JPS6326751B2 - - Google Patents
Info
- Publication number
- JPS6326751B2 JPS6326751B2 JP55069991A JP6999180A JPS6326751B2 JP S6326751 B2 JPS6326751 B2 JP S6326751B2 JP 55069991 A JP55069991 A JP 55069991A JP 6999180 A JP6999180 A JP 6999180A JP S6326751 B2 JPS6326751 B2 JP S6326751B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- butoxy
- melting point
- carried out
- nitro
- 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
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000005606 carbostyryl group Chemical group 0.000 claims description 8
- -1 hydroxy, methoxy, amino, cyclohexyl Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- 238000002844 melting Methods 0.000 description 33
- 230000008018 melting Effects 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- RGHZFRRLCRAWPU-UHFFFAOYSA-N methyl 3-(5-hydroxy-2-nitrophenyl)prop-2-enoate Chemical compound COC(=O)C=CC1=CC(O)=CC=C1[N+]([O-])=O RGHZFRRLCRAWPU-UHFFFAOYSA-N 0.000 description 5
- 150000002828 nitro derivatives Chemical class 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- BSLNASIIJWWYOU-UHFFFAOYSA-N COC(C=CC(C=C(C=C1)OCCCCS(C(C=C2)=CC(Cl)=C2Cl)=O)=C1[N+]([O-])=O)=O Chemical compound COC(C=CC(C=C(C=C1)OCCCCS(C(C=C2)=CC(Cl)=C2Cl)=O)=C1[N+]([O-])=O)=O BSLNASIIJWWYOU-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229940046892 lead acetate Drugs 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- ILAIRHNIGUVLCZ-UHFFFAOYSA-N methyl 3-[2-nitro-5-(4-pyridin-2-ylsulfanylbutoxy)phenyl]prop-2-enoate Chemical compound COC(C=CC1=C(C=CC(=C1)OCCCCSC1=NC=CC=C1)[N+](=O)[O-])=O ILAIRHNIGUVLCZ-UHFFFAOYSA-N 0.000 description 2
- KHYJWJQEQGMQOT-UHFFFAOYSA-N methyl 3-[2-nitro-5-(4-pyridin-2-ylsulfonylbutoxy)phenyl]prop-2-enoate Chemical compound COC(C=CC1=C(C=CC(=C1)OCCCCS(=O)(=O)C1=NC=CC=C1)[N+](=O)[O-])=O KHYJWJQEQGMQOT-UHFFFAOYSA-N 0.000 description 2
- RIJAFJFYYMYUJM-UHFFFAOYSA-N methyl 3-[5-(4-bromobutoxy)-2-nitrophenyl]prop-2-enoate Chemical compound COC(=O)C=CC1=CC(OCCCCBr)=CC=C1[N+]([O-])=O RIJAFJFYYMYUJM-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- SPWWWLCTUNXBRR-UHFFFAOYSA-N 3-(5-hydroxy-2-nitrophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC(O)=CC=C1[N+]([O-])=O SPWWWLCTUNXBRR-UHFFFAOYSA-N 0.000 description 1
- SRGYBRHWRBDUJM-UHFFFAOYSA-N 4-(4-bromobutylsulfanyl)-1,2-dichlorobenzene Chemical compound ClC1=CC=C(SCCCCBr)C=C1Cl SRGYBRHWRBDUJM-UHFFFAOYSA-N 0.000 description 1
- ICFZWESBQTTYOC-UHFFFAOYSA-N 4-(4-bromobutylsulfinyl)-1,2-dichlorobenzene Chemical compound ClC1=CC=C(S(=O)CCCCBr)C=C1Cl ICFZWESBQTTYOC-UHFFFAOYSA-N 0.000 description 1
- UXBIFQZFTVFCDC-UHFFFAOYSA-N 6-(4-pyridin-2-ylsulfonylbutoxy)-1h-quinolin-2-one Chemical compound C1=CC2=NC(O)=CC=C2C=C1OCCCCS(=O)(=O)C1=CC=CC=N1 UXBIFQZFTVFCDC-UHFFFAOYSA-N 0.000 description 1
- FFOAMIRPYWTXQX-UHFFFAOYSA-N 6-(4-quinolin-2-ylsulfinylbutoxy)-1h-quinolin-2-one Chemical compound C1=CC=CC2=NC(S(CCCCOC=3C=C4C=CC(=O)NC4=CC=3)=O)=CC=C21 FFOAMIRPYWTXQX-UHFFFAOYSA-N 0.000 description 1
- XZBRSPKSBBZSCA-UHFFFAOYSA-N 6-[4-(2,5-dichlorophenyl)sulfinylbutoxy]-3,4-dihydro-1h-quinolin-2-one Chemical compound ClC1=CC=C(Cl)C(S(=O)CCCCOC=2C=C3CCC(=O)NC3=CC=2)=C1 XZBRSPKSBBZSCA-UHFFFAOYSA-N 0.000 description 1
- RDJSMZHIMWPJCI-UHFFFAOYSA-N 6-[4-(3,4-dichlorophenyl)sulfinylbutoxy]-1h-quinolin-2-one Chemical compound C1=C(Cl)C(Cl)=CC=C1S(=O)CCCCOC1=CC=C(NC(=O)C=C2)C2=C1 RDJSMZHIMWPJCI-UHFFFAOYSA-N 0.000 description 1
- PPABMMXAJNWWHO-UHFFFAOYSA-N 6-[4-(3,5-ditert-butyl-4-hydroxyphenyl)sulfinylbutoxy]-1h-quinolin-2-one Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(S(=O)CCCCOC=2C=C3C=CC(=O)NC3=CC=2)=C1 PPABMMXAJNWWHO-UHFFFAOYSA-N 0.000 description 1
- LOVABRWXJRAPRS-UHFFFAOYSA-N 6-[4-(4-chlorophenyl)sulfinylbutoxy]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC(Cl)=CC=C1S(=O)CCCCOC1=CC=C(NC(=O)CC2)C2=C1 LOVABRWXJRAPRS-UHFFFAOYSA-N 0.000 description 1
- NMUWLPZCRYURDW-UHFFFAOYSA-N 6-[4-(4-cyclohexylphenyl)sulfinylbutoxy]-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=CC2=CC=1OCCCCS(=O)C(C=C1)=CC=C1C1CCCCC1 NMUWLPZCRYURDW-UHFFFAOYSA-N 0.000 description 1
- YKKCAQSYVSZODS-UHFFFAOYSA-N 6-[4-(4-phenylphenyl)sulfinylbutoxy]-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=CC2=CC=1OCCCCS(=O)C(C=C1)=CC=C1C1=CC=CC=C1 YKKCAQSYVSZODS-UHFFFAOYSA-N 0.000 description 1
- KXXKYHLGSYNQNH-UHFFFAOYSA-N 6-[4-(4-tert-butylphenyl)sulfinylbutoxy]-1h-quinolin-2-one Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)CCCCOC1=CC=C(NC(=O)C=C2)C2=C1 KXXKYHLGSYNQNH-UHFFFAOYSA-N 0.000 description 1
- NHKIFYDGOCNNEL-UHFFFAOYSA-N 6-[4-(benzenesulfinyl)butoxy]-1h-quinolin-2-one Chemical compound C=1C=C2NC(=O)C=CC2=CC=1OCCCCS(=O)C1=CC=CC=C1 NHKIFYDGOCNNEL-UHFFFAOYSA-N 0.000 description 1
- KSUKFRAZFFLINQ-UHFFFAOYSA-N 6-[4-(benzenesulfinyl)butoxy]-4-methyl-1h-quinolin-2-one Chemical compound C1=C2C(C)=CC(=O)NC2=CC=C1OCCCCS(=O)C1=CC=CC=C1 KSUKFRAZFFLINQ-UHFFFAOYSA-N 0.000 description 1
- AARFVSSGWMEZIE-UHFFFAOYSA-N 6-[4-(benzenesulfinyl)butoxy]-5-bromo-1h-quinolin-2-one Chemical compound C1=CC=2NC(=O)C=CC=2C(Br)=C1OCCCCS(=O)C1=CC=CC=C1 AARFVSSGWMEZIE-UHFFFAOYSA-N 0.000 description 1
- ZWSJTKSIRMBTRY-UHFFFAOYSA-N CCC(COC(=CC1=CC(=CC=C1)S(=O)C2=CC(=C(C=C2)Cl)Cl)C(=O)OC)[N+](=O)[O-] Chemical compound CCC(COC(=CC1=CC(=CC=C1)S(=O)C2=CC(=C(C=C2)Cl)Cl)C(=O)OC)[N+](=O)[O-] ZWSJTKSIRMBTRY-UHFFFAOYSA-N 0.000 description 1
- RWJPWMCCTIJSSR-UHFFFAOYSA-N COC(=O)C=CC1=C(C=CC(=C1)OCCCCS(=O)C2=CC(=C(C=C2)Cl)Cl)N Chemical compound COC(=O)C=CC1=C(C=CC(=C1)OCCCCS(=O)C2=CC(=C(C=C2)Cl)Cl)N RWJPWMCCTIJSSR-UHFFFAOYSA-N 0.000 description 1
- CRXZROMIWRFKST-UHFFFAOYSA-N COC(=O)C=CC1=C(C=CC(=C1)OCCCCSC2=CC(=C(C=C2)Cl)Cl)[N+](=O)[O-] Chemical compound COC(=O)C=CC1=C(C=CC(=C1)OCCCCSC2=CC(=C(C=C2)Cl)Cl)[N+](=O)[O-] CRXZROMIWRFKST-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 240000005499 Sasa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 244000172533 Viola sororia Species 0.000 description 1
- BYHQZKJXCMXMFX-UHFFFAOYSA-N [Na].NN Chemical compound [Na].NN BYHQZKJXCMXMFX-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
Description
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The object of the present invention is to This is a new method for producing carbostyril derivatives. In the general formula, W represents a vinylene group, ethylene group or 2-methyl-vinylene group, and D
represents a linear or branched alkylene group having 2 to 6 carbon atoms, m represents 1,
R 1 represents a hydrogen atom, and R 2 represents a cycloalkyl group, phenyl group, naphthyl group, phenylalkyl group, pyridyl group, or quinolyl group having 3 to 6 carbon atoms (however, the above aromatic nucleus alkyl, hydroxy, methoxy, amino, cyclohexyl, phenyl or halogen atom), and R 3 and R 4 may be the same or different and may be substituted by a hydrogen atom or a halogen atom or an alkyl group. represent Compounds of the general formula have useful pharmacological properties. They not only have a positive inotropic effect but also particularly antithrombotic activity. Pharmacological tests were conducted on the following compounds for this antithrombotic effect: (Compound according to the method of the present invention) A=6-(4-phenylsulfinylbutoxy)-
3,4-dihydrocarbostyryl B=6-[4-(2-pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl C=6-(2-phenylsulfinyl-ethoxy)
-3,4-dihydrocarbostyryl D=6-(4-benzylsulfinyl-butoxy)
-3,4-dihydrocarbostyryl E=6-[4-(4-chlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl F=6-(4-cyclohexylsulfinyl-butoxy)- 3,4-dihydrocarbostyryl G=6-[4-(2-naphthylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl H=6-[4-(2-methoxyphenylsulfinyl)- butoxy]-3,4-dihydrocarbostyryl I = 6-(4-phenylsulfinyl-butoxy)
-Carbostyryl K=6-[4-(4-hydroxy-3,5-di-
tert-butyl-phenylsulfinyl)-butoxy]carbostyryl L = 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]carbostyryl M = 4-methyl-6-(4-phenylsulfinyl) rufinyl-butoxy)-carbostyryl N=6-[4-(2,5-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl O=6-[4-(3,4-dichloro phenylsulfinyl)-butoxy]-3,4-dihydro-carbostyryl P=6-[4-(3,4-dichloro-phenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl Q=6 -[4-(2-pyridylsulfinyl)-butoxy]carbostyryl R=4-methyl-6-[4-(2-pyridylsulfinyl)-butoxy]carbostyryl S=6-[4-(4 -cyclohexyl-phenylsulfinyl)-butoxy]carbostyryl T=6-[4-(4-biphenylylsulfinyl)
-butoxy]carbostyryl U=6-[4-(2-quinolylsulfinyl)-butoxy]carbostyryl V=6-[4-(4-tert, butyl-phenylsulfinyl)-butoxy]-3 ,4-dihydrocarbostyryl W=6-[4-(4-biphenylylsulfinyl)
-butoxy]-3,4-dihydrocarbostyryl X=6-[2-(phenylsulfinylmethyl)-
benzyloxy]-3,4-dihydrocarbostyryl Y = 5-nitro-6-(4-phenylsulfinyl-butoxy)-carbostyryl Z = 6-(6-phenylsulfinyl-hexoxy)-3,4 -dihydrocarbostyryl (control compound) AA=6-(3-ethylthio-propoxy)-3,
4-dihydrocarbostyryl BB=6-(3-ethylsulfonyl-propoxy)
-3,4-dihydrocarbostyryl CC=6-(3-ethylthio-propoxy)-carbostyryl DD=6-(3-ethylsulfonylpropoxy)-
Calbostyril. Test method: Determination of platelet aggregation according to the method of Born and Cross (J. Physiol. Vol. 170, p. 397 (1964)) Platelet aggregation was determined in platelet-rich blood glands of healthy individuals. The decrease in optical density was measured and recorded spectrophotometrically after addition of adenosine-diphosphate or collagen. The aggregation rate was calculated from the slope angle of this concentration curve (Vmax). Optical density is indicated as the point on the curve where the maximum amount of light is transmitted (OD). The EC 50 column in the table indicates optical density. Select a small but sufficient amount of collagen to cause irreversible aggregation. Approximately 0.01 ml of collagen solution was added to 1 ml of platelet-rich blood to induce maximum aggregation (commercially available collagen from Hormonchemie, Myuncheng). The amount of adenosine-diphosphate (ADP) was selected to produce only the first phase of the BORN curve. The required amount of ADP was approximately 1.10 -6 mol/. Boehringer
Commercially available ADP from Mannheim was used. The amount of compound that causes 50% inhibition of platelet aggregation was determined from the graph (EC 50 )
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ããŒã«ããïŒååçµæ¶ïŒ [Table] It has been recognized that carbostyril of the general formula can also be prepared according to the following method. General formula appropriately formed in the reaction mixture (In the formula, D, W, R 1 to R 4 and m are the same as defined above, and Z represents a nucleophilically convertible group such as a hydroxy group, a halogen atom, alkoxy, aryloxy or aralkoxy group) Cyclization of the compound. The cyclization is carried out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride as appropriate, in a solvent such as glacial acetic acid, tetrahydrofuran, dioxane, chloroform, triene, ethanol or in an excess of condensing agent used. at elevated temperatures, for example between 50 and 200°C, but preferably
Preferably it is carried out at a temperature between 80 and 150°C.
However, the reaction can also be carried out without solvent and/or condensing agent. It is not necessary to isolate the compound of the general formula and use it as is as a starting material. This compound can be prepared in situ from the corresponding nitro compound by, for example, reducing the nitro group with hydrogen in the presence of a hydrogenation catalyst such as palladium-charcoal, palladium-calcium carbonate or palladium-calcium carbonate plus lead acetate (Rindler's catalyst). Thus, by reduction with metals such as iron, tin or zinc in the presence of acids, salts such as iron()-sulfate, zinc()-chloride, chromium()-chloride or dithionite can be prepared. by reduction with sodium hydrazine or by reduction with hydrazine in the presence of Raney-nickel. When m represents 1 in the corresponding nitro compound, the reduction of the nitro group is carried out with an equivalent amount of the necessary reducing agent.
For example with metal salts such as iron-()-sulfate, tin-()-chloride, chromium-()-chloride or sodium dithionite or in the presence of a hydrogenation catalyst deactivated with hydrogen, e.g. palladium
It is appropriate to conduct this in the presence of calcium carbonate + lead acetate. If, for example, this reduction is carried out in the presence of palladium-charcoal, the sulfoxide groups will also be partially reduced. Furthermore, if W in the corresponding nitro compound represents a vinylene group, this group can be converted into the corresponding ethylene group by hydrogenation, in particular the reduction catalytically with activated hydrogen, for example palladium- This is the case when carried out with hydrogen in the presence of charcoal. The compounds of the general formula used as starting materials are partly known from the literature and they can be obtained by known methods. That is, compounds of the general formula are obtained by reducing the corresponding nitro compounds, which in turn are obtained by alkylating the corresponding 2-nitro-5-hydroxy compounds with the corresponding α,Ï dihalogen alkanes, and then by reducing the corresponding nitro compounds. by reaction with a mercapto compound and optionally subsequent oxidation with hydrogen peroxide. The following examples illustrate the invention. Example 1 (Reference example) 6-[4-(2-pyridylsulfonyl)-butoxy]-3,4-dihydro-carbostyryl (a) 2-nitro-5-hydroxy-cinnamic acid methyl ester 21.0 g of 2- Nitro-5-hydroxy-cinnamic acid [S. N. Chakravertei (SN
Chakravarti) and PLNRao, Chem. Sasa. (Chem.Soc.)
1938, 172] in 200 ml of methanol.
Add 86 ml of thionyl chloride to this solution while stirring.
Add dropwise within 45 minutes, at a temperature of 36°C.
It can be raised to After stirring for a further 25 minutes, the reaction mixture is cooled on an ice bath to obtain 18.6 g of 2-nitro-5-hydroxy-cinnamate methyl-ester. Melting point: 201-203â. (b) 2-Nitro-5-bromobutoxy-cinnamic acid methyl ester 22.3 g 2-nitro-5-hydroxy-cinnamic acid methyl ester, 59.7 ml 1,4-dibromobutane and 13.8 g in 200 ml dimethyl sulfoxide. A mixture of 15 g of potassium carbonate at room temperature
Stir for an hour. After adding 800 ml of water, the reaction mixture is extracted with chloroform and, after evaporation of the solvent, 31.7 g of 2-nitro-5-brombutoxy-cinnamate methyl ester are isolated. Melting point: 60.5-63â. (c) 2-Nitro-5-[4-(2-pyridylmercapto)-butoxy]-cinnamic acid methyl ester A mixture of 5 g potassium carbonate and 4.0 g 2-mercaptopyridine in 100 ml dimethyl sulfoxide for 60 minutes. After stirring, add 10.75g of 2
-Nitro-5-bromo-butoxy-cinnamic acid methyl ester is added and the mixture is stirred at room temperature for 18
Stir for an hour. 400 ml of water are added and the oily reaction product is isolated by ether extraction. Yield: 11.0g (94.2% of theory). (d) 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamate methyl ester 7.0 g of 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-cinnamate methyl ester Dissolve the acid methyl ester in 70 ml of acetic acid. 35% of 5.0ml
Hydrogen peroxide is added and the mixture is kept at room temperature for 3 days. After distilling off the glacial acetic acid, the reaction product is recrystallized from chloroform/methanol. Yield: 3.5g (46.2% of theory). Melting point: 118-121â. (e) 6-[4-(2-pyridylsulfonyl)-butoxy]-3,4-dihydrocarbostyryl 2.1 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamic acid Dissolve methyl ester in 20ml of glacial acetic acid and add 0.5g of this
hydrogenation using 10% palladium on charcoal at 3 bar hydrogen pressure at room temperature. After distilling off the glacial acetic acid,
The residue is refluxed with 20 ml of concentrated hydrochloric acid for 4 hours. The reaction product was neutralized with 2N sodium hydroxide solution,
and extract with chloroform. The evaporation residue is recrystallized from xylene. Yield: 1.06g (55.6% of theory). Melting point: 121-123â. Example 2 (Reference example) 6-[4-(2-pyridylsulfonyl)-butoxy]-carbostyryl 2.0 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamate methyl ester and 3.0 g of sodium dithionite.
Reflux in 20 ml water and 10 ml ethanol for 4 hours to obtain a clear solution. The reaction mixture is evaporated and refluxed for 3 hours with 20 ml of concentrated hydrochloric acid. 2n
After neutralization with sodium hydroxide solution, the reaction product is extracted with ether and recrystallized from xylene by addition of a small amount of dimethylformamide. Yield: 0.5g (29% of theory) Melting point: 176-179°C. This material can be obtained in a similar manner using a Lindlar catalyst (palladium partially inactivated by lead) instead of sodium dithionite as reducing agent. Thereby, only the nitro group is reduced, and 6-[4-(2-pyridylsulfonyl)
-butoxy]-carbostyril is obtained after treatment with concentrated hydrochloric acid. Example 3 (Reference example) 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-carbostyryl 4.5 g of 2-nitro-5-[4-(3,4-dichlorophenylmercapto)- butoxy]-cinnamic acid methyl ester (melting point: 91-92â, 2-nitro-
5-Hydroxy-cinnamate methyl-ester and 4
-(3,4-dichlorophenylmercapto)-butyl-bromide) is refluxed for 4 hours in a mixture of 50 ml of ethanol and 50 ml of water. After removing the solvent, the residue is refluxed for 4 hours with 100 ml of concentrated hydrochloric acid. The crystalline material obtained is filtered by absorption and recrystallized from xylene. Yield: 1.2g (31% of theory). Melting point: 144â. Example 4 6-[4-(3,4-dichlorophenyl-sulfinyl)-butoxy]-carbostyryl(a) 2-nitro-5-[4-(3,4-dichlorophenyl-sulfinyl)-butoxy]- Cinnamic acid methyl ester 11.2 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester are dissolved in 150 ml of dimethyl sulfoxide. This solution is mixed with 9.2 g of anhydrous potassium carbonate and stirred for 15 minutes.
16.5 g of 4-(3,4-dichlorophenylsulfinyl)-butyl bromide are added and the mixture is stirred for 40 hours at room temperature. reaction mixture
Dilute with 1000 ml of water and extract with a mixture of 200 ml of chloroform and 100 ml of methanol.
Evaporation of the organic solvent yields an oily residue,
On treatment with ether it is obtained in crystalline form. Yield: 13g (57% of theory). Melting point: 78-81°C (b) 2-Amino-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamate methyl ester 4.2 g of 2-nitro-5-[4 -(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamate methyl ester was prepared in 100 ml of methanol with 0.5 g of Lindlar's catalyst (palladium partially deactivated by lead acetate). Hydrogenate with calcium carbonate) at a hydrogen pressure of 3 bar for 12 hours at room temperature. After removing the catalyst, the solvent is evaporated and the resinous dark residue is used directly in the next reaction. (c) 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl The above-mentioned 2-amino-5-[4-(3,4-dichlorophenylsulfinyl)- [butoxy]-cinnamic acid methyl ester is heated to boiling for 3 hours with 80 ml of 5N hydrochloric acid and filtered hot. After cooling the filtrate, colorless crystals are obtained. Yield: 2.1 g (56% of theory). Melting point: 191-192â. In the above reaction method, if iron powder and 80% acetic acid are used as the ring group of 2-nitro-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamate methyl ester, too,
Furthermore, 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl is obtained as a reaction product. Example 5 2.3 g of 2-nitro-5-(3,4-dichlorophenylsulfinyl)-butoxy-cinnamic acid methyl ester are dissolved in 20 ml of glacial acetic acid as in Example 5b.
Hydrogenation is carried out using 0.2 g of palladium on charcoal at a hydrogen pressure of 3 bar for 7 hours at room temperature. After removing the catalyst, the glacial acetic acid was distilled off and the residue was poured into 40 ml of
Heat with 5N hydrochloric acid until boiling for 1 hour.
The reaction mixture is extracted with a small amount of chloroform and chromatographed on thin layer plates (Merck silica gel 60F 254 ) with ethylene chloride/methanol 9:1. The obtained compound
Confirm by spraying with UV-light and iodine spray. Rf value: 0.30: 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl. Blue-violet color with iodine spray. Rf value: 0.42: 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-carbostyryl.
Iodine spray turns orange-yellow at first, then gradually gray-
Violet. Rf value: 0.45: 6-[4-(3,4-dichlorophenyl-sulfinyl)-butoxy]-3,4-dihydro-carbostyryl. Strong orange-yellow color with iodine spray. Rf value: 0.57: 6-[4-(3,4-dichlorophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyryl. Pale egg yellow with iodine spray. The following compounds are prepared analogously to the above examples. 6-(4-phenylsulfinylbutoxy)-
3,4-dihydrocarbostyryl melting point: 144.5-145.5°C 6-[4-(2-pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl melting point: 144.5-146°C. 6-(2-phenylsulfinyl-ethoxy)-
3,4-dihydro-carbostyryl Melting point: 171-172°C 6-(4-benzylsulfinyl-butoxy)-
3,4-dihydrocarbostyryl Melting point: 141.5-142â 6-[4-(4-chlorophenylsulfinyl)
-butoxy]-3,4-dihydrocarbostyril melting point: 148-149.5°C 6-(4-cyclohexylsulfinyl-butoxy)-3,4-dihydrocarbostyryl melting point: 153-155.5°C 6-[4-(2 -naphthylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl melting point: 147.5-148.5°C 6-[4-(2-methoxyphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl melting point: 130.5-133â 6-(4-phenylsulfinyl-butoxy)-
Carbostyril melting point: 181-182.5â 6-[4-(4-hydroxy-3,5-di-tert
-butyl-phenylsulfinyl)-butoxy]-
Carbostyril melting point: 192-194â 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyril melting point: 191-196â 4-methyl-6-(4-phenylsulfinyl -butoxy)-carbostyril melting point: 167-168â 6-[4-(2,5-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril melting point: 185-186â 6-[4 -(2-naphthyl-sulfinyl)-butoxy]-3,4-dihydrocarbostyryl Melting point: 147.5-148.5°C 6-[4-(4-biphenylylsulfinyl)-
Butoxy]-carbostyril melting point: 196-197â 6-[4-(2-quinolylsulfinyl)-butoxy]-carbostyril melting point: 197-198â 6-[4-cyclohexylsulfinyl)-butoxy] -Carbostyril melting point: 169-170â 5-bromo-6-(4-phenylsulfinyl-butoxy)-carbostyril melting point: 190-191â 6-[4-(3,5-dibromo-4-aminophene) 6-[4-(3,5-dibromo-4-aminophenylsulfinyl)-butoxy]-carbostyryl Melting point: 205 -207â 6-[4-(4-cyclohexylphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl Melting point: 155-157â 6-[4-(4-cyclohexylphenylsulfinyl)-butoxy ]-Carbostyril melting point: 188-190â 6-[4-(4-tert-butylphenylsulfinyl)-butoxy]-carbostyril melting point: 164-166â 6-[4-(3,4-dichlor Phenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl Melting point: 106.5-108°C Melting point: 148-149°C (recrystallized once from toluene and once from ethanol)
Claims (1)
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åã¯å¡©åããªãã«ã®ååšäžã«è¡ãªãç¹èš±è«æ±ã®ç¯
å²ç¬¬ïŒé ã®æ¹æ³ã ïŒ åå¿ã50ãš200âã®éã®æž©åºŠã§ã奜ãŸããã¯
80ãš150âãšã®éã®æž©åºŠã§è¡ãªããç¹èš±è«æ±ã®ç¯
å²ç¬¬ïŒé ããã³ç¬¬ïŒé ã®ããããäžé ã®æ¹æ³ã ïŒ åå¿ã溶åªäžã§è¡ãªããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒ
é ã第ïŒé ããã³ç¬¬ïŒé ã®ããããäžé ã®æ¹æ³ã[Claims] 1. General formula [In the formula, W represents a vinylene group, ethylene group or 2-methyl-vinylene group, D represents a linear or branched alkylene group having 2 to 6 carbon atoms, m represents 1, R 1 represents a hydrogen atom, and R 2 represents a cycloalkyl group, phenyl group, naphthyl group, phenylalkyl group, pyridyl group, or quinolyl group having 3 to 6 carbon atoms (however, the above aromatic nucleus is an alkyl group). , hydroxy, methoxy, amino, cyclohexyl, phenyl or halogen atoms), and R 3 and R 4 may be the same or different and represent a hydrogen atom, a halogen atom or an alkyl group ] A method for producing a carbostyryl derivative represented by the general formula (wherein D, W, R 1 to R 4 and m are the same as defined above, and Z represents a nucleophilically exchangeable group) is characterized by cyclizing the compound represented by Production method. 2. A process according to claim 1, wherein the reaction is carried out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride. 3. The reaction is carried out at a temperature between 50 and 200°C, preferably
3. The method of any one of claims 1 and 2, carried out at a temperature between 80 and 150<0>C. 4 Claim 1 in which the reaction is carried out in a solvent
2. The method of any one of paragraphs 2 and 3.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792928583 DE2928583A1 (en) | 1979-07-14 | 1979-07-14 | Substd. alkoxy-carbostyril derivs prodn. - e.g. by cyclising 2-carboxyethyl-1-aminobenzene derivs., useful as antithrombotic and positive inotropic agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5616470A JPS5616470A (en) | 1981-02-17 |
| JPS6326751B2 true JPS6326751B2 (en) | 1988-05-31 |
Family
ID=6075786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6999180A Granted JPS5616470A (en) | 1979-07-14 | 1980-05-26 | Novel manufacture of carbostyril derivative |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5616470A (en) |
| DE (1) | DE2928583A1 (en) |
| DK (1) | DK150156C (en) |
| FI (1) | FI70408C (en) |
| NO (1) | NO154131C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI77852C (en) * | 1981-02-17 | 1989-05-10 | Otsuka Pharma Co Ltd | Process for the preparation of novel, such as cardiac drugs, useful s unsubstituted amide and (saturated heterocycle) carbonyl carbostyril derivatives. |
| US4442111A (en) * | 1981-07-25 | 1984-04-10 | Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung | Antithrombotic sulfimino and sulfoximino indolinones-2 |
| AU532361B2 (en) * | 1981-09-01 | 1983-09-29 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| DK167187A (en) * | 1986-04-02 | 1987-10-03 | Otsuka Pharma Co Ltd | CARBOSTYRIC DERIVATIVES AND SALTS THEREOF, PROCEDURE FOR THE PREPARATION OF SUCH COMPOUNDS AND MEDICINAL CONTAINING THESE |
| KR940000785B1 (en) * | 1986-04-02 | 1994-01-31 | ì€ì€ì°ê¹ìžìŽìŒêŸž ê°ë¶ìëŒê°ìŽì€ | Process for the preparation of carbostyril derivatives and salts thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5321176A (en) * | 1976-08-09 | 1978-02-27 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivatives |
-
1979
- 1979-07-14 DE DE19792928583 patent/DE2928583A1/en not_active Withdrawn
- 1979-08-03 FI FI792426A patent/FI70408C/en not_active IP Right Cessation
- 1979-08-15 DK DK342079A patent/DK150156C/en not_active IP Right Cessation
- 1979-08-15 NO NO792659A patent/NO154131C/en unknown
-
1980
- 1980-05-26 JP JP6999180A patent/JPS5616470A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5321176A (en) * | 1976-08-09 | 1978-02-27 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DK150156C (en) | 1987-10-12 |
| NO154131C (en) | 1986-07-23 |
| NO792659L (en) | 1981-01-15 |
| FI70408B (en) | 1986-03-27 |
| FI70408C (en) | 1986-09-19 |
| NO154131B (en) | 1986-04-14 |
| FI792426A (en) | 1981-01-15 |
| DE2928583A1 (en) | 1981-01-29 |
| DK342079A (en) | 1981-01-15 |
| DK150156B (en) | 1986-12-22 |
| JPS5616470A (en) | 1981-02-17 |
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