observing the disappearance of the characteristic color of phosphorane, and the reaction is usually completed in about 1 to 6 hours. [Manufacturing method 3] General formula (In the formula, R 1 , R 2 , R 3 and n have the same meanings as above, and R 9 represents a hydrogen atom, a lower alkyl group or an arylthio group.) and the general formula R 10 -X () (wherein, X has the same meaning as above, and R 10 represents a lower aliphatic hydrocarbon group). (In the formula, each symbol has the same meaning as above.) A compound represented by the following can be produced. The lower alkyl group represented by R 9 in the general formulas () and (-2) is R 4 or R 5
It is the same as the definition of the lower alkyl group shown in
Examples of the arylthio group represented by R 9 include phenylthio and naphthylthio. In addition, in the general formulas () and (-2),
The lower aliphatic hydrocarbon group represented by R 10 is R 4
Or it is the same as the definition of lower aliphatic hydrocarbon shown by R5 . This reaction is usually carried out in a solvent in the presence of a base. Examples of the base include n-butyllithium, lithium diisopropylamide, lithium isopropylcyclohexylamide, sodium hydride, and tertiary-butoxypotassium. As the solvent, for example, ether, tetrahydrofuran, dimethyl sulfoxide, hexamethylphosphortriamide, or a mixed solvent of two or more selected from these solvents is used. The reaction temperature is usually preferably -78°C to 0°C, and the reaction time is usually 1 to 3 hours. [Manufacturing method 4] General formula (In the formula, R 1 , R 2 , R 3 and n have the same meanings as above, and R 11 represents a hydrogen atom or a lower alkyl group.) and the general formula (R 12 -S-) 2 () (In the formula, R 12 represents a lower alkyl group or an aryl group.) By reacting with a compound represented by the general formula A compound represented by (wherein each symbol has the same meaning as above) can be obtained. In the general formulas () and (-3), the lower alkyl group represented by R 11 is the same as the lower alkyl group represented by R 4 or R 5 , and the lower alkyl group represented by R 12 is, for example, Methyl,
Examples include those having 1 to 8 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl. This reaction is usually carried out in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane at a reaction temperature of -70°C to 0°C in the presence of lithium diisopropylamide or lithium isopropylcyclohexylamide under an inert gas atmosphere. done below. The reaction takes 1-3 hours. [Manufacturing method 5] General formula (In the formula, R 1 , R 2 , R 3 and n have the same meanings as above, and R 13 represents a hydrogen atom or a lower alkyl group.) and the general formula (In the formula, R 14 and R 15 each represent a lower alkyl group and an aromatic group, or R 14 and R 15 combine with each other and R 14 and R 15 represent one alkylene group.) By reacting with the general formula A compound represented by (wherein each symbol has the same meaning as above) can be obtained. In the formulas (X) and (-4), the lower alkyl group represented by R 13 is the same as the lower alkyl group represented by R 4 or R 5 , and R 14 , R 15
Examples of lower alkyl represented by include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl. Further, aromatic groups include phenyl and naphthyl. R14 and
When R 15 is bonded to the same carbon and R 4 and R 5 represent one alkylene group, this alkylene group is a chain of 2 to 6 methylene groups; It forms a ring together with the carbon atom to which R 5 is bonded. This reaction can be carried out under the same conditions as the base, solvent, reaction temperature, inert gas, etc. used in Production Method 4 above. [Manufacturing method 6] General formula (In the formula, each symbol has the same meaning as above.) By subjecting the compound represented by the formula to a dehydration reaction, the general formula or general formula (In the formula, R 1 , R 2 , R 3 , n, R 13 , R 14 and R 15 have the same meanings as above, and R 16 and R 17 have one hydrogen atom or lower alkyl group and the other lower alkyl represents a group, or R 16 and R 17 are combined, and R 16 and R 17
represents one alkylene group having 1 to 5 carbon atoms. )
A compound represented by can be obtained. This reaction is carried out in an inert solvent such as methylene chloride, chloroform, ethyl acetate, toluene, ether, or tetrahydrofuran in the presence of an organic base such as pyridine or triethylamine using a dehydrating agent such as thionyl chloride or phosphorus oxychloride. . The substituted vinyl carboxylic acid derivative () produced in this manner can be separated and purified by conventional means such as extraction, concentration, crystallization, liquid chromatography, etc. In addition, compound () belongs to the trisubstituted olefin compound and may exist in two types of geometric isomers. The isomers can be separated by fractional crystallization, chromatography, or a combination of these, if necessary. You can do it by leaning. When the compound represented by the general formula () is a carboxylic acid [R 3 in the formula () is a hydrogen atom], it can be esterified if necessary to form an ester [R 3 in the formula () is a lower alkyl group]. Conversely, when it is an ester, it can be converted into a free carboxylic acid if necessary. The compound represented by the general formula () can be obtained by reacting an organolithium compound with an aldehyde compound to obtain compound (XI), and then adding manganese dioxide or dimethyl sulfoxide to the compound (XI), as shown below. It can be produced by reacting oxalic acid chloride. The compound represented by the general formula () is, for example, (In the formula, R 1 , R 2 , R 3 and n have the same meanings as above.) is reduced with lithium aluminum hydride etc. to convert it into the corresponding alcohol, and then a halogenation reaction is carried out. It can be manufactured by Further, the triphenylphosphonium salt represented by the general formula () can be produced, for example, by the reaction shown below. (R 3 , R 7 , R 8 n and X have the same meanings as above.) The present invention will be explained in more detail by referring to Reference Examples, Examples and Experimental Examples below. In addition, isomer indication is (E)-isomer when the 3-pyridyl group and the olefin proton are in the same direction in the double bond substituted by the 3-pyridyl group,
Those in which the 3-pyridyl group and the olefin proton are in opposite directions are defined as (Z)-isomers. In the table below, the correspondence between the abbreviations and the groups they represent is as follows. 3-Py: 3-pyridyl group; 2-Th, 3-Th:
2-thienyl group, 3-thienyl group; Ph: phenyl group; Me: methyl group; Et: ethyl group; PhCH 2 :
Benzyl group; PhO: phenoxy group; i-Pr-
S: isopropylthio; MeS-: methylthio;
PhS: Phenylthio group Nuclear magnetic resonance spectra were obtained in deuterated chloroform.
Measurement was performed using an EM-390 (manufactured by Varian) device. Reference Example 1 Methyl (E+Z)-6-phenyl-6-(3-pyridyl)-5-hexenoate (23 g) was dissolved in anhydrous tetrahydrofuran (100 ml) and cooled on ice at 5°C. This is added to lithium aluminum hydride (4
g) was gradually added and stirred at room temperature for 3 hours. After the reaction, saturated potassium sodium tartrate water was added to decompose the excess reagent and solidify the inorganic substance. The organic layer was separated, the remaining inorganic matter was washed with ethyl acetate, and the organic layer and ethyl acetate layer were combined and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate to give (E+Z)-6-phenyl-6-(3-pyridyl)-5-heptene-
1-ol (16 g) was obtained. This alcohol (15 g) was dissolved in 47% hydrobromic acid water (100 ml) and reacted by heating at 100° C. for 18 hours. After cooling, sodium hydrogen carbonate was added to adjust the pH to 8, and the product was extracted with ethyl acetate. The organic layer was treated according to a conventional method, ethyl acetate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with ethyl acetate:isopropyl ether (1:1) to give (E+
Z)-1-bromo-6-phenyl-6-(3-pyridyl)-5-hexene (15 g) was obtained. NMR (δ value): 8.50 (2H, m), 7.30 (7H, m),
6.16 (1/2H), t, 7Hz), 6.08 (1/2H, t, 7
Hz), 3.34 (2H, t, 6Hz), 2.05 (3H, m), 1.80
(3H, m). The prome compound (15 g) obtained above was dissolved in acetone (100 ml), sodium iodide (25 g) was added, and the mixture was stirred at room temperature for 1 hour. Water after reaction (50
ml), extracted with ethyl acetate, washed the organic layer with water,
After drying, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with ethyl acetate:isopropyl ether (1:1). Z-form was eluted first, and then E-form was eluted [(E)-1-iodo -6-
Phenyl-6-(3-pyridyl)-5-hexene: NMR (δ value) 8.50 (2H, m), 7.30 (7H, m),
6.08 (1H, t, 7Hz), 3.15 (2H, t, 6Hz),
2.02 (2H, m), 1.80 (2H, m); (Z)-1-iodo-6-phenyl-6-(3-pyridyl)-5-
Hexene: NMR (δ value) 8.50 (2H, m), 7.31
(7H, m), 6.16 (1H, t, 7Hz), 3.18 (2H, t,
6Hz), 2.00 (2H, m), 1.78 (2H, m)]. Reference example 2 (E+Z)-5-phenyl-5-(3-pyridyl)-4-penten-1-ol (prepared from 3-benzoylpyridine and 4-hydroxybutyltriphenylphosphonium bromide by Wittetsu reaction) [NMR (δ value): 8.34-8.60 (2H, m),
7.1~7.6 (7H, m), 6.0~6.3 (1H, m), 3.40 (2H,
t), 2.0 to 2.4 (2H, m), 1.5 to 1.9 (2H, m)] (12
Dissolve g) in dichloromethane (100ml) and heat at 0°C.
It was cooled to Add triethylamine (6.0g) to this
was added and stirred under the same conditions. A solution of methanesulfonyl chloride (6.2 g) in dichloromethane (20 ml) was added to this solution. Water after the reaction (100ml)
After adding and shaking well, the organic layer was separated, further washed with water, dried, and the solvent was concentrated under reduced pressure. Acetone (100 ml) and sodium iodide (8 g) were added to the residue, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, acetone was removed under reduced pressure, and ethyl acetate (100 ml) and water (50 ml) were added to extract the product. After washing the organic layer with water and drying, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography using isopropyl ether:ethyl acetate (1:
When developing in 1), the Z form was eluted first, followed by the E form [(E)-1-iodo-5-phenyl-
5-(3-pyridyl)-4-pentene: NMR
(δ value) 8.35 to 8.60 (2H, m), 7.1 to 7.6 (7H, m),
6.07 (1H, t, 7Hz), 3.42 (2H, t), 3.27 (2H,
t), 2.35 (2H, m); (Z)-1-iodine-5-
Phenyl-5-(3-pyridyl-4-pentene:
NMR (δ value) 8.35-8.60 (2H, m), 7.1-7.6 (7H,
m), 6.20 (1H, t, 7Hz), 3.43 (2H, t), 3.28
(2H, t), 2.36 (2H, m)]. Reference Example 3 Production of 5-carboxy-5,5-dimethylpentyltriphenylphosphonium bromide a Ethyl 6-acetoxy-2,2-dimethylhexanoate Diisopropylamine (8.25 ml) was added to anhydrous tetrahydrofuran (100 ml) under an argon atmosphere.
and cooled to -70°C. This is 1.6M n
-Butyllithium hexane solution (37ml,
60 mmole) was added dropwise. Then the reaction temperature is -
Ethyl isobutyrate (5.6g,
48 mmole) of anhydrous tetrahydrofuran (5 ml)
solution was added. After stirring for 30 minutes under the same reaction conditions, 4-acetoxybutyl iodide (12 g,
A solution of 50 mmole) of hexamethylphosphortriamide (5 ml) was added dropwise, and the reaction was continued until the temperature reached room temperature. After the reaction was completed, 2N hydrochloric acid (10ml) was added, concentrated under reduced pressure, and the product was dissolved in ethyl acetate (100ml).
ml), and the organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and developed with isopropyl ether to obtain ethyl 6-acetoxy-2,2-dimethylhexanoate (5.6 g, 50%). b 6-Prom-2,2-dimethylhexanoic acid 6-acetoxy-2,2-dimethylhexanoic acid (4.5 g) was dissolved in 47% hydrobromic acid water (25 ml) and heated at 130°C for 4 hours. Cool after reaction,
Water (100ml) was added and the product was extracted with ether. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and developed with isopropyl ether to give 6-bromo-2,2-dimethylhexanoic acid (4 g, 91
%)was gotten. c 5-Carboxy-5,5-dimethylpentyltriphenylphosphonium bromide 6-bromo-2,2-dimethylhexanoic acid (3.8 g, 17 mmole) and triphenylphosphine (4.9 g, 18.7 mmole) were dissolved in acetonitrile (30 g, 18.7 mmole).
ml) and heated under reflux for 20 hours. After the reaction was completed, the solvent was removed under reduced pressure, toluene (100 ml) was added to the residue, and the mixture was thoroughly stirred, and then the insoluble matter and the toluene solution were separated. When the insoluble matter was crystallized from ethyl acetate, 5-carboxy-5,5-dimethylpentyltorphenylphosphonium bromide (4.8 g, 58%) was obtained [NMR (δ
Value): 1.10 (6H, s), 1.4~1.6 (6H), 3.4~3.8
(2H)]. Reference Example 4 Preparation of 5-carboxy-5-methylpentyltriphenylphosphonium bromide a 2-Methylcaprolactam A solution of 1.6 M diisopropylamine (6.5 ml, 46.4 mmole) in tetrahydrofuran (50 ml) at -60° under an argon atmosphere. A solution of n-butyllithium in hexane (28.9 ml, 46.2 mmole) was added dropwise with stirring. After 10 minutes, a solution of caprolactone (5.0 g, 43.8 mmole) in tetrahydrofuran (10 ml) was added dropwise at -60°C or lower. After reacting for 20 minutes under the same conditions, methyl iodide (7.5 g,
Gradually add a solution of 52.8 mmole) in hexamethylphosphortriamide (9.2 ml), and after the dropwise addition -
The mixture was kept at 40° to -45°C and stirred for 1 hour. Saturated ammonium chloride water (20 ml) was added to the reaction solution to stop the reaction, water (100 ml) was added, and the product was extracted with ethyl acetate. After washing the organic layer with water and drying,
After concentration, the residue was subjected to silica gel column chromatography and developed with isopropyl ether to yield 2-methylcaprolactam (3.7 g, 66%).
was obtained [NMR (δ value): 1.18 (3H, d, 6
Hz), 2.5-2.9 (1H, m), 4.18-4.34 (2H,
m)]. b 6-bromo-2-methylhexanoic acid 2-methylcaprolactone (1.8g,
A mixture of 47% aqueous hydrobromic acid (10.5 ml) and concentrated sulfuric acid (2.6 ml) was added to the solution (14 mmole), and a heating reaction was carried out at 130°C for 3 hours. After cooling the reaction solution, add water,
The product was extracted with ether. Wash the organic layer with water,
After drying, the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography in a conventional manner and developed with isopropyl ether to give 6-bromo-2-methylhexanoic acid (1.56 g, 53.3
%) was obtained [NMR (δ value): 1.18 (3H, d,
6Hz), 2.25-2.8 (1H, m), 3.40 (2H, t, 6
Hz), 11.56 (1H, COOH)]. c 5-carboxy-5-methylpentyltriphenylphosphonium bromide 6-bromo-2-methylhexanoic acid (1.08
A solution of triphenylphosphine (1.42 g, 5.4 mmole) in toluene (5 ml) was heated under reflux for 18 hours. After cooling, the precipitated crystals were collected and washed with toluene and ethyl acetate.
-Carboxy-5-methylpentyltriphenylphosphonium bromide (1.6 g, 64%) was obtained. Reference Example 5 Production of 5-carboxy-5-phenylpentyltriphenylphosphonium bromide a Ethyl 6-acetoxy-2-phenylhexanoate Diisopropylamine (2.4 g, 23.8 mmole) was dissolved in anhydrous tetrahydrofuran (50 ml) under an argon atmosphere. It was combed and cooled to -70°C. A 1.6M n-butyllithium hexane solution (14.8ml, 23.7mmole) was added dropwise to this and stirred at -70°C for 10 minutes. Then, a solution of ethyl phenyl acetate (3.24 g, 20 mmole) in tetrahydrofuran (10 ml) was added while keeping the temperature below -60°C. After stirring for 30 minutes under the same conditions, 4-acetoxypentyl iodide (4.8 g, 20 mmole) dissolved in hexamethylphosphortriamide (4 ml) was added dropwise. After the dropwise addition was completed, the mixture was stirred at -70°C for an additional hour, then the reaction temperature was raised to room temperature, 2N hydrochloric acid (30ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with isopropyl ether:hexane (1:1) to give ethyl 6-acetoxy-2-phenylhexanoate (5
g, 90%) was obtained. b 6-Bromo-2-phenylhexanoic acid Ethyl 6-acetoxy-2-phenylhexanoate (22 g) was dissolved in 47% hydrobromic acid water (100 ml) and heated at 130°C for 4 hours. After the reaction was cooled, brine (300 ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and developed with isopropyl ether to obtain 6-bromo-2-phenylhexanoic acid (16 g, 75%). c 5-carboxy-5-phenylbentyltriphenylphosphonium bromide 6-bromo-2-phenylhexanoic acid (16
g, 59 mmole) and triphenylphosphine (20 g, 76 mmole) in acetonitrile (100 ml).
The mixture was stirred and heated at 100°C for 18 hours. After the reaction, the mixture was cooled, the solvent was concentrated under reduced pressure, and toluene was added to the residue and washed three times to precipitate crystals. When this is crystallized from ethyl acetate, 5-carboxy-5-
Phenylpentyltriphenylphosphonium bromide (21 g, 67%, mp210-215°C) was obtained. Example 1 (Production method 1) Method A: Diisopropylamine (0.6 g, 6 mmole) was added to tetrahydrofuran (20 ml) under an argon atmosphere.
and cooled to -70°C. This includes 1.6M n-
Butyl lithium hexane solution (4 ml) was added dropwise,
The mixture was stirred for 10 minutes under the same reaction conditions. Methyl cyclohexanecarboxylate (0.86g,
A solution of 5.5 mmole) in tetrahydrofuran (2 ml) was added and stirred at -70°C for 15 minutes. Then (E)―
A solution of 6-phenyl-6-(3-pyridyl)-1-iodo-5-hexene (1.8 g, 5 mmole) in hexamethylphosphoramide (3 ml) was added dropwise. The reaction temperature was gradually increased to room temperature, and under the same conditions
I stirred it for 30 minutes. After the reaction was completed, water was added and the product was extracted with ethyl acetate. After treating the organic layer according to a conventional method, the crude product was subjected to silica gel chromatography and developed with isopropyl ether:ethyl acetate (2:1) to obtain the desired product (E)-2,2-
(1,5-pentamethylene)-8-phenyl-8
-(3-pyridyl)-7-methyl octenoate (1
-h) (1.2g) was obtained. Method B: Methyl p-methylphenylsulfonylacetate (0.43 g, 2 mmole) was dissolved in dimethylformamide, cooled to 0°C under an argon atmosphere, and then
Sodium hydride (0.1g) was added and stirred for 10 minutes. In this reaction solution, (Z)-6-phenyl-6-
A solution of (3-pyridyl)-1-iodo-5-hexene (0.8 g) in dimethylformamide (4 ml) was added and the reaction was carried out at room temperature for 3 hours. After the reaction, add water (30
ml) was added and the product was extracted with ethyl acetate. After treating the organic layer according to a conventional method, the crude product was subjected to silica gel chromatography and developed with isopropyl ether:ethyl acetate (1:1) to obtain the desired (Z)-8-phenyl-8. -(3-pyridyl)-2-(p-methylphenylsulfonyl)
-7-Methyl octenoate (1-c) (0.6g, 61
%) was obtained. Method C: (E)-2,2-(1,5-pentamethylene)-8
-Phenyl-8-(3-pyridyl)-7-methyl octenoate (1-h) (0.2g) was dissolved in aqueous methanol (40ml), and lithium hydroxide (0.3g) was dissolved.
was added and heated under reflux for 48 hours. After the reaction, the solvent was concentrated under reduced pressure, the pH was adjusted to 6 with 2N hydrochloric acid, and the product was extracted with ethyl acetate. After washing the extract with water and drying, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, developed with ethyl acetate, and after removing the first effluent, the eluted fraction (E)-2,2-
(1,5-pentamethylene)-8-phenyl-8
-(3-pyridyl)-7-octenoic acid (1-
f) (0.18 g) was obtained. Compounds shown in the table (-a
~-u) was produced.
【表】【table】
【表】【table】
【表】
実施例 ２
Ａ法：
水素化ナトリウム（2.5ｇ，60％油性懸濁）を
ヘキサンで油性分を洗浄除去し、減圧乾燥後、こ
れにジメチルスルホキサイド（25ml）を加え、ア
ルゴン雰囲気下に80℃で１時間加熱してジムシル
アニオンを生成させた。反応溶液を10℃に冷却後
５―カルボキシ―５，５―ジメチルペンチルトリ
フエニルホスホニウムブロマイド（８ｇ，
16mmole）を加え、さらに室温で10分間かきま
ぜた。この混合液に３―ベンゾイルピリジン（３
ｇ，16mmole）を含むジメチルスルホキサイド
溶液（５ml）を滴下した。滴下終了後、室温で30
分間かきまぜ、ついで水（50ml）を加え振りまぜ
たのち有機層を分離し、水層を２規定塩酸でPH
6.0に調節し、生成物を酢酸エチル（50ml）で３
回抽出した。酢酸エチル層を合併し、水洗，乾燥
（硫酸マグネシウム）後、減圧で濃縮した。残渣
をシリカゲルカラムクロマトグラフイーに付し、
酢酸エチルで展開すると(E)＋（Ｚ）―２，２―ジ
メチル―７―フエニル―７―（３―ピリジル）―
６―ヘプテエン酸（２―ａ，２―ｂ）（2.2ｇ）が
得られた。
Ｂ法：
窒素雰囲気下に５―カルボキシ―５，５―ジメ
チルペンチルトリフエニルホスホニウムブロマイ
ド（３ｇ，6mmole）を無水ジメチルスルホキサ
イド（30ml）に溶解し、30〜35℃でナトリウムア
ミド（0.25ｇ，64mmole）を加え、25〜30℃で30
分間かきまぜた。この溶液に３―ベンゾイルピリ
ジン（0.9ｇ，5mmole）を加え室温でさらに１時
間かきまぜた。反応液に水（100ml）とトルエン
（100ml）を加え、有機層を分離し、水層を２規定
塩酸でPH6.0に調節し、生成物を酢酸エチルで抽
出した。酢酸エチル層を水洗，乾燥後、減圧濃縮
し、残渣をシリカゲルカラムクロマトグラフイー
に付し、酢酸エチルで展開すると（Ｅ＋Ｚ）―
２，２―ジメチル―７―フエニル―７―（３―ピ
リジル）―６―ヘプテエン酸（２―ａ，２―ｂ）
（1.36ｇ，88％）が得られた。
１―法
（Ｅ＋Ｚ）―２，２―ジメチル―７―フエニル
―７―（３―ピリジル）―６―ヘプテン酸（622
mg，2mmole）をヘキサメチルホスホトリアミド
（10ml）に溶解し、水酸化カリウム（120mg）とベ
ンジルブロマイド（350mg）を加え室温でかきま
ぜた。反応終了後水（50ml）を加え、酢酸エチル
で生成物を抽出し、有機層を水洗，乾燥，減圧濃
縮後、残渣をシリカゲルクロマトグラフイーに付
し、酢酸エチル：イソプロピルエーテル（１：
１）で展開するとまず（Ｚ）―２，２―ジメチル
―７―フエニル―７―（３―ピリジル）―６―ヘ
プテン酸ベンジルエステル（２―ｇ）（262mg）が
得られた。ついで(E)―２，２―ジメチル―７―フ
エニル―７―（３―ピリジル）―６―ヘプテン酸
ベンジルエステル（２―ｆ）（282mg）が得られ
た。
２―法
（Ｅ＋Ｚ）―２―フエニル―７―（３―ピリジ
ル）―７―（２―チエニル）―６―ヘプテン酸
（660mg）をエタノール（10ml）に溶解し、氷冷下
に硫化チオニル（450mg）を加え、ついで室温で
５時間放置した。反応液を減圧で濃縮、残渣に水
を加え、炭酸ナトリウムを加えて中和し、生成物
を酢酸エチルで抽出した。有機層を水洗，乾燥，
濃縮して、残渣をシリカゲルクロマトグラフイー
に付し、酢酸：イソプロピルエーテル（２：１）
で展開すると（Ｚ）―２―フエニル―７―（３―
ピリジル）―７―（２―チエニル）―６―ヘプテ
ン酸エチルエステル（２―ｉ）（220mg）が得ら
れ、ついで(E)―２―フエニル―７―（３―ピリジ
ル）―７―（２―チエニル）―６―ヘプテン酸エ
チルエステル（２―ｈ）（235mg）が得られた。
上記Ａ法，Ｂ法，１―法および２―法に準じた
方法に従つて表に示す化合物（２―ａ〜２―
ｎ）を製造した。[Table] Example 2 Method A: Sodium hydride (2.5 g, 60% oil suspension) was washed with hexane to remove the oil content, dried under reduced pressure, dimethyl sulfoxide (25 ml) was added thereto, and the mixture was placed in an argon atmosphere. The mixture was heated at 80° C. for 1 hour to generate dimsyl anion. After cooling the reaction solution to 10°C, 5-carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (8 g,
16 mmole) was added, and the mixture was further stirred at room temperature for 10 minutes. Add 3-benzoylpyridine (3-benzoylpyridine) to this mixture.
A dimethyl sulfoxide solution (5 ml) containing 16 mmole) was added dropwise. After dropping, leave at room temperature for 30 minutes.
Stir for a minute, then add water (50 ml) and shake. Separate the organic layer and PH the aqueous layer with 2N hydrochloric acid.
6.0 and the product was diluted with ethyl acetate (50 ml).
Extracted twice. The ethyl acetate layers were combined, washed with water, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography,
When developed with ethyl acetate, (E)+(Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-
6-heptenoic acid (2-a, 2-b) (2.2 g) was obtained. Method B: Dissolve 5-carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (3 g, 6 mmole) in anhydrous dimethyl sulfoxide (30 ml) under nitrogen atmosphere, and dissolve sodium amide (0.25 g, 64 mmole) and 30 at 25-30℃.
Stir for a minute. 3-benzoylpyridine (0.9 g, 5 mmole) was added to this solution and stirred for an additional hour at room temperature. Water (100 ml) and toluene (100 ml) were added to the reaction solution, the organic layer was separated, the aqueous layer was adjusted to pH 6.0 with 2N hydrochloric acid, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and developed with ethyl acetate to give (E+Z)-
2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2-a, 2-b)
(1.36g, 88%) was obtained. 1-method (E+Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (622
mg, 2 mmole) was dissolved in hexamethylphosphotriamide (10 ml), and potassium hydroxide (120 mg) and benzyl bromide (350 mg) were added and stirred at room temperature. After the reaction was completed, water (50 ml) was added, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and ethyl acetate:isopropyl ether (1:
1), first, (Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid benzyl ester (2-g) (262 mg) was obtained. Then, (E)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid benzyl ester (2-f) (282 mg) was obtained. 2-Method (E+Z)-2-phenyl-7-(3-pyridyl)-7-(2-thienyl)-6-heptenoic acid (660 mg) was dissolved in ethanol (10 ml), and thionyl sulfide ( 450 mg) was added thereto, and then allowed to stand at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, neutralized by adding sodium carbonate, and the product was extracted with ethyl acetate. Wash the organic layer with water, dry it,
After concentration, the residue was subjected to silica gel chromatography using acetic acid:isopropyl ether (2:1).
When expanded, (Z)-2-phenyl-7-(3-
pyridyl)-7-(2-thienyl)-6-heptenoic acid ethyl ester (2-i) (220 mg) was obtained, followed by (E)-2-phenyl-7-(3-pyridyl)-7-(2 -Thienyl)-6-heptenoic acid ethyl ester (2-h) (235 mg) was obtained. The compounds shown in the table (2-a to 2-
n) was produced.
【表】【table】
【表】
実施例 ３―１
（製造法３）
アルゴン雰囲気下ジイソプロピルアミン（0.21
ml，1.46mmole）のテトラヒドロフラン（３ml）
溶液を−60℃に冷却し、これにｎ―ブチルリチウ
ムのヘキサン溶液（1.6M，0.92ml，1.46mmole）
を滴下した。10分間かきまぜたのち、(E)―７―フ
エニル―７―（３―ピリジル）―６―ヘプテエン
酸メチル（360mg，1.22mmole）のテトラヒドロ
フラン（２ml）溶液を滴下し、−60℃〜−70℃で
20分間かきまぜた。ついでヨードメチル（0.12
ml，1.83mmole）を加え、同温度で１時間反応し
た。反応液に飽和塩化アンモニウム水を加え、酢
酸エチルで生成物を抽出し、有機層を水洗，乾燥
（硫酸マグネシウム）後濃縮した。残渣をシリカ
ゲルクロマトグラフイーに付し、イソプロピルエ
ーテル：酢酸エチル（７：３）で展開し、目的と
する(E)―２―メチル―７―フエニル―７―（３―
ピリジル）―６―ヘプテン酸メチル（３―ａ）
（270mg，71.6％）を得た。
上記方法に準じ表―１に示す化合物（３―ａ
〜３―ｐ）を製造した。[Table] Example 3-1 (Production method 3) Diisopropylamine (0.21
ml, 1.46 mmole) of tetrahydrofuran (3 ml)
The solution was cooled to -60°C, and a hexane solution of n-butyllithium (1.6M, 0.92ml, 1.46mmole) was added to it.
was dripped. After stirring for 10 minutes, a solution of methyl (E)-7-phenyl-7-(3-pyridyl)-6-heptenoate (360 mg, 1.22 mmole) in tetrahydrofuran (2 ml) was added dropwise, and the mixture was heated at -60°C to -70°C. in
Stir for 20 minutes. Then iodomethyl (0.12
ml, 1.83 mmole) and reacted at the same temperature for 1 hour. Saturated ammonium chloride water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate), and then concentrated. The residue was subjected to silica gel chromatography and developed with isopropyl ether:ethyl acetate (7:3) to obtain the desired (E)-2-methyl-7-phenyl-7-(3-
Methyl pyridyl)-6-heptenoate (3-a)
(270 mg, 71.6%) was obtained. Compounds shown in Table-1 (3-a
~3-p) was produced.
【表】【table】
【表】
実施例 ３―２
(E)―２―メチル―７―フエニル―７―（３―ピ
リジル）―６―ヘプテエン酸メチル（270mg，
0.87mmole）をメタノール（２ml）に溶解し、水
酸化ナトリウム（300mg）と水（１ml）を加え、
80℃で２時間反応した。反応液を冷却後、水を加
え２規定塩酸を加えてPH5.0に調整し、生成物を
酢酸エチルで抽出した。有機層を水洗，乾燥（硫
酸マグネシウム）後、濃縮し、残渣をシリカゲル
クロマトグラフイーに付し、酢酸エチルで展開
し、目的とする(E)―２―メチル―７―フエニル―
７―（３―ピリジル）―６―ヘプテエン酸（3′―
ａ）（217mg，84％）を得た。
上記方法に準じ表―２に示す化合物（3′―ａ
〜3′―ｑ）を製造した。[Table] Example 3-2 Methyl (E)-2-methyl-7-phenyl-7-(3-pyridyl)-6-heptenoate (270 mg,
Dissolve 0.87 mmole) in methanol (2 ml), add sodium hydroxide (300 mg) and water (1 ml),
The reaction was carried out at 80°C for 2 hours. After cooling the reaction solution, water was added, 2N hydrochloric acid was added to adjust the pH to 5.0, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate), concentrated, and the residue was subjected to silica gel chromatography and developed with ethyl acetate to obtain the desired (E)-2-methyl-7-phenyl-
7-(3-pyridyl)-6-heptenoic acid (3'-
a) (217 mg, 84%) was obtained. According to the above method, the compound shown in Table-2 (3'-a
~3'-q) was produced.
【表】【table】
【表】
／
CH３
7.60(7H),8.45(1H,d
d,J＝1.0 and 3.0Hz),8.52(1H,d,
J＝1.0Hz),8.55(1H)
3′−ｌ ３−Py Ph H CH３(CH２)２C≡C−
CH２− H ３ Ｅ C２４H２７NO２ 0.9(3
H),1.30−1.80(6H),1.90−2.70(7H),6.13(1H),
7.00−7.60(7H),8.4
3(1H),8.53(1H)10.17(1H)
【table】 /
CH3
7.60(7H),8.45(1H,d
d,J＝1.0 and 3.0Hz),8.52(1H,d,
J=1.0Hz),8.55(1H)
3'-l 3-Py Ph H CH 3 (CH 2 ) 2 C≡C-
CH 2 − H 3 E C 24 H 27 NO 2 0.9(3
H),1.30−1.80(6H),1.90−2.70(7H),6.13(1H),
7.00−7.60(7H),8.4
3(1H),8.53(1H)10.17(1H)
【表】
実施例 ４
（製造法４）
アルゴン雰囲気下にジイソプロピルアミン
（0.8ｇ，8mmole）をテトラヒドロフラン（10ml）
に溶かし、−70℃に冷却し、これに1.6Mのｎ―ブ
チルリチウムヘキサン溶液（５ml）を滴下し、５
分間かきまぜた。この反応液に(E)―７―フエニル
―７―（３―ピリジル）―６―ヘプテエン酸メチ
ル（1.2ｇ，4mmole）をテトラヒドロフラン（２
ml）に溶かし同条件下に滴下した。15分後フエニ
ルジスルフイド（１ｇ，5mmole）をヘキサメチ
ルホスホルアミド（１ml）に溶解して同条件下に
滴下した。30分間反応後、２規定塩酸（５ml）を
加え、室温にまで戻してから炭酸水素ナトリウム
水でPHを８に調節し、生成物を酢酸エチルで抽出
した。有機層を水洗，乾燥、濃縮後、残渣をシリ
カゲルクロマトグラフイーに付し、イソプロピル
エーテル：酢酸エチル（１：１）で展開して目的
とする(E)―２―フエニルチオ―７―フエニル―７
―（３―ピリジル）―６―ヘプテエン酸メチル
（４―ｅ）（1.4ｇ，85％）を得た。
上記方法に準じて表に示す化合物（４―ａ〜
４―ｉ）を製造した。[Table] Example 4 (Production method 4) Diisopropylamine (0.8 g, 8 mmole) was added to tetrahydrofuran (10 ml) under an argon atmosphere.
and cooled to -70°C, 1.6M n-butyllithium hexane solution (5ml) was added dropwise to the solution, and 5ml of
Stir for a minute. To this reaction solution was added methyl (E)-7-phenyl-7-(3-pyridyl)-6-heptenoate (1.2 g, 4 mmole) in tetrahydrofuran (2
ml) and added dropwise under the same conditions. After 15 minutes, phenyl disulfide (1 g, 5 mmole) was dissolved in hexamethylphosphoramide (1 ml) and added dropwise under the same conditions. After reacting for 30 minutes, 2N hydrochloric acid (5 ml) was added, the temperature was returned to room temperature, the pH was adjusted to 8 with sodium bicarbonate water, and the product was extracted with ethyl acetate. After washing the organic layer with water, drying, and concentrating, the residue was subjected to silica gel chromatography and developed with isopropyl ether:ethyl acetate (1:1) to obtain the desired product (E)-2-phenylthio-7-phenyl-7.
Methyl -(3-pyridyl)-6-heptenoate (4-e) (1.4 g, 85%) was obtained. Compounds shown in the table (4-a~
4-i) was produced.
【表】
実施例 ５
Ａ法 （製造法５）
アルゴン雰囲気下にジイソプロピルアミン
（0.8ｇ，8mmole）をテトラヒドロフラン（10ml）
に溶かし、−70℃に冷却した。これに1.6Mのｎ―
ブチルリチウムヘキサン溶液（５ml）を滴下し、
５分間かきまぜた。この反応液に７―フエニル―
７―（３―ピリジル）―６―ヘプテエン酸メチル
（1.19ｇ，4mmole）を含むテトラヒドロフラン
（２ml）溶液を滴下した。同反応条件下に15分間
かきまぜたのち、アセトン（0.5ml）を加えさら
に10分間反応を行つた。ついで２規塩酸（５ml）
を加え反応を止め室温にまで上昇させたのち、炭
酸水素ナトリウム水を加えてPHを８とし、生成物
を酢酸エチルで抽出した。有機層を水洗，乾燥後
残渣をシリカゲルクロマトグラフイーに付し、イ
ソプロピルエーテル：酢酸エチル（１：１）で溶
出させると目的とする(E)―２―（１―ヒドロキシ
―１―メチルエチル）―７―フエニル―７―（３
―ピリジル）―６―ヘプテエン酸メチル（５―
ａ）（1.2ｇ）が得られた。
Ｂ法 （製造法６）
(E)―２―（１―ヒドロキシ―１―メチルエチ
ル）―７―フエニル―７―（３―ピリジル）―６
―ヘプテエン酸メチル（0.3ｇ，0.89mmole）を
ジクロロメタン（10ml）に溶かし−10℃に冷却し
た。これにチオニルクロライド（0.15ml）を滴下
し、ついでピリジン（0.4ml）を加え、同反応条
件下に10分間かきまぜた。反応後、炭酸水素ナト
リウム水（５ml）を加え、生成物を酢酸エチルで
抽出した。有機層を常法に従つて処理したのち、
粗生成物をシリカゲルクロマトグラフイーに付
し、イソプロピルエーテル：酢酸エチル（１：
１）で溶出させると目的とする(E)―２―（１―メ
チレンエチル）―７―フエニル―７―（３―ピリ
ジル）―６―ヘプテエン酸メチル（５―ｅ）
（0.25ｇ，70％）が得られた。
上記Ａ法またはＢ法に準じて表Ｖに示す化合物
（５―ａ〜５―ｍ）を製造した。[Table] Example 5 Method A (Production method 5) Diisopropylamine (0.8 g, 8 mmole) was added to tetrahydrofuran (10 ml) under an argon atmosphere.
and cooled to -70°C. In addition to this, 1.6M n-
Add butyl lithium hexane solution (5 ml) dropwise,
Stir for 5 minutes. This reaction solution contains 7-phenyl-
A solution of methyl 7-(3-pyridyl)-6-heptenoate (1.19 g, 4 mmole) in tetrahydrofuran (2 ml) was added dropwise. After stirring for 15 minutes under the same reaction conditions, acetone (0.5 ml) was added and the reaction was continued for an additional 10 minutes. Then 2N hydrochloric acid (5ml)
was added to stop the reaction and the temperature was raised to room temperature, and then sodium bicarbonate water was added to adjust the pH to 8, and the product was extracted with ethyl acetate. After washing the organic layer with water and drying, the residue was subjected to silica gel chromatography and eluted with isopropyl ether:ethyl acetate (1:1) to obtain the desired product (E)-2-(1-hydroxy-1-methylethyl). -7-phenyl-7-(3
-pyridyl)-6-methyl heptenoate (5-
a) (1.2 g) was obtained. Method B (Production method 6) (E)-2-(1-hydroxy-1-methylethyl)-7-phenyl-7-(3-pyridyl)-6
-Methyl heptenoate (0.3 g, 0.89 mmole) was dissolved in dichloromethane (10 ml) and cooled to -10°C. Thionyl chloride (0.15 ml) was added dropwise to this, then pyridine (0.4 ml) was added, and the mixture was stirred for 10 minutes under the same reaction conditions. After the reaction, aqueous sodium hydrogen carbonate (5 ml) was added, and the product was extracted with ethyl acetate. After treating the organic layer according to conventional methods,
The crude product was subjected to silica gel chromatography using isopropyl ether:ethyl acetate (1:
When eluted with 1), the target methyl (E)-2-(1-methyleneethyl)-7-phenyl-7-(3-pyridyl)-6-heptenoate (5-e)
(0.25g, 70%) was obtained. Compounds (5-a to 5-m) shown in Table V were produced according to Method A or Method B above.
【表】【table】
【表】
実験例 １
トロンボキサンA2（TXA2）合成酵素阻害作用
TXA2合成酵素の標品として、ニーデンマン
（Needleman）らの方法（Science193 363，
1976）に従つて調製したインドメサシン処理の馬
血小板ミクロゾーム（インドメサシン処理馬血小
板ミクロゾーム：IPM）を用いた。先づIPMの
50mMトリス緩衝溶液（PH7.5）60μ（蛋白とし
て140μｇ含有）に種々の濃度の薬物を含む溶液
60μを加え、室温で５分間放置した。この混液
の100μを採取し、氷冷下にプロスタグランジ
ンH2（PGH2）30ngを含む緩衝液20μを加え０
℃，５分間放置しトロンボキサンA2（TXA2）生
成させた。トリス緩衝液500μを添加して停止
させた後、その50μを用いてTXA2の安定代謝
物であるトロンボキサンB2（TXB2）のラジオイ
ムノアツセイ〔柴生田ら（Shibouta et.al）
Biochem.Pharmacol28 3601 1979〕による定量
を行つた。薬物未添加群と添加群のTXB2の生成
能の差よりTXA2合成酵素に対する阻害率（％）
を求めた。
以下代表的な化合物についての結果を表に示
す。[Table] Experimental example 1 Thromboxane A 2 (TXA 2 ) synthase inhibitory effect
As a standard of TXA 2 synthase, the method of Needleman et al. (Science 193 363,
Horse platelet microsomes treated with indomethacin (indomethacin-treated horse platelet microsomes: IPM) prepared according to the method (1976) were used. First of all, IPM
Solutions containing various concentrations of drugs in 60μ of 50mM Tris buffer solution (PH7.5) (containing 140μg of protein)
60μ was added and left at room temperature for 5 minutes. Take 100μ of this mixture, add 20μ of a buffer solution containing 30ng of prostaglandin H 2 (PGH 2 ) under ice-cooling, and add 20μ of a buffer containing 30ng of prostaglandin H 2 (PGH 2 ).
The mixture was allowed to stand at 50° C. for 5 minutes to generate thromboxane A 2 (TXA 2 ). After stopping by adding 500μ of Tris buffer, the 50μ was used for radioimmunoassay of thromboxane B 2 (TXB 2 ), a stable metabolite of TXA 2 [Shibouta et.al.
Biochem. Pharmacol 28 3601 1979]. Inhibition rate (%) of TXA 2 synthase based on the difference in TXB 2 production ability between the drug-free group and the drug-added group
I asked for The results for representative compounds are shown in the table below.
【表】【table】
Claims (1)
シ基，低級アルキル基，ハロゲン原子，トリフル
オロメチル基、低級アルケニル基またはメチレン
ジオキシ基を置換基として有していてもよいフエ
ニル基，チエニル基，フリール基，ナフチル基，
ベンゾチエニル基またはピリジル基を、R3は水
素原子，ベンジル基または低級アルキル基を示
す。R4およびR5はいずれか一方が水素原子また
は低級アルキル基で他方はアリールオキシ基また
は置換基を有していてもよい低級脂肪族炭化水素
基，炭素数６以下の脂環族炭化水素基，芳香族基
または式―Ｓ（Ｏ）n――R6（ただし、R6はフエニル
基または低級アルキル基を、ｍは０〜２の整数を
示す。）で示される基を示すか、またはR4とR5が
互いに結合してR4とR5で一個のアルキレン基を
示す。ｎは２〜６の整数を示す。〕で表わされる
置換ビニルカルボン酸誘導体。[Claims] 1. General formula [In the formula, R 1 is a pyridine group, and R 2 is a phenyl group which may have a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylenedioxy group as a substituent. , thienyl group, furyl group, naphthyl group,
R 3 represents a benzothienyl group or a pyridyl group, and R 3 represents a hydrogen atom, a benzyl group or a lower alkyl group. One of R 4 and R 5 is a hydrogen atom or a lower alkyl group, and the other is an aryloxy group, a lower aliphatic hydrocarbon group which may have a substituent, or an alicyclic hydrocarbon group having 6 or less carbon atoms. , an aromatic group or a group represented by the formula -S(O) n --R 6 (wherein R 6 is a phenyl group or a lower alkyl group, and m is an integer of 0 to 2), or R 4 and R 5 are bonded to each other and R 4 and R 5 represent one alkylene group. n represents an integer of 2 to 6. ] A substituted vinyl carboxylic acid derivative represented by
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17691882A JPH0233704B2 (en) | 1982-10-07 | 1982-10-07 | CHIKANBINIRUKARUBONSANJUDOTAI |
| US06/537,862 US4518602A (en) | 1982-10-07 | 1983-09-30 | Vinyl carboxylic acid derivatives, their production and use as inhibitors of thromboxane synthetase |
| CA000438497A CA1246077A (en) | 1982-10-07 | 1983-10-06 | Vinyl carboxylic acid derivatives, their production and use |
| DE8383306078T DE3382247D1 (en) | 1982-10-07 | 1983-10-07 | VINYL CARBONIC ACID DERIVATIVES, THEIR PRODUCTION AND USE. |
| AT83306078T ATE62478T1 (en) | 1982-10-07 | 1983-10-07 | VINYL CARBONIC ACID DERIVATIVES, THEIR PREPARATION AND USE. |
| EP83306078A EP0111997B1 (en) | 1982-10-07 | 1983-10-07 | Vinyl carboxylic acid derivatives, their production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17691882A JPH0233704B2 (en) | 1982-10-07 | 1982-10-07 | CHIKANBINIRUKARUBONSANJUDOTAI |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5967266A JPS5967266A (en) | 1984-04-16 |
| JPH0233704B2 true JPH0233704B2 (en) | 1990-07-30 |
Family
ID=16022035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17691882A Expired - Lifetime JPH0233704B2 (en) | 1982-10-07 | 1982-10-07 | CHIKANBINIRUKARUBONSANJUDOTAI |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0233704B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE163006T1 (en) | 1993-06-01 | 1998-02-15 | Ono Pharmaceutical Co | PENTANIC ACID DERIVATIVES |
| US5672746A (en) | 1994-08-30 | 1997-09-30 | American Biogenetic Sciences, Inc. | Antiproliferative and neurotrophic molecules |
| US6300373B1 (en) | 1993-09-10 | 2001-10-09 | American Biogenetic Sciences, Inc. | Antiproliferative and neurotrophic molecules |
| AU750698B2 (en) * | 1994-08-30 | 2002-07-25 | American Biogenetic Sciences, Inc. | Neurotrophic and antiproliferative compounds |
| KR20010071572A (en) | 1998-06-22 | 2001-07-28 | 아메리칸 바이오지네틱 사이언스, 인코포레이티스 | The Use of Valproic Acid Analog for the Treatment and Prevention of Migraine and Affective illness |
-
1982
- 1982-10-07 JP JP17691882A patent/JPH0233704B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5967266A (en) | 1984-04-16 |
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