CN1040025A - 新的四氢苯并吲哚丙酸磺酰胺的制备 - Google Patents
新的四氢苯并吲哚丙酸磺酰胺的制备 Download PDFInfo
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- CN1040025A CN1040025A CN89105633A CN89105633A CN1040025A CN 1040025 A CN1040025 A CN 1040025A CN 89105633 A CN89105633 A CN 89105633A CN 89105633 A CN89105633 A CN 89105633A CN 1040025 A CN1040025 A CN 1040025A
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- Prior art keywords
- formula
- alkyl
- aryl
- hydrogen
- trifluoromethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 tetrahydrobenzindolepropionic acid sulfonamide Chemical class 0.000 title claims description 94
- 229940124530 sulfonamide Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 13
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- OZEDQORHGRJQAF-UHFFFAOYSA-N 1h-indole-7-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CC2=C1NC=C2 OZEDQORHGRJQAF-UHFFFAOYSA-N 0.000 claims abstract 4
- 230000007062 hydrolysis Effects 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 150000002475 indoles Chemical class 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 16
- 229910052782 aluminium Inorganic materials 0.000 description 16
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 13
- 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000011737 fluorine Substances 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 239000011888 foil Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 8
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- GOLXRNDWAUTYKT-UHFFFAOYSA-N 3-(1H-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(CCC(=O)O)=CNC2=C1 GOLXRNDWAUTYKT-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 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 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003461 sulfonyl halides Chemical class 0.000 description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- MQJXSROJQOIHDI-UHFFFAOYSA-N 2-(2-methyl-1h-indol-3-yl)butanedioic acid Chemical compound C1=CC=C2C(C(CC(O)=O)C(O)=O)=C(C)NC2=C1 MQJXSROJQOIHDI-UHFFFAOYSA-N 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 150000003385 sodium Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ILROLYQPRYHHFG-UHFFFAOYSA-N 1-$l^{1}-oxidanylprop-2-en-1-one Chemical group [O]C(=O)C=C ILROLYQPRYHHFG-UHFFFAOYSA-N 0.000 description 1
- RYMYQAMZUWJAEO-UHFFFAOYSA-N 1h-indole-2-sulfonamide Chemical compound C1=CC=C2NC(S(=O)(=O)N)=CC2=C1 RYMYQAMZUWJAEO-UHFFFAOYSA-N 0.000 description 1
- WVBRUJBXXAPCHY-UHFFFAOYSA-N 2-(5-fluoro-2-methyl-1h-indol-3-yl)butanedioic acid Chemical compound C1=C(F)C=C2C(C(CC(O)=O)C(O)=O)=C(C)NC2=C1 WVBRUJBXXAPCHY-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- YEYKMVJDLWJFOA-UHFFFAOYSA-N 2-propoxyethanol Chemical compound CCCOCCO YEYKMVJDLWJFOA-UHFFFAOYSA-N 0.000 description 1
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- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了式(I)新的化合物的制备方法,该方法是将四氢-1-苯并[c,d]吲哚磺酰胺与丙烯腈反应,然后水解,式(I)化合物可用于抑制血小板凝聚。
Description
本发明涉及新的四氢-1-苯并[c,d]吲哚丙酸磺酰胺及其制备方法和药物用途。
已公开了环烷烃并[1,2-d]吲哚和N-二氢吲哚基乙基磺酰胺具有抑制血小板凝聚的作用(参见DE-A3,631,824和3,613,623)。
现在,本文公开式(Ⅰ)所示新的四氢-1-苯并[c,d]吲哚丙酸磺酰胺及其盐,式(Ⅰ)为
式中
R1为氢,卤素,三氟甲基,羧基,烷氧羰基或-S(O)nR3,NR4R5或OR6,其中
R3是烷基或芳基,
R4R5是相同的或不同,它们各自为氢,烷基,芳基或芳烷基,
R6是氢,烷基,芳基或芳烷基或三氟甲基,
n是数字0,1或2,
或
R1为任意被羧基,烷氧羰基,卤素,羟基,烷氧基,烷硫基或氰基取代的烷基,链烯基或环烷基,
R2为含有6-10个碳原子的芳基,该芳基可被下述相同或不同的基团单至三取代,这些基团是卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,烷基,羧基烷基,烷基羰烷基,烷氧基,烷硫基,羟基,烷氧羰基,苯氧基,苄氧基,苄硫基或-NR4R5,其中R4和R5的定义同前,
R7为氢,烷基或环烷基。
本发明的化合物可存在各种立体化学异构体,本发明既涉及单一异构体也涉及它们的混合物。
本发明的化合物也可以以其盐的形式存在,本文所述的盐通常指与有机或无机碱形成的盐。
就本发明而言,生理学上可接受的盐是优选的盐。生理学上可接受的盐可以是具有游离羧基的本发明化合物的金属盐或铵盐。特别优选的盐是。例如钠盐,钾盐,镁盐或钙盐及铵盐,铵盐由下列物质衍生而得,即氨或有机胺如乙胺,二或三乙胺,二或三乙醇胺,二环己基胺,二甲氨基乙醇,精氨酸或乙二胺。
本发明物质具有惊人的抑制血小板凝聚的作用,可用于治疗人和动物的疾病。
烷基一般代表含有1-12碳原子的直链或支链烃基。优选的烷基是含1-6个碳原子的低级烷基,值得一提的实例是甲基,乙基,丙基,异丙基,丁基,异丁基,戊基,异戊基,己基,异己基,庚基,异庚基,辛基和异辛基。
链烯基一般代表含有2-12个碳原子和一个或多个(最好是一个或两个)双键的直链或支链烃基,优选的链烯基是含有2-6个碳原子和一个双键的低级链烯基,特别优选的是含有2-6个碳原子和一个双键的链烯基。值得一提的实例是乙烯基,丙烯基,异丙烯基,丁烯基,异丁烯基,戊烯基,异戊烯基,己烯基,异己烯基,庚烯基,异庚烯基,辛烯基和异辛烯基。
环烷基一般代表含有5-8个碳原子的环烃基。优选的环烷基是环丙基,环戊基和环己基。值得一提的是环戊基,环己基,环庚基和环辛基。
烷氧基一般代表通过一个氧原子连接的含有1-12个碳原子的直链或支链烃基。含有1至6个碳原子的低级烷氧基是优选基团,含有1-4个碳原子的烷氧基是特别优选的基团。值得一提的实例是甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,戊氧基,异戊氧基,己氧基,异己氧基,庚氧基,异庚氧基,辛氧基和异辛氧基。
烷硫基一般代表通过一个硫原子连接的的直链或支链烃基。含有1-6个碳原子的低级烷硫基是优选的基团,含有1-4个碳原子的烷硫基是特别优选的基团。值得一提的实例是甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,戊硫基,异戊硫基,己硫基,异己硫基,庚硫基,异庚硫基,辛硫基和异辛硫基。
芳基一般代表含6-12个碳原子的芳香族基团,优选的芳基是苯基,萘基和联苯基。
芳烷基一般代表含7-14个碳原子的连接有亚烷基的芳基。优选的芳烷基是脂肪族部分含1-6个碳原子,而芳香族部分含6-12个碳原子的芳烷基。值得一提的是下述芳烷基:苄基,萘甲基,苯乙基和苯丙基。
烷氧羰基可用下列式代表
式中烷基代表含有1-8个碳原子的直链或支链烃基。烷基部分含有1至约6个碳原子的低级烷氧羰基是优选的基团,烷基部分含有1-4个碳原子的烷氧羰基是特别优选的基团。值得一提的实例是下列羰基:异丙氧羰基,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基或异丁氧羰基。
羧基烷基一般代表含1-12个碳原子并被羧基取代的直链或支链烃基。含1-6个碳原子的羧基低级烷基是优选的基团。值得一提的实例是:羧甲基,1-羧基乙基,1-羧基丙基,1-羧基丁基,1-羧基戊基,1-羧基己基,2-羧基乙基,2-羧基丙基,2-羧基丁基,3-羧基丙基,3-羧基丁基,4-羧基丁基,2-羧基-1-丙基,或1-羧基-1-丙基。
烷氧羰基一般代表含1-12个碳原子并被一个烷氧羰基取代的直链或支链烃基。烷氧羰基部分各含有1至约6个碳原子的低级烷氧羰基低级烷基是优选基团。值得一提的实例是:甲氧羰基甲基,乙氧羰基甲基,丙氧羰基甲基,丁氧羰基甲基,异丙氧羰基甲基,异丁氧羰基甲基,1-甲氧羰基乙基,1-乙氧羰基乙基,1-丙氧羰基乙基,1-丁氧羰基乙基,1-异丙基羰基乙基,1-异丁基羰基乙基,2-甲氧基羰基乙基,2-乙氧羰基乙基,2-丙氧羰基乙基,2-丁氧羰基乙基,2-异丙基羰基乙基,2-异丁基羰基乙基,2-甲氧羰基-2-丙基,2-乙氧羰基-2-丙基,2-丙氧羰基-2-丙基,2-丁氧羰基-2-丙基,2-异丙氧羰基-2-丙基,2-异丁氧羰基-2-丙基,2-甲氧羰基-2-丙基,1-乙氧羰基-2-丙基,2-丙氧羰基-2-丙基,1-异丁氧羰基-2-丙基,3-甲氧羰基丙基,3-乙氧羰基丙基,3-异丙氧羰基丙基或3-异丁氧羰基丙基。
卤素一般代表氟、氯、溴或碘,优选的是氟,氯或溴,特别优选的卤素是氟或氯。
式(Ⅰ)化合物中的优选化合物是下述化合物及它们的盐,即式(Ⅰ)中
R1代表氢,氟,氯,溴,三氟甲基,羧基或低级烷氧羰基,或
代表-S(O)nR3,-NR4R5或OR6,其中
R3为低级烷基或苯基,
R4和R5可相同或不同,它们是氢,低级烷基,苯基或苄基,
R6为氢,低级烷基,苯基,苄基或三氟甲基,和
n为数字0或2,
或
R1代表低级烷基,低级链烯基,环丙基,环戊基或环己基,上述基团可任意被羧基,低级烷氧基,氟,氯,溴,羟基,低级烷氧羰基,低级烷硫基或氰基取代,
R2代表苯基或萘基,它们可被下述相同或不同的基团单至三取代,这些基团是氟,氯,溴,氰基,三氟甲基,三氟甲硫基,低级烷基,羧甲基,羧乙基,甲氧羰基甲基,乙氧羰基甲基,甲氧羰基乙基,低级烷氧基,低级烷硫基,羟基,低级烷氧羰基,苯基,苯氧基,苄氧基或苄硫基,或被-NR4R5单至三取代,其中R4和R5的定义同前,
R7代表氢,低级烷基,环丙基,环戊基或环己基。
特别优选的式(Ⅰ)化合物是下述化合物及它们的盐,即式(Ⅰ)中
R1代表氢、氟,氯,溴,三氟甲基,甲硫基,乙硫基,甲磺酰基,乙磺酰基,苯硫基,苯磺酰基,氨基,二甲氨基或二乙氨基,或代表-OR6,其中R6为氢,甲基,乙基,丙基,苯基或
苄基,或
代表甲基,乙基,丙基或异丙基,
R2代表苯基或萘基,它们可被相同或不同的下述基团单取代或双取代,这些基团是氟,氯,溴,氰基,三氟甲基,三氟甲硫基,甲基,乙基,丙基,甲氧基,乙氧基,丙氧基,甲硫基,羟基,甲氧羰基,乙氧羰基,苯基,二甲氨基或二乙氨基,
R7代表氢或甲基。
最优选的式(Ⅰ)化合物是下述化合物及它们的盐,即式(Ⅰ)中
R1为氢或氟,
R2为被氟,氯,溴,甲基,甲氧基或苯基取代的苯基或萘基,
R7为甲基。
值得一提的实例如下:
2-甲基-3-(苯磺酰)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸
2-甲基-3-(4-氟苯磺酰)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸
2-甲基-3-(4-溴苯磺酰基)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸
2-甲基-3-(4-氯苯磺酰基)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸
2-甲基-3-(4-甲苯磺酰基)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸
2-甲基-3-(4-甲氧苯磺酰基)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸
2-甲基-3-(4-萘磺酰基)-氨甲基-1,3,4,5-四氢-1-苯并[c,d]吲哚丙酸(钠盐)。
本文公开了式(Ⅰ)的四氢-1-苯并[c,d]吲哚丙酸磺酰胺的制备方法,式(Ⅰ)为
式中R1,R2和R7的定义同前。该制备方法的特征在于:将式(Ⅳ)的四氢-1-苯并[c,d]吲哚磺酰胺与式(Ⅴ)的丙烯腈于惰性溶剂中和在碱的存在下(根据需要)进行反应,得式(Ⅵ)的N,N′-双氰乙基化合物,然后将其水解。式(Ⅳ)为
式中R1,R2和R7的定义同前,
式(Ⅴ)为
式(Ⅵ)为
式中R1,R2和R7的定义同前。
本发明的制备方法用反应方程式表示如下:
本发明的制备方法使用的溶剂可以是在反应条件下无变化的惰性有机溶剂,这些溶剂最好包括醇类如甲醇,乙醇,丙醇或异丙醇;醚类如乙醚,四氢呋喃,二恶烷,乙二醇单甲醚或乙二醇二甲基醚;烃类如苯,甲苯,二甲苯,环己烷,己烷或石油馏分,二甲基亚砜,二甲基甲酰胺,六甲基磷酰胺,乙酸乙酯或吡啶。也可用上述溶剂的混合物。
本发明制备方法所用的碱是惯用碱,它们最好包括:碱金属氢氧化物和碱土金属氢氧化物如氢氧化锂,氢氧化钠,氢氧化钾,氢氧化钡;碱金属氢化物如氢化钠;碱金属碳酸盐或碱土金属碳酸盐如碳酸钠,碳酸钾;或碱金属烷氧化物如甲醇钠或乙醇钠,甲醇钾或乙醇钾或叔丁醇钾;或有机胺如苄基三甲基氢氧化铵,四丁基氢氧化铵,吡啶,三乙胺或N-甲基哌啶。
本发明的制备方法一般在0℃-150℃,最好在20℃-100℃下实施。
本发明的制备方法一般在常压下实施,但也可在减压或加压(如0.5-5巴)下实施。
1摩尔[芳基磺酰氨基烷基]-1,3,4,5-四氢苯并[cd]吲哚一般要用2-20摩尔,最好是2-10摩尔丙烯腈。
通常采用周知的方法,在碱如碱金属氢氧化物或烷氧化物,或者碱土金属氢氧化物或烷氧化物的存在下于惰性溶剂如水或醇中进行N,N′-双氰乙基化合物的水解反应。最好用NaOH,KOH,Ba(OH)2,CH3ONa,CH3OK,CH3CH2ONa或CH3CH2OK作为碱,用水,甲醇,乙醇,丙醇,异丙醇或它们的混合物作为溶剂。
1摩尔N,N′-双氰乙基化合物通常需用1-100摩尔,最好为2-50摩尔的碱。
水解反应在0℃-100℃,最好在20℃-80℃下进行。
式(Ⅳ)化合物是新化合物,本发明也公开了制备它们的方法,其特征在于:在惰性溶剂中和在碱存在下(必要时),将式(Ⅶ)的吲哚与式(Ⅷ)的磺酰卤反应,式(Ⅶ)为
式中R1和R7的定义同前,
式(Ⅷ)为
式中R2的定义同前,X为卤素。
上述反应可用反应方程式表示如下:
本发明的制备方法所用的溶剂可以是在反应条件下无变化的惰性有机溶剂,它们最好包括醇类如甲醇,乙醇,正丙醇,异丙醇,乙二醇;醚类如乙醚,二噁烷,四氢呋喃,乙二醇单甲醚或乙二醇二甲基醚,卤代烃如二,三或四氯甲烷,1,2-二氯乙烷,1,1,2-三氯乙烷,乙酸乙酯,甲苯,乙腈,冰醋酸,六甲基磷酰胺,吡啶和丙酮。当然也可以用上述溶剂的混合物。
本发明的制备方法所用的碱是惯用碱,它们最好包括碱金属氢氧化物和碱土金属氢氧化物如氢氧化锂,氢氧化钠,氢氧化钾,氢氧化钡;碱金属氢化物如氢化钠;碱金属碳酸盐或碱土金属碳酸盐如碳酸钠,碳酸钾;或碱金属烷氧化物如甲醇钠或乙醇钠,甲醇钾或乙醇钾或叔丁醇钾;或有机胺如苄基三甲基氢氧化铵,四丁基氢氧化铵,吡啶,三乙胺或N-甲基吡啶。
本发明的制备方法一般在0℃-150℃,最好在25℃-40℃下进行。
本发明的制备方法一般在常压下进行,但也可在减压或加压(如0.5-5巴)下进行。
反应中1摩尔3-(1-氨基烷基)-1,3,4,5-四氢苯并[c,d]吲哚一般需用1-5摩尔,最好是1-2摩尔,最好用1摩尔的磺酰卤。
按本发明的方法,可用的磺酰卤包括:苯磺酰氯,4-氟苯磺酰氯,4-溴苯磺酰氯,4-氯苯磺酰氯,4-甲苯磺酰氯,1-萘磺酰氯。
式(Ⅶ)化合物为已知物或可用已知方法制得(NL-A6,409,079)。
式(Ⅷ)的磺酰卤和式(Ⅴ)的丙烯腈是已知化合物;参见[Houben-Weyls“Methoden der organischen Chemie”(“Methods of Organic Chemistry”),Volume Ⅸ,p.407 ff.and p.547 ff.(1959)]。
新的四氢-1-苯并[c,d]吲哚丙酸磺酰胺或其盐可用作药物中的活性物质,该活性物质具有抑制血小板凝聚和拮抗凝血噁烷A2的作用。最好将它们用于治疗血栓形成,血栓栓塞和局部缺血,也可用作抗气喘剂和抗变应剂。用已知方法,采用惰性的无毒的,适合药用的赋形剂或溶剂可将本发明所述的新的活性物质制备成惯用剂型,如片剂,胶囊,包衣片,丸剂,颗粒,气雾剂,糖浆,乳化液,混悬液和溶液。上述每个剂型中存在的治疗活性化合物的浓度应为剂型重量的约0.5-90%,最好为5-70%;这样的浓度足以达到所要求的剂量范围。
任意地采用乳化剂和/或分散剂,用溶剂和/或赋形剂分散所述活性化合物,可以制得上述制剂,但如果用水作稀释剂时,可采用适宜的有机溶剂作为助溶剂。
值得一提的辅剂是:例如水,无毒有机溶剂如链烷烃(如石油馏分),植物油(如花生/芝麻油),醇类(如乙醇,丙三醇),二醇类(如丙二醇,丙基乙二醇),固体赋形剂如研磨的天然无机物(如高岭土,矾土,滑石,白垩),研磨的合成无机物(如高分散二氧化硅,硅酸盐),糖类(如蔗糖,乳糖和右旋糖),乳化剂(如聚乙二醇脂肪酸酯,聚乙二醇脂肪醇醚,烷基磺酸盐,芳基磺酸盐),分散剂(如木素亚硫酸酯废水溶液,甲基纤维素,淀粉和聚乙烯吡咯烷酮)和润滑剂(如硬脂酸镁,滑石,硬脂酸和月桂基磺酸钠)。
可以以惯用方法给药,优选的是口服或非肠道给药,更好的是舌下或静脉给药。口服给药时,除了上述的赋形剂外,片剂中还可含有其它添加成分如柠檬酸钠,碳酸钙,磷酸二钙及各种添加剂如淀粉,最好是土豆淀粉,明胶等。此外润滑剂如硬脂酸镁,月桂基磺酸钠和滑石也可用于压片中。在用于口服给药的水混悬液和/或酏剂中,除前述的辅剂外,在活性化合物中也可加入各种调味剂或着色剂。
当非肠道给药时,可采用适宜的赋形剂制成活性化合物的溶液。
已证明,通常静脉给药更具优越性,给药量为约0.001-1mg/Kg(体重),最好为0.01-0.05mg/Kg(体重)便可获得满意结果。口服给药时,通常的剂量为0.01-20mg/Kg(体重),最好为0.1-10mg/Kg(体重)。
然而,最好根据体重,给药的途径,病人对药物的敏感性,药物的剂型及给药的次数或间隔时间来确定给药剂量。因此在某些情况下,用低于上述的最小剂量也足以凑效,而在另一些情况中必须超过上述的最大剂量方可奏效。大剂量给药时,最好一天的剂量分成数次给药。
本发明的四氢-1-苯并[cd]吲哚丙酸磺酰胺可作为人用和兽用药。
实施例1
2-甲基吲哚-3-丁二酸
将13.1g(0.1mol)2-甲基吲哚和11.6g(0.1mol)马来酸的混合物于水浴上加热至固化静置30分钟,然后加入氢氧化钾(11.3g,0.2mol)的水(200ml)溶液,搅拌下加热30分钟,冷却,先用乙醚提取反应液,然后用活性碳处理,过滤,冷却,用HCl酸化,将析出的沉淀滤出,水洗,得产物。
m.p:210-211℃(分解)
TLC:CHCl3/CH3OH=3∶1,硅胶铝箔/Merck 5562,Rf=0.32
产率:17.2g(69.6%)
实施例2
5-氟-2-甲基吲哚-3-丁二酸
按类似于实施例1的方法制备了标题化合物。
m.p.220℃
TLC:CHCl3/CH3OH=3∶1,硅胶铝箔/Merck 5562,Rf=0.21
产率:57.1%
实施例3
1-乙酰基-2-甲基-3-吲哚丁二酸酐
将24.7g(0.1mol)2-甲基-3-吲哚丁二酸,200ml乙酸异丙烯酯和2g(0.011mol)P-甲苯磺酸单水合物的混合物加热回流30分钟,慢慢蒸除丙酮,将反应液减压浓缩,残留物于60ml乙酸和15ml乙酸酐中结晶,得标题化合物。
m.p.192-193℃
TLC:CHCl3/CH3OH=3∶1,硅胶铝箔/Merck 5562,Rf=0.71。
产率:12.1g(44.6%)
实施例4
1-乙酰基-5-氟-2-甲基-3-吲哚丁二酸酐
按类似于实施例3的方法制备了标题化合物。
m.p.178℃
TLC:CHCl3/CH3OH=3∶1,硅胶铝箔/Merck 5562,Rf=0.65
产率:47.6%
实施例5
1-乙酰基-2-甲基-1,3,4,5-四氢-5-氧-苯并[c,d]吲哚3-羧酸
将实施例3制备的2.71g(0.01mol)化合物溶于60ml热二氯乙烷中,搅拌下冷却该溶液直至成为混悬液为止。在室温下将66.7g(0.05mol)氯化铝加入60ml酸酐和60ml二氯乙烷的混悬液中,将该溶液于40C加热4小时,冷却,加入50ml 2N HCl液,滤出生成的沉淀,水洗后将其溶于热丙酮中,用活性炭处理该丙酮液,冷却,结晶得产物。
m.p:215-217℃
TLC:CHCl3/CH3OH=3∶1,硅胶铝箔/Merck 5562,Rf=0.50
产率:0.75g(27.7%)
实施例6
1-乙酰基-6-氟-2-甲基-1,3,4,5-四氢-5-氧-苯并[cd]吲哚3-羧酸
用0.27g(0.01mol)实施例4制备的化合物,按类似于实施例5的方法制备了标题化合物。
m.p:248℃
TLC:CHCl3/CH3OH=3∶1,硅胶铝箔/Merck 5562,Rf=0.36
产率:82.4%
实施例7.
2-甲基-1,3,4,5-四氢-5-氧-苯并[c,d]吲哚3-羧酸
将1g(0.0037mol)实施例5制备的化合物溶于50ml0.2N NaOH中,于室温静置3小时后,用稀HCl酸化,将生成的沉淀滤出,水洗,于稀醋酸中重结晶,得产物。
m.p:235-239℃
TLC:CHCl3/CH3OH=3∶1,硅胶铝板/Merck 5562,Rf=0.50
产率:0.60g(71.4%)
实施例8.
2-甲基-1,3,4,5-四氢苯并[c,d]吲哚3-羧酸
将22.9g(0.1mol)实施例7制备的化合物和0.5mol水合肼(溶液浓度85%)于室温下加入冷却的NaOH(0.5mol)乙二醇(250ml)溶液中,加热回流20分钟,用500ml水稀释,用乙醚提取。将水溶液于冰浴中冷却,用浓HCl酸化,用水洗醚液,MgSO4干燥,减压浓缩醚液。将残留物溶于氯仿,用活性炭处理,滤除炭,将溶液浓缩并冷却,产物以黄色片状结晶析出。
m.p:103℃
TLC:甲苯/乙醇=3∶1,硅胶铝板/Merck 5562,Rf=0.53
产率:14.2g(66.0%)
实施例9.
6-氟-2-甲基-1,3,4,5-四氢苯并[cd]吲哚3-羧酸
用22.9g(0.01mol)实施例6制备的化合物,按类似于实施例8的方法制备了标题化合物。
m.p:190℃
TLC:甲苯/乙醇=3∶1,硅胶铝板/Merck 5562,
Rf=0.55
产率:53.8%
实施例10.
2-甲基-1,3,4,5-四氢苯并[c,d]吲哚-3-羧酸
将4.30g(0.02mol)实施例8制备的化合物溶于50ml无水四氢呋喃中,加入3.89g(0.024mol)N,N′-羰基二咪唑,将该混合物搅拌过夜,浓缩,将残留物溶于二氯甲烷,用水洗两次,用MgSO4干燥,浓缩,将残留物溶于四氢呋喃中,加入20ml 5N氨一甲醇液,室温搅拌2小时,浓缩,残留物于乙酸乙酯中结晶,得产物。
m.p:218℃
TLC:CH2Cl2/乙酸乙酯=1∶1,硅胶铝板/Merck 5562,Rf=0.21
产率:3.50g(81.8%)
实施例11.
6-氟-2-甲基-1,3,4,5-四氢苯并[c,d]吲哚-3-酰胺
用4.30g(0.02mol)实施例9制备的化合物,按类似于实施例10的方法制备了标题化合物。
m.p:230℃
TLC:CH2Cl2/乙酸乙酯=1∶1,硅胶铝板/Merck 5562,Rf=0.20
产率:68.8%
实施例12.
3-氨甲基-2-甲基-1,3,4,5-四氢苯并[cd]吲哚
将3.21g(0.015mol)实施例10制备的化合物混悬于70ml无水四氢呋喃中,然后于室温下滴入30ml 1M的氢化锂铝(0.03mol)四氢呋喃液,搅拌下回流二小时。在冰浴冷却下滴入20ml乙酸乙酯,2ml水和4mlKOH(浓度15%),再搅拌30分钟,滤除生成的盐,滤液浓缩,将残留物溶于二氯甲烷,水洗,干燥,蒸发,所得残留物经Merck硅胶60闪层析纯化(CH2Cl2/乙酸乙酯1∶1,CH3Cl2/CH3OH 1∶1),得产物。(黄褐色树脂状)。
TLC:CH2Cl2/CH3OH=1∶1,硅胶铝板/Merck 5562,Rf=0.16
产率:2.80g(93%)
实施例13.
3-氨甲基-6-氟-2-甲基-1,3,4,5-四氢苯并[c,d]吲哚
用3.2g(0.015mol)实施例11制备的化合物,按类似于实施例12的方法制备了标题化合物。
m.p:230℃
TLC:CH2Cl2/乙酸乙酯=1∶1,硅胶铝板/Merck 5562,Rf=0.20
产率:68.8%
实施例14.
2-甲基-3-(4-甲苯磺酰)-氨甲基-1,3,4,5-四氢苯并[c,d]吲哚
将3.00g(0.015mol)3-氨甲基-2-甲基-1,3,4,5-四氢苯并[c,d]吲哚和5ml三乙胺溶于100ml二氯甲烷中,然后将2.86g(0.015mol)P-甲苯磺酰氯溶于40ml二氯甲烷中并于30分钟内滴加到上述吲哚溶液中,于室温搅拌2小时。先用1N HCl振摇提取,再用水提取,用MgSO4干燥有机相后,减压蒸发,所得残留物于异丙醇中结晶,抽滤,用异丙醇和乙醚洗涤沉淀,用高真空于50C干燥后得产物。
产率:3.96g(74.7%)
m.p:211℃
Rf:0.48(硅胶铝箔/Merck 5562,流动相:甲苯/乙酸乙酯=3∶1)
用类似于实例14的方法制备了表1表2所示的实例化合物。
表1
实施例27
1-(2-氰乙基)-3-[N-(2-氰乙基)-N-(4-甲苯磺酰基)-氨甲基]-2-甲基-1,3,4,5-四氢苯并[cd]吲哚
将3.86g(0.01mol)2-甲基-3-(4-甲苯磺酰)-氨甲基-1,3,4,5-四氢苯并[c,d]吲哚溶于50ml无水1,4-二噁烷中,然后依次加入4ml丙烯腈和4滴苄基三甲基氢化铵的甲醇液(浓度40%),于80℃搅拌3小时,蒸除溶剂后将残留物溶于乙酸乙酯中,用水提取2次,MgSO4干燥。蒸发,将残留物于甲醇中结晶,抽滤,用甲醇洗涤沉淀后于50C高真空干燥,得产物。
产率:4.47g(89.2%)
m.p:163℃
Rf:0.20(硅胶铝箔/Merck 5562,流动相:甲苯/乙酸乙酯=6∶1)
用类似于实例27的方法制备了表3和表4所示的实例化合物。
实施例40.
将15g KOH和85ml水加入4.38g(0.0095mol)1-(2-氰乙基)-3-[N-(2-氰乙基)-N-(4-甲苯磺酰基)-氨甲基]-2-甲基-1,3,4,5-四氢苯并[cd]吲哚中,剧烈搅拌下回流6小时,然后在冰冷却下用6NHCl将反应混合物调PH至酸性,用二氯甲烷提取3次,合并有机相,用水洗一次,MgSO4干燥蒸发,将残留物与甲苯一起搅拌,使其结晶,用甲苯和正戊烷洗涤,于50℃高真空下干燥,得产物。
产率:4.05g(100%)
m.p:154C
Rf:0.54(硅胶铝箔/Merck 5562,流动相:甲苯/乙醇=3∶1)
用类似于实例40的方法制备了表5和表6所示的实例化合物。
实施例53(应用实例)
用男性和女性健康受试者的血测定抑制血小板凝聚的作用。将1份浓度为3.8%的柠檬酸钠水溶液与9份血混合液作为抗凝剂,将其离心得到富含血小板的柠檬酸血浆(PRP),参见Jurgens/Beller,Klinische Methoden der Blutgerinnungsanalyse;(Clinical Methods of Blood Coagulation Analysis);Thieme Verlag,1959。
为进行上述研究,将0.8mlPRP和0.1ml活性化合物溶液于37℃水浴中预保温。然后通过比浊计法[参见Born,G.V.R.,J.Physiol.(London),162,67,1962]于37℃,用集合度计(参见Therapeutische Berichte 47,80,1975)测定血小板凝聚作用。此后将0.1ml骨胶原-凝聚诱导剂加入上述预保温样品中,记录6分钟内PRP样品光密度的变化,6分钟后测定结果。结束后与对照组比较,计算出百分抑制率。最小有效浓度范围定为临界浓度。
临界浓度为0.003-10mg/升
以实例18作为例子:EC=0.01-0.003mg/升。
Claims (3)
1、制备式(Ⅰ)所示四氢-1-苯并[c,d]吲哚磺酰胺及其盐的方法,式(Ⅰ)为
R1为氢,卤素,三氟甲基,羧基,烷氧羰基或为-S(O)nR3,
NR4R5或OR6,其中
R3是烷基或芳基,
R4R5是相同的或不同,它们各自为氢,烷基,芳基或芳烷基,
R6是氢,烷基,芳基或芳烷基或三氟甲基,
n是数字0,1或2,
或
R1为任意被羧基,烷氧羰基,卤素,羟基,烷氧基,烷硫基或氰基取代的烷基,链烯基或环烷基,
R2为含有6-10个碳原子的芳基,该芳基可被下述相同或不同的基团单至三取代,这些基团是卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,烷基,羧基烷基,烷基羰烷基,烷氧基,烷硫基,羟基,烷氧羰基,苯基,苯氧基,苄氧基,苄硫基或-NR4R5,其中R4和R5的定义同前,
R7为氢,烷基或环烷基,
该方法的特征在于将式(Ⅳ)四氢-1-苯并[c,d]吲哚磺酰胺与式(Ⅴ)的丙烯腈在惰性溶剂中,必要时在碱存在下进行反应,得式(Ⅵ)化合物,然后将其水解得式(Ⅰ)化合物,
式(Ⅳ)为
式中R1,R2和R7的定义同前,
式(Ⅵ)为
式中R1,R2和R7的定义同前。
2、按权利要求1的方法,其特征在于该反应在0-15℃下进行。
3、制备式(Ⅳ)所示四氢-1-苯并[c,d]吲哚磺酰胺及其盐的方法,式(Ⅳ)为
式中
R1为氢,卤素,三氟甲基,羧基,烷氧羰基或为-S(O)nR3,NR4R5或OR6,其中
R3是烷基或芳基,
R4R5是相同的或不同,它们各自为氢,烷基,芳基或芳烷基,
R6是氢,烷基,芳基或芳烷基或三氟甲基,
n是数字0,1或2,
或
R1为任意被羧基,烷氧羰基,卤素,羟基,烷氧基,烷硫基或氰基取代的烷基,链烯基或环烷基,
R2为含有6-10个碳原子的芳基,该芳基可被下述相同或不同的基团单至三取代,这些基团是卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,烷基,羧基烷基,烷基羰烷基,烷氧基,烷硫基,羟基,烷氧羰基,笨基,苯氧基,苄氧基,苄硫基或-NR4R5,其中R4和R5的定义同前,
R7为氢,烷基或环烷基,
其特征在于将式(Ⅶ)的吲哚与式(Ⅷ)的磺酰卤于惰性溶剂中,必要时可在碱存在进行反应,得到式(Ⅳ)化合物,
式(Ⅶ)为
式中R1和R7的定义相同,
式中R2为芳基或萘基,它们可被相同或不同的下述基团单至三取代,这些基团是卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,烷基,羧基烷基,烷氧基羰烷基,烷氧基,烷硫基,羟基,烷氧羰基,苯基,苯氧基,苄氧基,苄硫基或-NR4R5,其中R4和R5的定义同前,
X为卤素。
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- 1989-08-02 ZA ZA895892A patent/ZA895892B/xx unknown
- 1989-08-02 AU AU39210/89A patent/AU616035B2/en not_active Ceased
- 1989-08-02 KR KR1019890011039A patent/KR900003121A/ko not_active Withdrawn
- 1989-08-02 DK DK379089A patent/DK379089A/da not_active Application Discontinuation
- 1989-08-02 IE IE892499A patent/IE892499L/xx unknown
- 1989-08-02 HU HU893943A patent/HU207717B/hu not_active IP Right Cessation
- 1989-08-03 CN CN89105633A patent/CN1040025A/zh active Pending
-
1992
- 1992-09-17 GR GR920401993T patent/GR3005720T3/el unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108752256A (zh) * | 2018-04-24 | 2018-11-06 | 六盘水师范学院 | 一种基于羧酸烯基酯作为酰基化试剂的n-酰基吲哚类化合物制备方法 |
CN108752256B (zh) * | 2018-04-24 | 2021-04-13 | 六盘水师范学院 | 一种基于羧酸烯基酯作为酰基化试剂的n-酰基吲哚类化合物制备方法 |
Also Published As
Publication number | Publication date |
---|---|
HU207717B (en) | 1993-05-28 |
GR3005720T3 (zh) | 1993-06-07 |
DK379089D0 (da) | 1989-08-02 |
PT91337A (pt) | 1990-03-08 |
PT91337B (pt) | 1995-05-04 |
DK379089A (da) | 1990-02-04 |
FI893644A7 (fi) | 1990-02-04 |
NO892982L (no) | 1990-02-05 |
KR900003121A (ko) | 1990-03-23 |
NO892982D0 (no) | 1989-07-20 |
AU616035B2 (en) | 1991-10-17 |
DD284000A5 (de) | 1990-10-31 |
JPH0278660A (ja) | 1990-03-19 |
EP0353557B1 (de) | 1992-09-16 |
IL91159A0 (en) | 1990-03-19 |
HUT53076A (en) | 1990-09-28 |
DE3826371A1 (de) | 1990-02-08 |
ZA895892B (en) | 1990-05-30 |
EP0353557A1 (de) | 1990-02-07 |
IE892499L (en) | 1990-02-03 |
FI893644L (fi) | 1990-02-04 |
ES2052831T3 (es) | 1994-07-16 |
DE58902284D1 (de) | 1992-10-22 |
AU3921089A (en) | 1990-02-08 |
FI893644A0 (fi) | 1989-08-01 |
ATE80618T1 (de) | 1992-10-15 |
US5079258A (en) | 1992-01-07 |
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