CN1053429A - 吲哚取代五元芳杂环化合物 - Google Patents
吲哚取代五元芳杂环化合物 Download PDFInfo
- Publication number
- CN1053429A CN1053429A CN91100380A CN91100380A CN1053429A CN 1053429 A CN1053429 A CN 1053429A CN 91100380 A CN91100380 A CN 91100380A CN 91100380 A CN91100380 A CN 91100380A CN 1053429 A CN1053429 A CN 1053429A
- Authority
- CN
- China
- Prior art keywords
- indol
- ethamine
- oxadiazole
- dimethyl
- ylmethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000002390 heteroarenes Chemical class 0.000 title abstract description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical group C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 28
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 426
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 397
- 229910052757 nitrogen Inorganic materials 0.000 claims description 247
- -1 fontanel element Chemical group 0.000 claims description 150
- 150000001875 compounds Chemical class 0.000 claims description 110
- 238000000034 method Methods 0.000 claims description 76
- 238000002360 preparation method Methods 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 27
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 239000005864 Sulphur Substances 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 150000002431 hydrogen Chemical group 0.000 claims description 13
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 150000003053 piperidines Chemical class 0.000 claims description 9
- 125000001118 alkylidene group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 238000007126 N-alkylation reaction Methods 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- LLJRXVHJOJRCSM-UHFFFAOYSA-N 3-pyridin-4-yl-1H-indole Chemical group C=1NC2=CC=CC=C2C=1C1=CC=NC=C1 LLJRXVHJOJRCSM-UHFFFAOYSA-N 0.000 claims description 2
- 238000006352 cycloaddition reaction Methods 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- PXJJSXABGXMUSU-UHFFFAOYSA-N disulfur dichloride Chemical compound ClSSCl PXJJSXABGXMUSU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000004576 sand Substances 0.000 claims description 2
- JGASTEWEWNVFRL-UHFFFAOYSA-N 2-azanylidyne-n-sulfidoacetonitrilium Chemical compound [S-][N+]#CC#N JGASTEWEWNVFRL-UHFFFAOYSA-N 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 238000006356 dehydrogenation reaction Methods 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims 1
- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 claims 1
- 150000003556 thioamides Chemical class 0.000 claims 1
- 208000019695 Migraine disease Diseases 0.000 abstract description 6
- 206010027599 migraine Diseases 0.000 abstract description 6
- 230000008092 positive effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 139
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 131
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 102
- 239000000243 solution Substances 0.000 description 96
- 239000002585 base Substances 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 43
- 239000002253 acid Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229910021529 ammonia Inorganic materials 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 21
- 229910052710 silicon Inorganic materials 0.000 description 21
- 239000010703 silicon Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000005227 gel permeation chromatography Methods 0.000 description 15
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 14
- 229960004592 isopropanol Drugs 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- AZDOLIXTFBPILY-UHFFFAOYSA-N butanedioic acid;dihydrate Chemical compound O.O.OC(=O)CCC(O)=O AZDOLIXTFBPILY-UHFFFAOYSA-N 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000007738 vacuum evaporation Methods 0.000 description 8
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 7
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000013375 chromatographic separation Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- BOKWMAAFRMIAMM-UHFFFAOYSA-N 1-methylpiperidine;oxalic acid Chemical compound OC(=O)C(O)=O.CN1CCCCC1 BOKWMAAFRMIAMM-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- OFJBYLCQNJHFMI-UHFFFAOYSA-N 2,5-dihydro-1,2-oxazole Chemical compound C1ONC=C1 OFJBYLCQNJHFMI-UHFFFAOYSA-N 0.000 description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 4
- LTLKJYMNUSSFAH-UHFFFAOYSA-N 4-chloro-1,1-dimethoxybutane Chemical compound COC(OC)CCCCl LTLKJYMNUSSFAH-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 3
- 125000004391 aryl sulfonyl group Chemical group 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
- SXDQRQUWNQKZBL-UHFFFAOYSA-N butanedioic acid;hydrate Chemical compound O.OC(=O)CCC(O)=O SXDQRQUWNQKZBL-UHFFFAOYSA-N 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- RLZPCFQNZGINRP-UHFFFAOYSA-N n'-hydroxypropanimidamide Chemical compound CCC(N)=NO RLZPCFQNZGINRP-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000004533 oil dispersion Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 2
- NANQJUFFKXWVJR-UHFFFAOYSA-N 1-(benzenesulfonyl)piperazine Chemical compound C=1C=CC=CC=1S(=O)(=O)N1CCNCC1 NANQJUFFKXWVJR-UHFFFAOYSA-N 0.000 description 2
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 2
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- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
一种吲哚取代五元芳杂环化合物,它是5-HT1
类受体的特效兴奋剂,因而可用于临床,特别对于治
疗偏头疼及其相关病症有明显效果。
Description
本发明涉及一类吲哚取代五元芳杂环化合物,该化合物作用于5-羟色胺(5-HT)受体,是所谓“5-HT1类”受体的特效兴奋剂,因而可用于临床治疗,对这类受体有明显的效果。
5-HT1类受体兴奋剂具有选择性血管收缩效能,最近已有报导将其用于治疗偏头痛(如:A.Doenicke et al.,The Lancet,1988,Vol.1,1309-11)。本发明化合物,作为5-HT1类受体的特效兴奋剂,也相应地特别用于治疗偏头痛及其相关病症,例如:阵发性头痛(cluster headache),慢性阵发性偏头痛和血管病引起的头痛。
欧洲专利申请EP-A-0313397公开了一类由五元杂脂环取代的色胺衍生物,并指出该色胺衍生物是一种特定类型的“5-HT1类”受体的特效兴奋剂,因而在临床上是一种有效治疗剂,特别对于需要这种效能的偏头痛更是如此。然而,欧洲专利申请EP-A-0313397号并未公开或提出本发明的芳杂环化合物。
欧洲专利申请EP-A-0328200公开了一类至少含有一个杂原子的五元杂环化合物,该化合物的杂环上联有氮杂环或氮杂二环或氨基取代基,并指出这类化合物可用于治疗精神病(例如:精神分裂症和躁狂症);焦虑症;疼痛;胃停滞(gastric stalis),胃机能不良;偏头痛;噁心;呕吐;和早老性及老年性痴呆,并可用于戒酒和戒毒。但是,该化合物对5-HT1类受体并无作用,而本发明的芳杂环化合物是上述受体的特效药,因此,可以得知它们作用的机理不同。
本发明提供一种式Ⅰ化合物或其盐或其前体药物。式Ⅰ如下:
其中虚线圆表示五元环上任何位置的两个不相邻双键;
W、X、Y、Z可各自代表氧、硫、氮或碳原子,只要,至少W、X、Y、和Z中之一代表氧或硫,且W、X、Y、Z中至少有一个代表碳;
A代表氢,烃基,囟素,氰基,三氟甲基,硝基,-ORx,-OCORx,-ONRxRy,-SRx,-NRxRy,-NRxORy,-NRxNRxRy,-NRxCORy,-NRxCO2Ry,-NRxSO2Ry,-NRZCVNRxRy,-CORx,-CO2Rx或-CONRxRy;
E代表一个化学键或一个含有1至4个碳原子的直链或支链亚烷基;
F代表下式所示的基团
式中R1代表-CH2·CHR4·NRxRy或不列基团之一:
其中虚线表示任意的化学键。
R2,R3,R4和R5可各自代表氢,1-6C烷基,2-6C烯基或2-6C炔基;
Rx和Ry可各自代表氢或烃基,或Rx与Ry一起代表2-6C亚烷基;
RZ代表氢或烃基;
V代表氧,硫或基团=N·G;
G代表烃基或吸电子基团。
本发明还提供一种Rx,Ry和RZ各自代表氢或烃基的上述式Ⅰ化合物及其盐和前体药物。
用作药物时,式Ⅰ化合物的盐是无毒的药学上可接受的盐,其它盐也可以用来制备本发明式Ⅰ化合物或其无毒的药学上可接受盐。适宜的本发明化合物的药学上可接受盐包括酸加成盐,该酸加成盐可通过将本发明化合物溶液与药学上可接受的无毒酸(例如:氢氯酸,富马酸,马来酸,琥珀酸,乙酸,柠檬酸,酒石酸,碳酸或磷酸)溶液混合而生成。此外,对于带有酸性部分的本发明化合物,其适宜的药学上可接受盐可以包括碱金属盐(例如:钠盐和钾盐),碱土金属盐(例如:钙盐和镁盐)以及同适当的有机配位体形成的盐(例如:季铵盐)。
这里使用的“烃基”一词包括直链,支链和环状基团(包括杂环),这些基团含18个以下碳原子,适宜的数目为15以下,较适宜的为12以下。适宜的烃基包括1-6C烷基,2-6C烯基,2-6C炔基,3-7C环烷基,3-7C环烷基(1-6C)烷基,芳基,芳基(1-6C)烷基,3-7C杂环烷基,3-7C杂环烷基(1-6C)烷基,杂芳基和杂芳基(1-6C)烷基。
适宜的烷基包括含1至6个碳原子的直链和支链烷基。典型的例子包括甲基和乙基以及直链或支链的丙基和丁基,特别是甲基,乙基和叔丁基。
适宜的烯基包括含2至6个碳原子的直链和支链烯基,典型的例子包括乙烯基和烯丙基。
适宜的炔基包括含2至6个碳原子的直链和支链炔基,典型的例子包括乙炔基和丙炔基。
适宜的环烷基包括含3至7个碳原子的基团。特别是环丙基和环己基。
适宜的芳基包括苯基和萘基。
具体的芳基(1-6C)烷基包括苄基,苯乙基和苯丙基。
适宜的杂环烷基包括氮杂环丁烷基,吡咯烷基,哌啶基,哌嗪基和吗啉基。
适宜的杂芳基包括吡啶基,喹啉基,异喹啉基,哒嗪基,嘧啶基,吡嗪基,吡喃基,呋喃基,苯并呋喃基,联苯呋喃基,噻吩基,苯噻吩基,咪唑基,噁二唑基,噻二唑基。
具体的杂芳基(1-6C)烷基是吡啶基甲基。
而烃基本身又可任意地被选自下列的一个或多个基团取代:1-6C烷基,金刚烷基,苯基,囟素,1-6C囟代烷基,1-6C氨基烷基,三氟甲基,羟基,1-6C烷氧基,芳氧基,酮基,1-3C亚烷基二氧基,硝基,氰基,羧基,2-6C烷氧基羰基,2-6C烷氧基羰基(1-6C)烷基,2-6C烷基羰基氧基,芳基羰基氧基,2-6C烷基羰基,芳基羰基,1-6C烷硫基,1-6C烷基亚磺酰基,1-6C烷基磺酰基,芳基磺酰基,-NRVRW,-NRVCORW,-NRVCO2RW,-NRVSO2RW,-CH2NRVSO2RW,-NHCONRVRW,-CONRVRW,-SO2NRVRW和-CH2SO2NRVRW,其中RV和RW各自代表氢,1-6C烷基,芳基或芳基(1-6C)烷基,或者RV与RW一道代表2-6C亚烷基。
当Rx与Ry,或RV与RW一道代表2-6C亚烷基时,该基团可以是亚乙基,亚丙基,亚丁基,戊基亚甲基或己基亚甲基,优选亚丁基或戊基亚甲基。
当基团G代表吸电子基团时,适宜的基团是氰基,硝基,-CORx,-CO2Rx或-SO2Rx,其中Rx如上文所定义。
这里“囟素”一词指氟,氯,溴和碘,特别是氟。
本发明的范围还包括上述式Ⅰ化合物的前体药物。通常,这些前体药物是式Ⅰ化合物的功能衍生物,它极易在体内转化为所需的式Ⅰ化合物,选择和制备合适的前体药物衍生物的常规方法已有描述。参见文献《Design of Prodrugs”(H.Bundgaard编,Elsevier出版,1985年)。
对于本发明的化合物中那些至少带有一个不对称中心的化合物来说相应地可存在对映结构体。对于那些具有两个或两个以上不对称中心的本发明化合物来说,还存在非对映异构体。可以理解,所有这些异构体及其混合物都属于本发明的范围。
带有W到Z取代基的式Ⅰ中的五元芳杂环可以是呋喃,噻吩,噁唑,噻唑,异噁唑,异噻唑,噁二唑或噻二唑环,特别是1,2,4-噁二唑,1,3,4-噁二唑,1,2,4-噻二唑,1,3,4-噻二唑,1,3-噁唑或1,3-噻唑环。优选1,2,4-噁二唑,1,2,4-噻二唑,1,3-噁唑或1,3-噻唑环。
亚烷基链E可以是亚甲基,亚乙基,1-甲基亚乙基,亚丙基或2-甲基亚丙基。另一方面,基团E也可以代表单键,这时式Ⅰ中的吲哚部分F便直接联在五元芳杂环上。
适宜的基团A包括1-6C烷基,3-7C环烷基,芳基,芳基(1-6C)烷基,3-7C杂环烷基或杂芳基(1-6C)烷基,上述的任一基团又可任意地被取代;还有氢,囟素,氰基,三氟甲基,硝基,1-6C烷氧基,1-6C烷硫基,-NRxRy或-CONRxRy。其中Rx与Ry按上文定义。基团A上适宜的取代基包括苯基,三氟甲基,1-6C烷氧基,2-6C烷氧基羰基,2-6C烷基羰基,1-6C烷基磺酰基,芳基磺酰基,氨基,一或二(1-6C)烷基氨基,2-6C烷基羰基氨基,芳基羰基氨基,2-6C烷氧基羰基氨基,1-6C烷基磺酰基氨基,芳基磺酰基氨基,1-6C烷基磺酰基氨基甲基,氨基羰基氨基,一或二(1-6C)烷基氨基羰基氨基,一或二芳基氨基羰基氨基,吡咯烷基羰基氨基,氨基羰基,一或二(1-6C)烷基氨基羰基,1-6C烷基氨基磺酰基,氨基磺酰基甲基和单或双(1-6C)烷基氨基磺酰基甲基。
具体地,基团A包括:甲基,甲氧基甲基,氨甲基,二甲基氨甲基,乙酰基氨甲基,苯甲酰基氨甲基,叔丁氧基羰基氨甲基,甲基磺酰基氨甲基,苯基磺酰基氨甲基,氨基羰基甲基,乙基,氨乙基,乙酰基氨乙基,苯甲酰基氨乙基,甲氧基羰基氨乙基,乙氧基羰基氨乙基,叔丁氧基羰基氨乙基,甲基磺酰基氨乙基,氨基羰基氨乙基,甲氨基羰基氨乙基,叔丁基氨基羰基氨乙基,苯基氨基羰基氨乙基,吡咯烷基羰基氨乙基,环丙基,苯基,甲基磺酰基氨基苯基,氨基羰基苯基,甲氨基羰基苯基,甲基磺酰基氨甲基苯基,氨基磺酰基甲基苯基,甲氨基磺酰基甲基苯基,二甲基氨基磺酰基甲基苯基,萘基,苄基,二苯甲基,三氟甲基苄基,甲氧基苄基,乙酰氨基苄基,甲磺酰氨基苄基,氨基羰基氨基苄基,氨基羰基苄基,甲氨基羰基苄基,甲磺酰基苄基,甲氨基磺酰基苄基,苯乙基,苯丙基,乙酰基哌嗪基,甲氧基羰基哌嗪基,叔丁氧基羰基哌嗪基,甲氨基羰基哌嗪基,甲磺酰基哌嗪基,苯磺酰基哌嗪基,吡啶基甲基,甲氧基吡啶基甲基,氨基,甲氨基,苄氨基,二甲氨基,叔丁氧基羰基氨基乙氨基,甲基磺酰基氨基乙氨基,氨基羰基,甲氨基羰基,氮杂环丁烷基羰基和吡咯烷基羰基。
具有代表性的R1包括氨乙基,N-甲基氨乙基,N,N-二甲基氨乙基和1-甲基-4-哌啶基。优选R1为氨乙基或N,N-二甲基氨乙基。
较为适宜地,基团R2到R5独立地代表氢或1-6C烷基,特别是氢或甲基。
本发明的特定亚类化合物是式ⅡA化合物及其盐和前体药物。式ⅡA如下:
其中:
Z1代表氧或硫,
n为0,1,2或3,
A1代表1-6C烷基,2-6C烯基,2-6C炔基,3-7环烷基,芳基,芳基(1-6C)烷基,3-7杂环烷基,杂芳基或杂芳基(1-6C)烷基,上述的任一基团可以任意被取代,还有代表氢,囟素,氰基,三氟甲基,硝基,1-6C烷氧基,1-6C烷硫基,-NRxRy或-CONRxRy,
R12,R13和R14独立地代表氢,1-6C烷基,2-6C烯基或2-6C炔基,
Rx和Ry独立地代表氢或烃基,或者Rx与Ry一道代表2-6C烯基。
基团A1上的任选取代基中,较为适宜的有苯基,三氟甲基,1-6C烷氧基,2-6C烷氧基羰基,2-6C烷基羰基,1-6C烷基磺酰基,芳基磺酰基,氨基,一或二(1-6C)烷基氨基,2-6C烷基羰基氨基,芳基羰基氨基,2-6C烷氧基羰基氨基,1-6C烷基磺酰基氨基,芳基磺酰基氨基,1-6C烷基磺酰氨基甲基,氨基羰基氨基,一或二(1-6C)烷基氨基羰基氨基,一或二芳基氨基羰基氨基,吡咯烷基羰基氨基,氨基羰基,一或二(1-6C)烷基氨基羰基,1-6C烷基氨基磺酰基,氨基磺酰基甲基和一或二(1-6C)烷基氨基磺酰基甲基。
具体地,式ⅡA中的基团A′包括:甲基,甲氧基甲基,氨甲基,二甲基氨甲基,乙酰基氨甲基,苯甲酰基氨甲基,叔丁氧基羰基氨甲基,甲基磺酰基氨甲基,苯基磺酰基氨甲基,氨基羰基甲基,乙基,氨乙基,乙酰基氨乙基,苯甲酰基氨乙基,甲氧基羰基氨乙基,乙氧基羰基氨乙基,叔丁氧基羰基氨乙基,甲基磺酰基氨乙基,氨基羰基氨乙基,甲氨基羰基氨乙基,叔丁基氨基羰基氨乙基,苯基氨基羰基氨乙基,吡咯烷基羰基氨乙基,环丙基,苯基,甲基磺酰基氨基苯基,氨基羰基苯基,甲氨基羰基苯基,甲基磺酰基氨甲基苯基,氨基磺酰基甲基苯基,甲氨基磺酰基甲基苯基,二甲基氨基磺酰基甲基苯基,萘基,苄基,二苯甲基,三氟甲基苄基,甲氧基苄基,乙酰氨基苄基,甲磺酰基氨基苄基,氨基羰基氨基苄基,氨基羰基苄基,甲氨基羰基苄基,甲磺酰基苄基,甲氨基磺酰基苄基,苯乙基,苯丙基,乙酰基哌嗪基,甲氧基羰基哌嗪基,叔丁氧基羰基哌嗪基,甲氨基羰基哌嗪基,甲磺酰基哌嗪基,苯磺酰基哌嗪基,吡啶基甲基,甲氧基吡啶基甲基,氨基,甲氨基,苄氨基,二甲氨基,叔丁氧基羰基氨基乙氨基,甲基磺酰基氨基乙氨基,氨基羰基,甲氨基羰基,氮杂环丁烷基羰基和吡咯烷基羰基。在一个优选实施例中,A1代表氨基。
优选的R12,R13和R14都代表氢。式ⅡA中的Rx和Ry的优选基团包括氢和甲基。
本发明的另一亚类化合物是式ⅡB化合物及其盐和前体药物,式ⅡB如下:
其中:
Y1代表氧或硫;
n为0,1,2或3;
A1按式ⅡA中的定义;
R22,R23和R24独立地代表氢,1-6C烷基,2-6C烯基或2-6C炔基,
Rx和Ry独立地代表氢或烃基,或者Rx与Ry一道表示2-6C烯基。
式ⅡB中A1可具体地代表甲基和苄基,优选R22,R23和R24均代表氢,式ⅡB中优选的Rx和Ry是氢和甲基。
本发明的另一亚类化合物是式ⅡC化合物及其盐和前体药物,式ⅡC如下:
其中:
W1代表氧或硫;
n为0,1,2或3;
A1按式ⅡA中的定义;
R32,R33和R34独立地代表氢,1-6C烷基,2-6C烯基或2-6C炔基,
Rx和Ry独立地代表氢或烃基,或者Rx与Ry一道表示2-6C烯基。
式ⅡC中A1可具体地代表甲基,优选R32,R33和R34均代表氢,式ⅡC中优选的基团Rx和Ry是氢和甲基。
本发明的另一亚类化合物是式ⅡD化合物及其盐和前体药物,式ⅡD如下:
其中:
Z1代表氧或硫;
n为0,1,2或3;
A1按式ⅡA中的定义;
R42,R43和R45独立地代表氢,1-6C烷基,2-6C烯基或2-6C炔基,
Rx和Ry独立地代表氢或烃基,或者Rx与Ry一道表示2-6C烯基。
式ⅡD中A1可具体地代表氨基,被任意取代的苄基或吡啶基甲基,特别是甲磺酰氨基苄基。
优选的R42和R43均代表氢,R45代表氢或1-6C烷基,特别是甲基。
本发明范围中具体包括以下化合物及其盐和前体药物:
2-[5-(3-苄基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苄基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺,
2-[5-(3-苄基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-苯基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(2-甲氧基苄基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苄基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-[2-(3-苄基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-二苯甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-苯基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(2-甲氧基苄基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-苄基-1,2,4-噁二唑-5-基)丙基]-1H-吲哚-3-基]乙胺;
2-[5-(3-苯乙基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(5-苄基-1,2,4-噁二唑-3-基]-1H-吲哚-3-基]乙胺;
2-[5-(5-苄基-1,2,4-噁二唑-3-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氧基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[2-(3-苄基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(1-萘基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-甲基-1,2,4-噁二唑-5-基)丙基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-环丙基-1,2,4-噁二唑-5-基)丙基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-甲氧基苄基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲氧基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-苯丙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-环丙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-乙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-三氟甲基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基)乙胺;
2-[5-[2-(3-氨基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
2-[5-[2-(3-二甲基氨基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
2-[5-(5-甲基-1,2,4-噁二唑-3-基)-1H-吲哚-3-基]乙胺;
2-[5-(5-甲基-1,2,4-噁二唑-3-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(5-苄基-1,2,4-噁二唑-3-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲氧基甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(4-甲氨基羰基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(4-甲氨基羰基苯基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(4-甲氨基磺酰基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(4-甲磺酰苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(3-甲磺酰基氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-(4-氨基羰基氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-乙酰氨基甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(2-乙酰氨基乙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-氨甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-乙酰氨基甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-乙酰氨基乙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基氨基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-叔丁氧基羰基氨基)乙基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基羰基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲磺酰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-氨基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氨基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氨基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氧基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-乙氧基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[2-(3-氨基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲基氨基-1,2,4-噁二唑-5-基)甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基苄基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-乙酰氨基苄基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基磺酰基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰基氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基羰基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-乙酰氨基甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲磺酰氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基羰基甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-乙酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-氨基羰基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰氨基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-甲氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-二甲氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-(叔丁酯基氨基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-叔丁酯基氨基)乙基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲酯基氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-二甲氨基甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲磺酰氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-乙酯基氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苯甲酰基氨甲基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-(2-苯甲酰基氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-(2-苯氨基羰基氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-(2-叔丁氨基羰基氨基)乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-甲基-2-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-(叔丁酯基)哌嗪-1-基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-(4-甲酯基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-(4-甲氨基羰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N′N-二甲基-2-[5-(3-(4-乙酰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N′N-二甲基-2-[5-(3-(4-甲磺酰基氨基甲苯基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N′N-二甲基-2-[5-(3-苯磺酰氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苄氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-吡啶基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氧基吡啶-5-基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[2-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-3-基]乙胺;
2-[5-[2-[3-(4-甲氧基苄基)-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(5-甲基-1,3-噁唑-2-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[2-(5-甲基-1,3-噁唑-2-基)乙基)-1H-吲哚-3-基]乙胺;
1-甲基-4-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]哌啶;
1-甲基-4-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]哌啶;
1-甲基-4-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]哌啶;
1-甲基-4-[5-[3-(3-吡啶基)甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]哌啶;
N,N-二甲基-2-[5-[3-(4-吡啶基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-(叔丁氧基羰基氨基)乙基)氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基羰基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲氨基羰基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(吡咯烷-1-基)羰基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(氨杂环丁烷-1-基)羰基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-苯磺酰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-吡咯烷-1-基羰基氨基)乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲磺酰氨乙基)氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-20[5-(3-氨基-1,4-噻二唑-5-基甲基)-1H-吲哚-3-基]乙胺。
本发明还提供了由一种或多种本发明化合物与药学上可接受载体组成的药用组合物,这些组合物采用单位剂型(如:片剂,丸剂,胶囊,粉剂,粒剂,无菌注射剂或混悬剂,或栓剂)以口服,注射或直肠给药较为适宜。在制备像片剂这样的固体组合物时,将主要的活性成份与药用载体(如:常规片剂成分像玉米淀粉,乳糖,蔗糖,山梨醇,滑石粉,硬脂酸,硬脂酸镁,磷酸钙和树胶等)以及其它的药用稀释剂(如:水)混合,形成由含有本发明化合物或其无毒性药学上可接受盐的均匀混合物所构成的固体预制剂组合物,我们说这些预制剂组合物是均匀的,意思是指活性成份在整个组合物中均匀分散,从而可以容易地再分割为同等有效的单位剂型,如片型,丸剂和胶囊。固体预制剂组合物接着再被细分为上述的单位剂型,每单位剂型含0.1至500mg左右的本发明活性成分。这种新组合物的片剂或丸剂可以包衣或者其它混合制成长效药。例如,片剂或丸剂可以由内部药和包覆药两部分构成,后者以包衣形式将前者包覆起来。这两部分之间还可以有一层肠溶衣,以抵抗胃的消化,从而使内部药物能够完整地进入十二指肠或延缓释放。可以使用多种材料作这种肠溶衣或包衣,这些材料包括许多聚合酸以及聚合酸与虫胶、十六烷醇、乙酸纤维素之类材料的混合物。
可加入本发明新组合物的液态药剂包括水溶液,适当调味的糖浆,水或油混悬剂,以及调味乳剂,可用来口服和注射。其制备方法是将新组合物加入到食油(如:棉籽油,芝麻油,椰子油和花生油)、配剂和类似的药用赋形剂中。水溶液混悬剂中适宜的分散剂或悬浮剂包括天然和人工胶,例如:黄蓍胶,阿拉伯胶,藻酸盐,葡聚糖,羧基甲基纤维素纳,甲基纤维素,聚乙烯基吡咯烷酮和明胶。
在治疗偏头痛时,适宜的日剂量约为0.01~250mg/kg,优选约0.05~100mg/kg,特别是约0.05~5mg/kg,本化合物可以按每天1~4次的服法给药。
本发明的噁二唑化合物可通过下述方法制得:使结构式为RC-CO2H的羧酸的活性衍生物与式Ⅲ或式Ⅳ的化合物或它们的盐反应。式Ⅲ与式Ⅳ如下:
其中RC和Rd之一是式A基团,另一个是-E-F基团,其定义参照上文式Ⅰ。
酸RC-CO2H的活性衍生物中适宜的有酯(如:1-4C烷基酯);硫酯(如:吡啶基硫酯);酸酐(如:(RCCO)2O);酰囟(如:酰氯);原酸酯;以及伯胺、仲胺和叔胺。
优选的酸RC-CO2H的活性衍生物是式Ⅴ亚氨醚衍生物,式Ⅴ如下:
其中R是1-4C烷基。
当使用式Ⅲ化合物时,反应产物是1,2,4-二唑。可以理解,式Ⅲ化合物也可以看成另一种异构体ⅢA:
其中Rd如前面定义。
如果RC代表基团-E-F,且式Ⅲ中Rd代表基团A,则可得到3位取代的1,2,4-噁二唑-5-基化合物,而当RC代表基团A,Rd代表基团-E-F时,按照本发明方法则可得到5位取代的1,2,4-噁二唑-3-基化合物。在这种情况下,酸RC-CO2H的活性衍生物优选1-4C烷基酯。反应在强碱(如氢化钠)的存在下,适当的溶剂(如:四氢呋喃,二甲基甲酰胺或低级烷醇像乙醇、丙醇或异丙醇)中极易进行,反应在约20~100℃下进行1~6小时左右。
当使用式Ⅳ化合物时,按本发明方法得到的产物是1,3,4-噁二唑。在这种情况下,酸RC-CO2H的活性衍生物优选结构式为RCC(ORP)3的原酸酯,其中RP代表1-3C烷基。该方法是将酰肼Ⅳ与原酯酸在溶剂(如:甲醇)中加热回流约2~8小时。反应极易进行。蒸发溶剂便得到结构式为Rd·CO·NH·N=C(RC)ORP的中间体,然后在约90~150℃下使中间体与强碱(如:叔丁醇钾或1,8-重氮双环[5.4.0]十一-7-碳烯)在丁醇中反应约10~24小时。
结构式为RC-CO2H的羧酸的活性衍生物或式Ⅲ或式Ⅳ化合物(其中RC或Rd代表结构式为-E-F的基团)可通过将式Ⅵ化合物与式Ⅶ化合物或其羰基保护式反应得到。
式Ⅵ如下:
其中Q代表活性羧酸部分或结构式为-C(NOH)NH2或-CONHNH2的基团或者上述基团的保护衍生物或其前体,E的定义同前。式Ⅶ如下:
其中R2如上文定义,R11对应于上文定义的R1或代表基团-CH2·CHR4D,其中R4如上文定义,D代表易被取代基;然后,需要时按标准方法N-烷基化引进R3基团。
当式Ⅵ化合物中的Q部分代表基团-C(NOH)NH2或-CONHNH2的前体时,该基团以腈基为宜。
式Ⅶ化合物的适宜的羰基保护形式包括二甲基乙缩醛或缩酮衍生物。
式Ⅶ化合物中的易被取代基团D代表囟素基团较宜,优选氯。当式Ⅶ化合物中的R11部分是基团-CH2·CHR4D时,在一般的反应条件下取代基D可直接被置换得到最终产物式Ⅰ,其中R1代表基团-CH2·CHR4·NH2。接着,在需要时按先有技术可将末端氨基进一步精制为R1代表期望的基团-CH2·CHR4·NRxRy的式Ⅰ化合物。
化合物Ⅵ和Ⅶ的反应可以一步完成(Fischer吲哚合成法),或在低温下进行初步非环化得到式Ⅷ化合物。
其中Q,E,R2和R11如上文定义。然后,使用适当的试剂(如:聚磷酸酯)环化,得到结构式为Q-E-F的化合物。
式Ⅵ肼可从相应的式Ⅸ苯胺经重氮化接着还原得到。式Ⅸ如下:
其中Q和E如上文定义。重氮化时使用常规的亚硝酸钠/浓盐酸,得到的重氮化合物用二氯化锡(Ⅱ)/浓盐酸进行直接还原。
式Ⅸ苯胺可通过将相应的式Ⅹ硝基化合物还原得到,式Ⅹ如下:
其中Q和E如上文定义,通常该还原过程是用催化氢化或用二氯化锡(Ⅱ)进行的。
当式Ⅹ硝基化合物不能在市场上买到时,可使用本领域技术人员所熟知的标准方法制备。
式Ⅰ的1,2,4-噻二唑可通过式Ⅺ化合物环化制得,式Ⅺ如下:
式中RC和Rd的定义同前,Re是氢或烷基。
化合物Ⅺ的环化可在-20℃~50℃下,在吡啶的存在下,用胺化剂(如:羟胺-O-磺酸)在低级烷醇(如:甲醇,乙醇或丙醇)中反应1~6小时。
Re是氢的式Ⅺ化合物的环化亦可通过使用像溴、碘、过氧化氢或硝酸之类的氧化剂来完成。
上述的式Ⅺ化合物可按文献《综合杂环化学》(A.R.Katritzky和C.W.Rees编,Pergamon出版社,1984,Vol.6,P.496)所述方法或类似方法制备。
1,2,4-噻二唑也可以通过腈硫化物RC-C=N+-S-与腈Rd-CN的环化加成制得,式中RC和Rd如上文定义。
本发明的1,3,4-噻二唑可以通过结构式为RCCSNHNHCONRsRt的氨基硫脲(式中RC如上文定义,Rs和Rt是氢或烷基)与脱水试剂(如:硫酸,聚磷酸或甲磺酸)进行脱水反应,接着按常规方法连接Rd基团而制得。
本发明的1,2,5-噻二唑可通过将下述形式的二胺
与氯化硫(如:亚硫酰氯或二氯化硫)反应制备。上式中RC和Rd如上文定义。
本发明的噁二唑与噻二唑可通过酰胺或式Ⅻ亚硫酰胺与式ⅩⅢα-囟代酮反应制得,式ⅩⅢ如下:
其中U是氧或硫,Hal代表囟素,RC和Rd如上文定义。反应条件按文献《合成》(1975,389)所述。
2,5取代型的呋喃可通过式ⅩⅣ化合物:
(式中Rd如前文定义)与能产生阴离子的试剂反应,脱除氧原子相邻的质子,接着将得到的阴离子物与能提供基团RC的亲电物反应而得到。RC如前文定义。
烷基锂(如:正丁基锂)是适宜的试剂,它能够脱除氧原子的相邻质子,产生式ⅩⅣ化合物的阴离子。
能提供RC基团的亲电物以含羰基的化合物或结构式为RC-L的化合物为宜,其中L代表适当的离去基(如;囟素原子氯或溴)。在前一种情况下,羰基化合物与化合物ⅩⅣ产生的阴离子反应所得产物将在最终的RC基团中含有羟基。这个羟基可根据需要保留不变或用规范的方法除去,例如:用POCl3进行脱除然后再氢化。完成上述方法的详细实验过程在文献《药物化学杂志》1990,33,1128中有所叙述。
式ⅪⅤ的中间体可通过常规方法制备,例如:
其中Rd如上文定义。
在另一种方法中,本发明化合物可通过将化合物ⅩⅤ:
与能提供阴离子-RC的试剂反应得到,其中W、X、Y、Z、RC和Rd如上文定义,且Hal代表囟素。
化合物ⅩⅤ可通过本领域熟知的常规方法制得。例如,如果化合物ⅩⅤ是1,2,4-噻二唑,便可按文献Chem.Ber.,1957,90,182所述方法制得。
可以提供阴离子-RC的试剂包括格利雅试剂RCMgHal(式中Hal=囟素),有机铜酸盐试剂(如:LiRC 2Cu),有机锂试剂RCLi或由相邻活性基团(如:酯或烯醇酮官能团)稳定的阴离子化合物。在这种情况下,相邻的酯或酮官能团在反应完毕后可以保留或除去。例如:酯基团可被水解和脱羧。
在另一方法中,本发明化合物可通过下述方法得到,将式ⅩⅥ化合物:
(其中W,X,Y,Z,A和E按上文定义)与上文定义的式Ⅶ化合物反应,或与其羰基保护剂(如:二甲基乙缩醛或二甲基缩酮)反应;接着,需要时按规范方法N-烷基化引入基团R3。
正如化合物Ⅵ与Ⅶ的反应一样,化合物ⅩⅥ与Ⅶ的反应可一步进行(Fischer吲哚合成)或先在低温下初步非环化得出式ⅩⅦ化合物:
其中W,X,Y,Z,A,E,R2和R11如上文定义,然后用适当试剂(如聚磷酸酯)进行环化。
式ⅩⅥ肼可按上述制备式Ⅸ化合物的类似方法由相应的式ⅩⅧ苯胺制得。
式ⅩⅧ如下:
其中W,X,Y,Z,A,和E如上文。
式ⅩⅧ苯胺可按类似于制备化合物Ⅲ和Ⅳ的方法由上述Ⅸ化合物改变基团Q来制备,例如:当式Ⅸ化合物中的Q代表-C(NOH)NH2或-CONHNH2时,则可通过与式A-CO2H的羧酸反应衍生物的反应制式ⅩⅧ化合物。式中A如前文定义。另一方面,当式Ⅸ化合物中的Q代表活性羧化物时,则可将其与结构式为A-C(NOH)NH2或A-CONHNH2的化合物反应,从而制得式ⅩⅧ化合物。
可以理解,按上述任一方法初步得到的任一式Ⅰ化合物都可在适当的条件下按本领域现有技术精制为式Ⅰ化合物的进一步形式。具体地说,初步得到的R3是氢的式Ⅰ化合物可以按规范的方法通常在碱性条件下(如:氢化钠的二甲基甲酰胺溶液),用碘代烷(如:一碘甲烷)处理的烷基化转化为R3代表1-6C烷基,2-6C烯基或2-6C炔基的式Ⅰ化合物。与此类似,初步得到的R1代表基团-CH2·CHR4·NH2的式Ⅰ化合物可以按常规的N-烷基化或N-芳基化技术(如:在氰基硼氢钠之类的还原剂存在下用适当的醛处理)转化为R1代表基团-CH2·CHR4·NRxRy(式中Rx和Ry如上文定义,但不为氢)的式Ⅰ化合物。
对于那些按上述方法制备本发明化合物过程中产生立体异构体混合物的,这些立体异构体可用常规技术(如制备色谱法)进行分离。
制备的新化合物可以是外消旋式,或者通过专门对映合成法(enantiospecifie synthesis)或拆分法得到单一的对映结构体,例如,用规范的技术可以将新化合物拆开为其组成的对映结构体,例如与旋光活性酸(比如(-)-二-对甲苯甲酰-d-酒石酸和/或(+)-二-对甲苯甲酰-1-酒石酸)形成盐,接着分步结晶和再生游离碱从而生成非对映对。新化合物也可以通过形成非对映酯或酰胺,接着进行色谱分离和除去手性助剂而得分开。
在上述的任何一种合成方法中,有时必须和/或希望将任一有关分子中的敏感或活泼基团保护起来。这点可借助常规的保护基团达到,例如:《有机化学中的保护基团》(J.F.W.McOmie编,Plenum出版,1973年版)和T.W.Greene编的《有机合成中的保护基团》(John Wiley & Sons,1981年版)中有上述方法的叙述,保护基团可按本领域技术人员熟知的方法在下步中方便地去除。
下列各例表明了本发明化合物的制备过程。
受试化合物与5-HT1类受体结合的能力是按《神经科学杂志》1987年,第7卷,894页所述方法在猪尾制成的薄膜上测定的。结合能力的测定以5-[1,2-3H(N)]作为放射性配体,用2nM-5羟色胺硫酸肌酐进行。方法中使用氰基心得乐(Cyanopindolol)(100nM)和mesulergine(100nM)分别划出5-HT1A和5-HT1C的结合位点。在每种情况下,除去特定结合(IC50)50%,所需化合物浓度都低于1μM。
受试化合物作为5-HT1类受体的特效药的活性按Arch,Pharm,1990,342,111所述方法,以其对于新西兰白兔隐静脉间接收缩能力为量度。其药效是从5-HT(1μm)的应答百分数对药物浓度的曲线图上计算-log10EC50(PEC50)值得出的。下列各实例中化合物所测PEC50值均不低于5.0:
实例1,4,6,19-21,27,28,30,39-42,44,45,49,52,53,56,61,65,88,93和110。
实施例1
2-[5-[5-(3-苄基-1,2,4-噁二唑)-基)-1H-吲哚-3-基]乙胺草酸氢盐水合物
1.对肼基苯甲酸乙酯·盐酸化物
将亚硝酸钠(17.0g,0.24mol)的水(90ml)溶液加入到冷却的对氨基苯甲酸乙酯(40g,0.24mol)的浓盐酸(225ml)溶液中,控制加入速率使溶液温度不超过0℃。将混合物在0℃下搅拌0.1小时后,加到搅拌中的氯化锡(Ⅱ)二水合物(202g,0.89mol)的浓盐酸(135ml)溶液中,控制加入速率使溶液温度不超过-5℃。让所得混悬液在1小时升到室温,过滤,用乙醚洗涤,m.p.215-217℃,δ(360MHz,D2O)1.38(3H,t,J=7.1Hz,Me)4.37(2H,q,J=7.1Hz,CH2),7.06(1H,d,J=9Hz,芳-H),8.03(1H,d,J=9Hz,芳-H)。
2,2-(5-乙酯基-1H-吲哚-3-基)乙胺·马来酸氢盐
将对肼基苯甲酸乙酯盐酸化物(10g,46mmol)和4-氯丁醛二甲基乙缩醛(7.8g,46mmol)的乙醇/水(5∶1,500ml)溶液加热回流2小时,真空除去溶剂,残留物以二氯甲烷/乙醇/氨(40∶8∶1)为洗提剂经硅凝胶色谱分离,得油状标题吲哚(3.69g),制得马来酸氢盐。
mp 127℃;(Found:C,59.46;H,5.96;N,8.47.C13H16N2O2.C4H4O4requires C,59.68;H,5.93;N,8.54%),m/e232(M+),δ(360MHz,D2O)1.43(3H,t,J=7.1Hz,Me);3.21(2H,t,J=7.0Hz,CH2);3.37(2H,t,J=7.0Hz,CH2);4.42(2H,q,J=7.1Hz,CH2);6.23(2H,s,maleate-H);7.40(1H,s,indole-H);7.56(1H,d,J=8.8Hz,aromatic-H);7.88(1H,dd,J=1.6and8.8Hz,aromatic-H);8.38(1H,d,J=1.6Hz,aromatic-H).
3,2-[5-(5-(3-苄基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸氢盐水合物
将氢化钠(80%油分散体,0.33g,11.0mmol)加到搅拌的苯基乙酰胺肟(1.74g,11.6mmol)的无水THF(50ml)溶液中,反应混合物加热回流0.5小时,再加入2-(5-乙酯基-1H-吲哚-3-基)乙胺(1.19g,5.0mmol)的THF(10ml)溶液,反应体系加热回流2小时,使混合物冷却至室温后加水(20ml),用二氯甲烷(3×100ml)萃取,真空去溶剂后的粗品用二氯甲烷/乙醇/氨(40∶8∶1)为洗提剂经硅凝胶色谱分离,得标题产品(0.68g),所得草酸氢盐的理化数据如下:
mp 229℃;(Found:C,59.42;H,4.92:N,13.02.C19H18N4O.C2H2O4.0.85H2O requires C,59.53;H,5.16;N,13.22%);δ(360MHz,D2O)3.18(2H,t,J=7.4Hz,CH2);3.31(2H,t,J=
7.4Hz,CH2);4.17(2H,s,CH2-Ph);7.35-7.43(6H,m,indole-Hand aromatics);7.63(1H,d,J=8.6Hz,aromatic-H);7.87(1H,d,J=8.6Hz,aromatic-H);8.40(1H,s,aromatic-H).
实施例2
2-[5-(5-(3-甲基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺。草酸氢盐
按实施例1所述方法,由甲基乙酰胺肟和2-(5-乙酯基-1H-吲哚-3-基)乙胺制备。所得草酸氢盐理化数据如下:mp 230℃.(Found:
C,52.91;H,4.85;N,16.01.C13H14N4O.1.2(C2H2O4)requires C,52.78;H,5.02;N,16.41%);m/e243(M+H)+;δ(360MHz,D2O)2.26(3H,s,Me);3.09(2H,t,J=7.3Hz,CH2);3.32(2H,t,J=7.3Hz,CH2);7.28(1H,s,indole-H);7.41(1H,d,J=8.6Hz,aromatic-H);7.53(1H,dd,J=1.6and8.6Hz,aromatie-H);7.86(1H,d,J=1.6Hz,aromatic-H).
实施例3
N,N-二甲基-2-[5-(5-(3-苄基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺。倍半草酸盐
1,N,N-二甲基-2-[5-乙酯基-1H-吲哚-3-基]乙胺。草酸盐
在室温下,将硼氢化钠(1.1g,2,2mmol)的水(15ml)溶液和甲醛(7.5ml)的甲醇(7.5ml)溶液在0.25小时内同时滴加到2-(5-乙酯基-1H-吲哚-3-基)乙胺(0.75g,4.3mmol)的甲醇(15ml)溶液中。混合液搅拌0.25小时后加入浓盐酸(10ml),真空浓缩,再加入浓盐酸(7.5ml),然后用碳酸钾(6.1g)将溶液碱化,用乙酸乙酯萃取,残留粗品以二氯甲烷/乙醇/氨(60∶8;1)为洗提剂经硅凝胶色谱分离,得到标题N,N-二甲胺(0.64g)。所得草酸盐理化数据:
mp 150℃;(Found C,52.76;H,5.67;N,6.65.C15H20N2O2.1.8.C2H2O4requires C,52.89;H,5.63;N,6.63%);δ(360MHz,D2O)1.42(3H,t,J=7.1Hz,Me);2.94(6H,s,N(Me)2);3.27(2H,t,J=7.0Hz,CH2);3.52(2H,t,J=7.0Hz,CH2);4.42(2H,q,J=7.1Hz,CH2);7.40(1H,s,indole-H);7.56(1H,d,J=8.6Hz,aromatic-H);7.88(1H,dd,J=1.6and 8.6Hz,aromatic-H);8.36(1H,d,J=1.6Hz,aromatic-H).
2.N,N-二甲基-2-[5-(5-(3-苄基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺。倍半草酸盐
按实施例1所述方法可由苯基乙酰胺肟和N,N-二甲基-2-(5-乙酯基-1H-吲哚-3-基)乙胺制备标题化合物。所得倍半草酸盐理化数据:
mp 157-158℃;(Found:C,59.14;H,5.29;N,11.35.C21H22N4O.1.6.C2H2O4requires C,59.26;H,5.19;N,11.42%);m/e 347(M+H)+;δ(360MHz,D2O)2.88(6H,s,N(Me)2);3.02(2H,br t,J=7.3Hz,CH2);3.32(2H,br t,J=7.3Hz,CH2);3.99(2H,s,CH2-phenyl);7.13(1H,s,indole-H);7.34-7.49(7H,m,aromatics);7.82(1H,s,aromatic-H).
实施例4
2-[5-(5-(3-苄基-1,2,4-噁二唑)基)甲基)-1H-吲哚-3-基]乙胺·草酸氢盐
1.对肼基苯乙酸乙酯,盐酸化物
按实施例1所述方法由对氨基苯乙酸乙酯制备,其理化数据:
mp 188-190℃,δ(360MHz,D6-DMSO)1.44(3H,t,J=7.1Hz,Me);3.88(2H,s,CH2);4.36(2H,t,J=7.1Hz,CH2);7.20(2H,d,J=8.5Hz,aromatics);7.50(2H,d,J=8.5Hz,aromatics).
2.2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺。马来酸氢盐
按实施例1所述方法由对肼基苯乙酸乙酯和4-氯丁醛二甲基乙缩醛制备,所得马来酸氢盐理化数据:
mp 105-108℃;(Found:C,59.31;H,6.07;N,7.43.C14H18N2O2.C4H4O4.0.1H2O requires C,59.36;H,6.14;N,7.69%);m/e 246(M+);δ(360MHz,D2O)1.23(3H,t,J=7.1Hz,Me);3.16(2H,t,J=7.0Hz,CH2);3.33(2H,t,J=7.0Hz,CH2);3.82(2H,s,CH2);4.18(2H,q,J=7.1Hz,CH2Me);6.29(2H,s,maleate-H);7.17(1H,dd,J=1.6and 8.4Hz,aromatic-H);7.32(1H,s,indole-H);7.49(1H,d,J=8.4Hz,aromatic-H);7.56(1H,s,aromatic-H).
3.2-[5-(5-(3-苄基-1,2,4-噁二唑)-基甲基)-1H-吲哚-3-基]乙胺。草酸氢盐
按实施例1所述方法由上述酯以及苯乙酰胺肟制备,所得草酸氢盐理化数据:mp 176-178℃(isopropyl alcohol);(Found:C,62.37;H,5.34;N,13.15.C20H20N4O.C2H2O4requires C,62.55;H,5.25;N,13.26%);m/e 333(M+H)+;δ(360MHz,D2O)3.10(2H,t,J=6.9Hz,CH2);3.28(2H,t,J=6.9Hz,CH2);4.01(2H,s,CH2);4.29(2H,s,CH2);7.11(1H,dd,J=1.6and8.4Hz,aromatic-H);7.25-7.38(6H,m,5x aromatic-H and 1 x indole-H);7.44(1H,d,J=8.4Hz,aromatic-H);7.53(1H,d,J=1.6Hz,aromatic-H).
实施例5
2-[5-(5-(3-甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺。草酸氢盐水合物
按实施例1所述方法由甲基乙酰胺肟和2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺制备。所得草酸氢盐理化数据:mp 72-74℃;(Found:C,53.45;H,5.26;N,15.15.C14H16N4O.C2H2O4.0.75H2O requires C,53.40;H,5.46;N,15.56%);δ(360MHz,D2O)2.32(3H,s,Me);3.15(2H,t,J=7.1Hz,CH2);3.33(2H,t,J=7.1Hz,CH2);4.37(2H,s,CH2);7.20(1H,dd,J=1.6and8.4Hz,aromatic-H);7.32(1H,s,indole-H);7.51(1H,d,J=8.4Hz,aromatic-H);7.62(1H,s,aromatic-H).
实施例6
2-[5-(5-(3-氨基-1,2,4-噁二唑)基甲基-1H-吲哚-3-基]乙胺。氢草酸盐
将羟基硫酸胍(2.76g,10.4mmol)加到搅拌着的钠(0.91g,39mmol)的乙醇(40ml)溶液中,混合液搅拌0.5小时后,加入2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺(0.85g,3.5mmol)的乙醇(20ml)溶液中回流2小时,冷却至室温后真空去乙醇,残留物以二氯甲烷/乙醇/氨(40∶8∶1)为洗提剂经硅凝胶色谱分离得到标题产物,所得草酸氢盐理化数据:mp85-87℃;(Found:C,47.07;H,5.28;N,20.71.C13H15N5O.C2H2O4.1.2H2O.0.3(C1H5N3O)requires C,46.73;H,5,41;N,21.01%);m/e 257(M+);δ(360MHz,D2O)3.14(2H,t,J=7.0Hz,CH2);3.32(2H,t,J=7.0Hz,CH2);4.23(2H,s,CH2);7.17(1H,dd,J=1.6and8.4Hz,aromatic-H);7.32(1H,s,indole-H);7.49(1H,d,J=8.4Hz,aromatic-H);7.58(1H,d,J=1.6Hz,aromatic-H).
实施例7
2-[5-(5-(3-苯基,1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸氢盐
按照实施例1所述方法从苯酰胺肟和2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺制得标题化合物,所得草酸氢盐理化数据:
mp 82-84℃;(Found:C,61.57;H,5.12;N,13.03.C19H18N4O.C2H2O4.0.3C2H5OH requires C,61.44;H,5.20;N,13.27%);m/e 318(M+);δ(360MHz,D2O)3.13(2H,t,J=7.0Hz,CH2);3.31(2H,t,J=7.0Hz);4.44(2H,s,CH2);7.23(1H,d,J=7.6Hz,aromatic-H);7.30(1H,s,indole-H);7.49-7.60(4H,m,aromatic-Hs);7.65(1H,s,aromatic-H);7.90(2H,d,J=7.6Hz,aromatic Hs).
实施例8
2-[5-(5-(3-[2-甲氧基苄基]-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸氢盐
按实施例1所述方法从2-甲氧基苄酰胺肟和2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺制备,所得草酸氢盐理化数据:mp 68-70℃;(Found:C,59.73;H,5.33;N,11.97.C21H22N4O2.1.2C2H2O4requires C,59.74;H,5.23;N,11.91%);m/e 363(M+H)+;δ(360MHz,D2O)3.10(2H,t,J=7.0Hz,CH2);3.29(2H,t,J=7.0Hz,CH2);3.68(3H,s,OMe);3.99(2H,s,CH2);4.31(2H,s,CH2);6.96-7.01(2H,m,aromatic-Hs);7.12(1H,dd,J=1.6and8.4Hz,aromatic-H);7.23(1H,d,J=8.4Hz,aromatic-H);7.29(1H,s,indole-H);7.29-7.35(1H,m,aromatic-H);7.45(1H,d,J=8.4Hz,aromatic-H);7.56(1H,s,aromatic-H).
实施例9
N,N-二甲基-2-[5-(5-(3-苄基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺。草酸氢盐
1.N,N-二甲基-2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺
按实施例3所述方法制备,其理化数据:δ(360MHz,CDCl3)1.26(3H,t,J=7.0Hz,Me);2.36(6H,s,N(Me)2);2.62(2H,t,J=7.0Hz,CH2);2.92(2H,t,J=7.0Hz,CH2);3.70(2H,s,CH2);4.16(2H,q,J=7.0Hz,CH2-Me);6.98(1H,br s,indole-H);7.10(1H,dd,J=1.6and8.6Hz,aromatic-H);7.28(1H,d,J=8.6Hz,aromatic-H);7.48(1H,s,aromatic-H).
2.N,N-二甲基-2-[5-(5-(3-苄基-1,2,4-噁二唑)基甲基-1H-吲哚-3-基)乙胺草酸氢盐
按实施例1所述方法从苯乙酰胺肟和前述酯制备,所得草酸氢盐理化数据:mp 174-176℃(isopropyl alcohol);(Found:C,63.79;H,5.91;N,12.31.C22H24N4O.C2H2O4requires C,63.99;H,5.82;N,12.44%);m/e 361(M+H)+;δ(250MHz,D2O)2.88(6H,s,N(Me)2);3.16(2H,t,J=7.3Hz,CH2);3.41(2H,t,J=7.3Hz,CH2);4.06(2H,s,CH2);4.35(2H,s,CH2);7.15(1H,dd,J=1.6and8.4Hz,aromatic-H);7.29-7.40(6H,m,1x indole-H and 5x aromatics);7.46(1H,d,J=8.5Hz,aromatic-H);7.58(1H,br s,aromatic-H).
实施例10
N,N-二甲基-2-[5-(5-(3-甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺。僮半草酸盐
按实施例1所述方法,从甲基乙酰胺肟和N,N-二甲基-2-(5-乙酯基甲基-1H-吲哚-3-基]乙胺制备,所得倍半草酸盐理化数据:mp 159-160℃(isopropyl alcohol);(Found:C,54.03;H,5.61;N,13.31.C16H20N4.1.5(C2H2O4).0.1H2O requires C,54.17;H,5.55;N,13.30%);δ(360MHz,D2O)2.32(3H,s,Me);2.91(6H,s,N(Me)2);3.09(1H,t,J=7.4Hz,CH2);3.21(1H,t,J=7.4Hz,CH2);4.36(2H,s,CH2);7.19(1H,dd,J=1.6and8.4Hz,
aromatic-H);7.34(1H,s,indole-H);7.50(1H,d,J=8.4Hz,aromatic-H);7.61(1H,s,aromatic-H).
实施例11
2-[5-(2-(5-[3-苄基-1,2,4-噁二唑]基)乙基)-1H-吲哚-3-基]乙胺,马来酸盐
1,2-[5-(2-(乙酯基)乙基)-1H-吲哚-3-基]乙胺。马来酸氢盐
按实施例1所述方法从对肼基苯丙酸乙酯和4-氯丁醛二甲基乙缩醛制备,所得马来酸氢盐理化数据:mp 114-116℃(isopropyl alcohol);(Found:C,60.67;H,6.49;N,7.43.C15H20N2O2.C4H4O4requires C,60.63;H,6.43;N,7.44%);m/e 260(M+);δ(360MHz,D2O)1.15(3H,t,J=7.2Hz,Me);2.75(2H,t,J=7.4Hz,CH2);3.06(2H,t,J=7.3Hz,CH2);3.15(2H,t,J=7.3Hz,CH2);3.32(2H,t,J=7.4Hz,CH2);4.08(2H,q,J=7.2Hz,CH2);6.29(2H,s,maleate-Hs);7.14(1H,dd,J=1and8.4Hz,aromatic-H);7.29(1H,s,indole-H);7.46(1H,d,J=8.4Hz,aromatic-H);7.50(1H,s,aromatic-H).
2,2-[5-(2-(5-[3-苄基-1,2,4-噁二唑]基)乙基)-1H-吲哚-3-基]乙胺,马来酸盐
按实施例1所述方法从前述色胺和苯乙酰胺肟制备,所得马来酸盐理化数据:mp 113-114℃(isopropyl-alcohol/ether);(Found:C,68.40;H,6.06;N,13.84.C21H22N4O.C2H2O2requires C,68.30;H,5.98;N,13.85%);m/e346(M+);δ(360MHz,D2O)3.05(2H,t,J=7.0Hz,CH2);3.21(4H,t,J=6.8Hz,2 of CH2);4.00(2H,s,CH2);6.01(1H,s,maleate-H);6.98(1H,dd,J=1.6and8.3Hz,aromatic-H);7.06(2H,d,J=6.7Hz,indole-H and aromatic-H);7.22-7.37(6H,m,aromatic-Hs).
实施例12
2-[5-(3-(5-[3-苄基-1,2,4-噁二唑]基)丙基)-1H-吲哚-3-基]乙胺,草酸盐
1,2-[5-(2-(乙酯基丙-3-基-1H-吲哚-3-基]乙胺
按实施例1所述方法,从对肼苯丁酸乙酯和4-氯丁醛二甲基乙缩醛制备,所得草酸盐理化数据:
δ(250MHz,CDCl3)1.24(3H,t,J=7.2Hz,Me);1.94-2.06(2H,m,CH2);2.34(2H,t,J=7.4Hz,CH2);2.76(2H,t,J=7.4Hz,CH2);2.90(2H,t,J=7.3Hz,CH2);3.03(2H,t,J=7.3Hz,CH2);4.12(2H,q,J=7.2Hz,CH2);7.01(1H,s,indole-H);7.02(1H,dd,J=1.0and8.4Hz,aromatic-H);7.28(1H,d,J=8.4Hz,aromatic-H);7.40(1H,s,aromatic-H);8.00(1H,br s,NH).
2,2-[5-(3-(5-[3-苄基-1,2,4-噁二唑]基)丙基)-1H-吲哚-3-基]乙胺,草酸盐
按常规方法由2-[5-乙氧基丙-3-基-1H-吲哚-3-基]乙胺和苯乙酰胺肟制备标题化合物,草酸盐的理化数据:
mp 188-189℃;(Found:C,68.32;H,6.30;N,13.76.C22H14N4O.0.5(C2H2O4)requires C,68.13;H,6.22;N,13.82%);δ(360MHz,D6-DMSO)1.98-2.07(2H,m,CH2);2.70(2H,t,J=7.3Hz,CH2);2.83-2.96(6H,m,3 of CH2);4.05(2H,s,CH2);6.91(1H,d,J=8.3Hz,aromatic-H);7.14(1H,s,indole-H);7.22-7.34(7H,m,aromatic-H's).
实施例13
2-[5-(3-(5-[3-甲基-1,2,4-噁二唑]基)丙基)-1H-吲哚-3-基]乙胺。马来酸氢盐
按常规方法从2-[5-乙酯基丙-3-基-1H-吲哚-3-基]乙胺和乙酰胺肟制备。所得马来酸氢盐理化数据:mp 136-137℃(isopropylalcohol/ether);(Found:C,60.33;H,6.14;N,14.35.C16H20N4O.0.9(C4H4O4)requires C,60.54;H,6.12;N,14.41%);m/e284(M+);δ(360MHz,D2O)2.14(3H,s,Me);2.80(2H,t,J=7.05Hz,CH2);2.87(2H,t,J=7.05Hz,CH2);3.13(2H,t,J=7.1Hz,CH2);3.34(2H,t,J=7.1Hz,CH2);7.05(1H,dd,J=1.5and8.4Hz,aromatic-H);7.27(1H,s,indole-H);7.38(1H,s,aromatic-H);7.39(1H,d,J=8.4Hz,aromatic-H).
实施例14
2-[5-(3-(5-[3-环丙基-1,2,4-噁二唑)基)丙基)-1H-吲哚-3-基]乙胺。马来酸氢盐
按实施例1所述方法从2-[5-乙酯基丙-3-基-1H-吲哚-3-基]乙胺和环丙酰胺肟制备。所得马来酸氢盐理化数据:mp 130-132℃;(Found:C,61.36;H,6.15;N,12.90.C18H22N4O.0.25H2O requires C,61.31;H,6.19;N,13.00%);m/e310(M+);δ(360MHz,D6-DMSO)0.83-0.88(2H,m,CH2);1.00-1.06(2H,m,CH2);1.98-2.11(3H,m,CH and CH2);2.71(2H,t,J=7.6Hz,CH2);2.90(2H,t,J=7.6Hz,CH2);3.00(2H,t,J=7.13Hz,CH2);3.08(2H,t,J=7.13Hz,CH2);6.95(1H,dd,J=1.4and8.2Hz,aromatic-H);7.19(1H,d,J=1.4Hz,aromatic-H);7.29(1H,d,J=8.2Hz,aromatic-H);7.33(1H,s,indole-H);7.70(1H,br s,NH).
实施例15
2-[5-(5-(3-苯基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺。草酸氢盐
按常规方法从2-(5-乙酯基-1H-吲哚-3-基)乙胺和苯酰胺肟制备,所得草酸氢盐理化数据:mp 212-213℃(methanol);(Found:C,61.90;H,4.97;N,14.64.C18H16N4O.0.85(C2H2O4)requires C,62.12;H,4.68;N,14.71%);δ(250MHz,CDCl3,freebase)3.00(2H,t,J=7.4Hz,CH2);3.10(2H,t,J=7.4Hz,CH2);7.16(1H,s,indole-H);7.46-7.54(5H,m,aromatic-H);8.05(1H,dd,J=1.8and8.4Hz,aromatic-H);8.18-8.22(2H,m,aromatic-H);8.18(1H,br s,NH);8.54(1H,s,aromatic-H).
除非另有说明,实施例16-26均按实施例1所述方法从2-(5-乙酯基-1H-吲哚-3-基乙胺和适当的酰胺肟制备。
实施例16
2-[5-(5-(3-二苯基甲基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,倍半草酸盐
粗品以二氯甲烷/乙醇/氨(60∶8∶1)为洗提剂经硅凝胶色谱分离。所得倍半草酸盐理化数据:mp 117-118℃;(Found:C,
63.22;H,5.40;N,9.90.C25H22N4O.1.4(C2H4O2).0.7.C2H5OH requires C,63.44;H,5.29;N,10.14%);δ(360MHz,D6-DMSO)3.06(4H,br s,2 of CH2);5.81(1H,s,CH);7.26-7.43(11H,m,aromatic-H's);7.57(1H,d,J=8.5Hz,aromatic-H);7.83(1H,dd,J=1.4and8.5Hz,aromatic-H);7.95(1H,br s,NH);8.37(1H,s,aromatic-H).
实施例17
2-[5-(5-(3-(2-甲氧基苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐
所得草酸盐理化数据:mp 244-245℃(isopropyl alcohol/ether);(Found:C,63.45;H,5.47;N,13.97.C20H20N4O2.0.6(C2H2O4)requires C,63.27;H,5.31;N,13.92%);m/e349(M++1);δ(360MHz,CF3CO2D)3.88(2H,br s,CH2);4.31(2H,br s,CH2);4.43(3H,s,OMe);4.93(2H,s,CH2);7.35(1H,br s,NH);7.57(2H,d,J=7.5Hz,aromatic-H's);7.85(1H,d,J=7.5Hz,aromatic-H);7.92-7.96(2H,m,aromatic-H's);8.22(1H,d,J=8.8Hz,aromatic-H);8.53(1H,d,J=8.8Hz,aromatic-H);9.10(1H,s,aromatic-H).
实施例18
2-[5-(5-(3-(3-甲氧基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,马来酸氢盐
所得马来酸氢盐理化数据:mp 173-175℃(isopropylalcohol/ether);(Found:C,61.82;H,5.33;N,11.92.C20H20N4O2.C4H4O4.0.1H2O requires C,61.82;H,5.23;N,12.01%);δ(360MHz,D6-DMSO)3.07(4H,br s,2 of CH2);3.75(3H,s,OMe);4.12(2H,s,CH2);6.85(1H,dd,J=2.2and8.6Hz,aromatic-H);6.92(1H,d,J=7.3Hz,aromatic-H);6.93(1H,s,aromatic-H);7.27(1H,dd,J=7.7and7.7Hz,aromatic-H);7.42(1H,d,J=2.2Hz,aromatic-H);7.56(1H,d,J=8.6Hz,aromatic-H);7.71(2H,br s,NH2);7.82(1H,dd,J=1.5and8.6Hz,aromatic-H);8.37(1H,s,aromatic-H);11.48(1H,s,NH).
实施例19
2-[5-(5-(3-(4-甲氧基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,马来酸氢盐
所得马来酸氢盐理化数据:mp 195-196℃(isopropyl alcohol/ether);(Found:C,61.95;H,5.30;N,11.99.C20H20N4O2.C4H4O4requires C,62.06;H,5.21;N,12.06%);δ(360MHz,D6-DMSO/D2O)3.15(2H,t,J=7.3Hz,CH2);3.32(2H,t,J=7.3Hz,CH2);3.80(3H,s,Me);4.04(2H,s,CH2);6.98(2H,d,J=8.7Hz,aromatic-H's);7.33(2H,d,J=8.7Hz,aromatic-H's);7.35(1H,s,aromatic-H);7.55(1H,d,J=8.6Hz,aromatic-H);7.76(1H,dd,J=1.6and8.6Hz,aromatic-H);8.24(1H,s,aromatic-H).
实施例20
2-[5-(5-(3-(4-乙酰氨基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,二草酸盐
按实施例6所述方法制备。所得二草酸盐理化数据:
mp 113-115℃;(Found:C,53.67;H,4.67;N,13.46.C21H21N5O2.2(C2H4O2).0.25H2O requires C,53.62;H,4.59;N,13.51%);δ(360MHz,D6-DMSO)2.03and2.08(total 3H,s,Me);3.07(4H,br s,2 of CH2);3.92and4.08(total 2H,s,CH2);6.53and7.27(total 2H,d,J=8.3Hz,aromatic-H's);7.41(1H,s,aromatic-H);7.53(1H,d,J=8.5Hz,aromatic-H);7.80(1H,dd,J=1.5and8.5Hz,aromatic-H);7.97(2H,br s,NH2);8.35(1H,s,aromatic-H);9.94(1H,s,NH);11.54(1H,s,NH).
实施例21
2-[5-[5-(3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,倍半草酸盐
按实施例6所述方法制备,所得倍半草酸盐理化数据:
mp 219-220℃;(Found:C,50.91;H,4.61;N,12.59.C20H21N5O3.1.5(C2H2O4)requires C,50.55;H,4.43;N,12.81%);δ(360MHz,D6-DMSO)2.97(3H,s,Me);3.06(4H,br s,2 of CH2);4.10(2H,s,CH2);7.18(2H,d,J=8.4Hz,aromatic-H's);7.32(2H,d,J=8.4Hz,aromatic-H's);7.42(1H,s,aromatic-H);7.55(1H,d,J=8.6Hz,aromatic-H);8.36(1H,s,aromatic-H);9.70(1H,br s,NH);11.50(1H,s,NH).
实施例22
2-[5-[5-(3-苯乙基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,倍半草酸盐
所得倍半草酸盐理化数据:mp 144-146℃;(Found:C,58.05;H,5.00;N,11.67.C20H20N4O.1.6(C2H2O4).0.2H2O requires C,57.90;H,5.20;N,11.53%);m/e 333(M++1);δ(360MHz,CD3OD)3.04-3.20(4H,m,2 of CH2);3.26-3.33(4H,m,2 of CH2);7.15-7.28(5H,m,aromatic-H's);7.33(1H,s,aromatic-H);7.55(1H,d,J=8.49Hz,aromatic-H);7.90(1H,dd,J=1.6 and8.49Hz,aromatic-H);8.42(1H,s,aromatic-H).
实施例23
2-[5-[5-(3-苯丙基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,马来酸氢盐
所得马来酸氢盐理化数据:mp 150-151℃(isopropyl alcohol/ether);(Found:C,63.65;H,5.64;N,11.87.C21H22N4O.1.17(C4H4O4)requires C,63.93;H,5.57;N,11.60%);δ(360MHz,D6-DMSO/D2O)2.02-2.18(2H,m,CH2);2.65-2.84(4H,m,2 of CH2);3.14-3.24(2H,m,CH2);3.28-3.40(2H,m,CH2);7.16-7.44(6H,m,aromatic-H);7.56-7.68(1H,m,aromatic-H);7.74-7.86(1H,m,aromatic-H);8.24-8.35(1H,m,aromatic-H).
实施例24
2-[5-[5-(3-环丙基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,半琥珀酸盐
所得半琥珀酸盐理化数据:mp 205-207℃(isopropylalcohol/ether);(Found:C,61.89;H,5.91;N,16.88.C15H16N3O.0.5(C4H6O4).0.15H2O requires C,61.86;H,5.89;N,16.97%);δ(360MHz,D6-DMSO)0.98-1.05(2H,m,CH2);1.07-1.13(2H,m,CH2);2.13-2.20(1H,m,CH);2.95(4H,m,2 of CH2);7.36(1H,s,aromatic-H);7.53(1H,d,J=8.6Hz,aromatic-H);7.77(1H,dd,J=1.5and8.6Hz,aromatic-H);8.30(1H,s,aromatic-H);11.39(1H,br s,NH).
实施例25
2-[5-[5-(3-乙基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,二草酸盐水半合物
所得二草酸盐半水合物理化数据:mp 195-197℃;(Found:C,48.34;H,4.71;N,12.41.C14H16N4O.2(C2H2O4).0.5H2Orequires C,48.54;H,4.75;N,12.57%);m/e 257(M++1);δ(360MHz,D6-DMSO)1.30(3H,t,J=7.6Hz,Me);2.78(2H,q,J=7.6Hz,CH2);3.08(4H,br s,2 of CH2);7.43(1H,d,J=1.8Hz,aromatic-H);7.57(1H,d,J=8.5Hz,aromatic-H);7.82(1H,dd,J=1.8and8.5Hz,aromatic-H);7.96(2H,br s,NH2);8.38(1H,s,aromatic-H).
实施例26
2-[5-[5-(3-(4-三氟甲基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,二草酸盐
所得二草酸盐理化数据:mp 125-127℃;(Found:C,50.26;H,4.07;N,9.73.C20H17F3N4O.2(C2H2O4).0.25H2O requires C,50.09;H,3.86;N,9.73%);m/e387(M++1);δ(360MHz,D6-DMSO)3.06(4H,br s,2 of CH2);4.29(2H,s,CH2);7.43(1H,s,aromatic-H);7.56(1H,d,J=8.5Hz,aromatic-H);7.60(2H,d,J=8.1Hz,aromatic-H's);7.73(2H,d,J=8.1Hz,aromatic-H's);7.81(1H,d,J=8.5Hz,aromatic-H);7.91(1H,br s,NH);8.36(1H,s,aromatic-H).
实施例27
N,N-二甲基-2-[5-[5-(3-(4-乙酰氨基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,琥珀酸盐二水合物
按实施例6所述方法从N,N-二甲基-2-(5-乙酯基-1H-吲哚-3-基)乙胺和4-乙酰氨基苄基酰胺肟制备标题化合物,所得琥珀酸盐理化数据。mp 76-79℃;(Found:C,58.05;H,6.02;N,12.52.C23H25N5O2.C4H6O4.2H2O requires C,58.12;H,6.32;N,12.56%);m/e404(M++1);δ(360MHz,D6-DMSO)2.02(3H,s,Me);2.44(6H,s,N(Me)2)2.81(2H,t,J=7.2Hz,CH2);2.97(2H,t,J=7.2Hz,CH2);4.08(2H,s,CH2);7.27(2H,d,J=8.5Hz,aromatic-H's);7.36(1H,s,aromatic-H);7.52(1H,d,J=8.5Hz,aromatic-H);7.53(2H,d,J=8.5Hz,aromatic-H's);7.78(1H,dd,J=1.5and8.5Hz,aromatic-H);8.32(1H,s,aromatic-H);9.90(1H,s,NH);11.37(1H,s,NH).
实施例28
N,N-二甲基-2-[5-[5-(3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,琥珀酸盐二水合物
按实施例6所述方法从N,N-二甲基-2-(5-乙酯基-1H-吲哚-3-基)乙胺和4-甲磺酰基氨基苄基酰胺肟制备,所得琥珀酸盐理化数据:mp 65-66℃;(Found:C,52.99;H,5.74;N,11.86.C22H15N5SO3.C4H6O4.1.75H2O requires C,53.00;H,5.90;N,11.88%);m/e440(M++1);δ(360MHz,D6-DMSO)2.50(6H,s,N(Me)2);2.96(3H,s,Me);2.86-3.04(4H,m,2 of CH2);4.10(2H,s,CH2);7.18(2H,d,J=8.3Hz,aromatic-H);7.32(2H,d,J=8.3Hz,aromatic-H);7.37(1H,s,aromatic-H);7.53(1H,d,J=8.4Hz,aromatic-H);7.79(1H,d,J=8.4Hz,aromatic-H);8.33(1H,s,aromatic-H);11.40(2H,s,2 of NH).
实施例29
2-[5-(5-(3-萘-2-基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基]乙胺,倍半草酸盐
按实施例1所述方法从2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺和2-萘酰胺肟制备,所得倍半草酸盐理化数据:mp 195-197℃(isopropylalcohol/ether);(Found:C,61.07;H,4.54;N,11.15.C23H21N4O.1.6(C2H2O4)requires C,61.28;H,4.75;N,10.91%);δ(360MHz,D6-DMSO)2.99(2H,t,J=7.3Hz,CH2);3.07(2H,t,J=7.3Hz,CH2);4.51(2H,s,CH2);7.15(1H,dd,J=1.6and8.4Hz,aromatic-H);7.26(1H,d,J=1.6Hz,aromatic-H);7.38(1H,d,J=8.4Hz,aromatic-H);7.59-7.64(3H,m,aromatic-H's);7.99-8.13(4H,m,aromatic-H's);8.60(1H,s,aromatic-H).
实施例30
N,N-二甲基-2-[5-[5-(3-氨基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基]乙胺,半琥珀酸盐水合物
按实施例6所述方法从N,N-二甲基-2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺和羟基硫酸胍制备,所得半琥珀酸盐理化数据:
mp 150-153℃;(Found:C,56.63;H,6.62;N,18.80.C15H19N5O.0.6(C4H6O4).0.75H2O requires C,56.53;H,6.57;N,18.94%);m/e285(M+);δ(360MHz,D2O)2.92(6H,s,Me);3.22(2H,t,J=7.4Hz,CH2);3.47(2H,t,J=7.4Hz,CH2);4.28(2H,s,CH2);7.22(1H,dd,J=1.5and8.4Hz,aromatic-H);7.35(1H,s,aromatic-H);7.52(1H,d,J=8.4Hz,aromatic-H);7.62(1H,s,aromatic-H).
实施例31
2-[5-[2-(5-(3-氨基-1,2,4-噁二唑)基)乙基]-1H-吲哚-3-基]乙胺,马来酸氢盐水合物
按实施例6所述方法从2-[5-(2-(乙酯基)乙基-1H-吲哚-3-基]乙胺和羟基硫酸胍制备标题化合物,所得马来酸氢盐理化数据:
mp 147-148℃(isopropylalcohol/ether);(Found:C,53.89;H,5.47;N,17.67.C14H17N5O.C4H4O4.0.75H2O requires C,53.93;H,5.65;N,17.47%);δ(360MHz,D2O)3.12(2H,t,J=6.9Hz,CH2);3.17(4H,t,J=4.1Hz,2 of CH2);3.29(2H,t,J=6.9Hz,CH2);7.11(1H,dd,J=1.5and8.4Hz,aromatic-H);7.27(1H,s,aromatic-H);7.40(1H,s,aromatic-H);7.44(1H,d,J=8.4Hz,aromatic-H).
实施例32
2-[5-[2-(5-(3-二甲氨基-1,2,4-噁二唑)基)乙基]-1H-吲哚-3-基]乙胺,半琥珀酸盐
按实施例6所述方法从2-[5-(2-(乙酯基)乙基-1H-吲哚-3-基]乙胺和二甲氨基酰胺肟制备,所得半琥珀酸盐理化数据:
mp 184-185℃;(Found:C,59.83;H,6.79;N,18.41.C16H21N5O.0.62(C4H6O4)requires C,59.57;H,6.69;N,18.79%);δ(360MHz,D2O)2.90(6H,s,N(Me)2);3.12-3.20(6H,m,3 of CH2);3.30(2H,t,J=6.7Hz,CH2);7.09(1H,dd,J=1.6and8.4Hz,aromatic-H);7.29(1H,s,aromatic-H);7.43(1H,s,aromatic-H);7.45(1H,d,J=8.4Hz,aromatic-H).
实施例33
2-[5-[3-(5-甲基-1,2,4-噁二唑)基]乙基]-1H-吲哚-3-基]乙胺,二草酸盐
1.2-(5-酰胺肟-1H-吲哚-3-基)乙胺
将羟基酰胺盐酸化物(1.2g,17.3mmol)加入搅拌着的钠金属(0.4g,17.5mmol)的甲醇(10ml)溶液中,接着再加入2-(5-氰基-1H-吲哚-3-基)乙胺(1.25g,6.8mmol)溶液,混合液回流16小时,经hyflo助滤剂过滤,真空去溶剂,残留物以二氯甲烷/乙醇/氨(30∶8∶1)为洗提剂经硅凝胶色谱分离得标题产物。其理化数据:
mp 79-82℃;δ(360MHz,CD3OD)2.90-2.96(4H,m,2 of CH2);7.12(1H,s,aromatic-H);7.34(1H,d,J=8.5Hz,aromatic-H);7.41(1H,dd,J=1.6and8.5Hz,aromatic-H);7.87(1H,s,aromatic-H).
2,2-[5-[3-(5-甲基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,二草酸盐
将前述吲哚基酰胺肟(0.35g,1.6mmol),氢化钠(80%油分散体,0.1g,3.2mmol)和乙酸乙酯(0.5g,5.7mmol)的乙醇(20mmol)溶液加热回流2小时,真空去溶剂,残留物以二氯甲烷/乙醇/氨(40∶8∶1)为洗提剂经硅凝胶色分离得标题产物(0.3g),其理化数据:
mp 178-180℃;(Found:C,48.68;H,4.58;N,13.04.C13H14N4O.2(C2H2O4)requires C,48.35;N,4.30;N,13.27%);m/e242(M+);δ(360MHz,D2O)2.55(3H,s,Me);3.15(2H,t,J=7.2Hz,CH2);3.34(2H,t,J=7.2Hz,CH2);7.33(1H,s,aromatic-H);7.51(1H,d,J=8.4Hz,aromatic-H);7.61(1H,dd,J=1.6and8.4Hz,aromatic-H);7.97(1H,d,J=1.6Hz,aromatic-H).
实施例34
2-[5-(3-(5-苄基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺,马来酸氢盐
按实施例33所述方法从2-(5-酰胺肟-1H-吲哚-3-基)乙胺和苯乙酸乙酯制备,所得马来酸氢盐理化数据:mp 184-186℃;(Found:C,64.10;H,5.23;N,13.25.C19H18N4O.0.9(C4H4O4)requires C,64.19;H,5.15;N,13.25%);δ(360MHz,D2O)3.13(2H,t,J=7.3Hz,CH2);3.22(2H,t,J=7.3Hz,CH2);4.35(2H,s,CH2);7.26(1H,s,aromatic-H);7.28-7.40(5H,m,aromatic-H's);7.47(1H,d,J=8.6Hz,aromatic-H);7.82(1H,dd,J=1.3and8.6Hz,aromatic-H);8.30(1H,s,aromatic-H).
实施例35
2-[5-(3-(5-甲基-1,2,4-噁二唑)基甲基[-1H-吲哚-3-基]乙胺,马来酸氢盐
1.2-(5-乙酰胺肟-1H-吲哚-3-基)乙胺
按实施例33所述制备方法从2-(5-氰基甲基-1H-吲哚-3-基)乙胺和羟基胺制备:
δ(360MHz,CD3OD)3.28-3.35(4H,m,2 of CH2);3.47(2H,s,CH2);7.04(1H,d,J=8.4Hz,aromatic-H);7.06(1H,s,aromatic-H);7.28(1H,d,J=8.4Hz,aromatic-H);7.48(1H,s,aromatic-H).
2.2-[5-(3-(5-甲基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基]乙胺,马来酸氢盐
按常规方法从前述吲哚基乙酰胺肟和乙酸乙酯制备,所得马来酸氢盐理化数据:mp 145-149℃;(Found:C,58.38;H,
5.70;N,15.30.C14H16N4O.C4H4O4requires C,58.06;H,5.41;N,15.05%);m/e256(M+);δ(360MHz,D2O)2.55(3H,s,Me);3.16(2H,t,J=7.0Hz,CH2);3.34(2H,t,J=7.0Hz,CH2);4.18(2H,s,CH2);7.18(1H,d,J=8.4Hz,aromatic-H);7.32(1H,s,aromatic-H);7.50(1H,d,J=8.4Hz,aromatic-H);7.60(1H,s,aromatic-H).
实施例36
2-[5-[3-(5-苄基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基)乙胺,马来酸氢盐
按常规方法从2-(5-乙酰胺肟-1H-吲哚-3-基)乙胺和苯乙酸乙酯制备,所得马来酸氢盐理化数据:
mp 143-144℃;(Found:C,64.27;H,5.56;N,12.42.C20H20N4O.C4H4O4requires C,64.28;H,5.39;N,12.49%);δ(360MHz,D2O)3.11(2H,t,J=7.3Hz,CH2);3.28(2H,t,J=7.3Hz,CH2);4.16(2H,s,CH2);4.27(2H,s,CH2);7.13(1H,dd,J=1.5and8.4Hz,aromatic-H);7.29(1H,s,aromatic-H);7.32-7.41(5H,m,aromatic-H);7.44(1H,d,J=8.4Hz,aromatic-H);7.56(1H,s,aromatic-H).
实施例37
N,N-二甲基-2-[5-[3-(5-苄基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基]乙胺,琥珀酸盐
将甲醛(35%水溶液,0.85ml)的甲醇(10ml)溶液滴加入搅拌的2-[5-[3-(5-苄基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基]乙胺(0.4g,1.2mmol)、氰基硼氢化钠(0.13g,2.05mmol)和冰醋酸(0.34g)的甲醇(15ml)溶液中,搅拌2.5小时后,用饱和K2CO3溶液碱化,用乙酸乙酯(3×50ml)萃取,合并的萃取液用MgSO4干燥,蒸发后,以二氯甲烷/乙醇/氨(60∶8∶1)为洗提剂经硅凝胶色谱分离,得标题产物(0.33g),所得琥珀酸盐理化数据:
mp 195-196℃;(Found:C,64.66;H,6.37;N,11.55.C22H24N4O.1.1(C4H6O4)requires C,64.66;H,6.29;N,11.43%);m/e360(M+);δ(360MHz,D2O)2.89(6H,s,N(Me)2);3.18(2H,t,J=7.4Hz,CH2);3.43(2H,t,J=7.4Hz,CH2);4.16(2H,s,CH2);4.27(2H,s,CH2);7.14(1H,d,J=8.4Hz,aromatic-H);7.31-7.40(6H,m,aromatic-H's);7.44(1H,d,J=8.4Hz,aromatic-H);7.56(1H,s,aromatic-H).
除非另有说明,实施例38-48均按实施例6所述方法从2-(5-乙酯基-1H-吲哚-3-基)乙胺和适当的酰胺肟制备。
实施例38
2-[5-(5-(3-甲氧基甲基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,半琥珀酸盐
所得半琥珀酸盐理化数据:
mp 207-210℃(methanol/diethylether);(Found:C,58.01;H,5.85;N,16.85.C14H16N4O2.0.5(C4H6O4)requires C,58.00;H,5.78;N,16.91%);δ(360MHz,D2O)3.21(2H,t,J=7.2Hz,CH2);3.35(2H,t,J=7.2Hz,CH2);3.51(3H,s,Me);4.68(2H,s,CH2OMe);7.43(1H,s,Ar-H);7.65(1H,d,J=8.6Hz,Ar-H);7.90(1H,dd,J=8.6and1.6Hz,Ar-H);8.41(1H,d,J=1.6Hz,Ar-H).
实施例39
2-[5-(5-(3-(4-N-甲基氨基甲酰苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,琥珀酸盐水合物
所得琥珀酸盐理化数据:
mp 108-110℃;(Found:C,59.12;H,5.59;N,14.05.C21H21N5O2.(C4H6O4).0.75H2O requires C,59.22;H,5.66;N,13.82%).δ(360MHz,D6-DMSO)2.77(3H,d,J=4.5Hz,CH3);3.01(4H,br s,2 of CH2);4.21(2H,s,CH2);7.40(1H,s,Ar-H);7.43(2H,d,J=8.2Hz,Ar-H);7.55(1H,d,J=8.6Hz,Ar-H);7.79-7.81(2H,d,J=8.2Hz,Ar-H);7.79-7.81(1H,d,J=8.6Hz,Ar-H);8.35(1H,s,Ar-H);8.39(1H,br q,J=4.5Hz,NH).
实施例40
2-[5-(5-(3-(4-N-甲基氨基甲酰苯基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,琥珀酸盐水合物
所得琥珀酸盐理化数据:mp 126-128℃;(Found:C,58.31;H,5.21;N,14.22.C20H19N5O2.(C4H6O4).0.75H2O requires C,58.47;H,5.41;N,14.21%);δ(360MHz,D6-DMSO)2.83(3H,d,J=4.5Hz,CH3);3.06(4H,br s,2 of CH2);3.37(2H,br s,NH2);7.44(1H,s,Ar-H);7.62(1H,d,J=8.5Hz,Ar-H);7.94(1H,dd,J=1.6and8.5Hz,Ar-H);8.04(2H,d,J=8.5Hz,Ar-H);8.19(2H,d,J=8.5Hz,Ar-H);8.49(1H,s,Ar-H);8.62(1H,br q,J=4.5Hz,NH).
实施例41
2-[5-(5-(3-(4-甲氨基磺酰基苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,二琥珀酸盐水合物
所得二琥珀酸盐理化数据:
mp 49-50℃(hygroscopic salt);(Found:C,50.91;H,5.47;N,10.79.C20H21N5SO3.2(C4H6O4).0.75H2O requires C,50.87;H,5.26;N,10.59%).δ(360MHz,D2O)2.55(3H,s,CH3);3.16(2H,t,J=7.1Hz,CH2);3.32(2H,t,J=7.1Hz,CH2);4.26(2H,s,CH2);7.38(1H,s,Ar-H);7.58(1H,d,J=8.9Hz,Ar-H);7.62(2H,d,J=8.4Hz,Ar-H);7.79(1H,dd,J=1.6and8.9Hz,Ar-H);7.84(2H,d,J=8.4Hz,Ar-H);8.31(1H,d,J=1.6Hz,Ar-H).
实施例42
2-[5-(5-(3-(4-二甲基氨基磺酰基苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,盐酸化物水合物
所得盐酸化物-水合物盐理化数据:mp 144-145℃(MeOH)/Et2O);(Found:C,52.71;H,5.50;N,14.44.C21H24N5SO3Cl.1H2O requires C,52.55;H,5.46;N,14.59%).
实施例43
2-[5-(5-(3-(3-甲磺酰氨基苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,盐酸化物二水合物
所得盐酸化物二水合物盐理化数据:
mp 241-242℃;(Found:C,48.54;H,5.05;N,13.59.C20H21N5SO3.1.2HCl.2.4H2O requires C,48.19;H,5.45;N,14.05%).
实施例44
2-[5-(5-(3-(4-氨基甲酰氨基苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,倍半草酸盐半水合物
所得倍半草酸盐半水合物盐理化数据:
mp 194-197℃;(Found:C,52.8;H,4.75;N,16.42.C20H21N6O2.1.5(C2H2O4).0.5H2O requires C,53.1;H,4.65;N,16.15%).
实施例45
2-[5-(5-(3-氨基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,二草酸盐水化物
所得二草酸盐理化数据:mp 160-164℃;(Found:C,39.90;H,4.29;N,21.37.C12H13N5O.2(C2H2O4).0.9(CH5N3O).0.75H2O requires C,40.24;H,4.60;N,21.38%);δ(360MHz,D2O)3.15(2H,t,J=7.1Hz,CH2);3.34(2H,t,J=7.1Hz,CH2);7.33(1H,s,Ar-H);7.51(1H,d,J=8.5Hz,Ar-H);7.69(1H,dd,J=1.5and8.5Hz,Ar-H);8.12(1H,d,J=1.5Hz,Ar-H).
实施例46
2-[5-(5-(3-乙酰氨基甲基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,半琥珀酸盐-水合物
所得半琥珀酸盐-水合物理化数据:
mp 107-110℃;(Found:C,54.47;H,6.28;N,17.81.C15H17N5O2.0.5(C4H6O4).1H2O.0.2(iPA)requires C,54.43;H,6.13;N,18.03%);δ(360MHz,D2O)2.14(3H,s,CH3);3.14(2H,t,J=7.1Hz,CH2);3.34(2H,t,J=7.1Hz,CH2);4.51(2H,s,CH2);7.33(1H,s,Ar-H);7.49(1H,d,J=8.7Hz,Ar-H);7.68(1H,dd,J=1.5and8.7Hz,Ar-H);8.09(1H,d,J=1.5Hz,Ar-H).
实施例47
2-[5-(5-(3-(2-乙酰氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐半水合物
所得草酸盐半水合物理化数据:mp 188-189℃;(Found:C,52.48;H,5.56;N,16.77.C16H19N5O2.C2H2O4.0.6H2O requires C,52.20;H,5.40;N,16.90%).
实施例48
2-[5-(5-(3-氨甲基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,琥珀酸盐二水合物
所得琥珀酸盐二水合物理化数据:mp 125-130℃;(Found:C,49.13;H,6.06;N,16.99.C13H15N5O.2(C4H6O4).2.2H2O requires C,49.19;H,6.16;N,16.87%).
实施例49-54均按实施例6所述方法从N,N-二甲基-2-(5-乙酯基-1H-吲哚-3-基)乙胺和适当的酰胺肟制备。
实施例49
N,N-二甲基-2-[5-(5-(3-氨基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,二草酸盐一水合物
所得二草酸盐一水化合物理化数据:
mp 156-158℃;(Found:C,46.49;H,4.66;N,15.83.C14H17N5O.1.8(C2H2O4)1H2O requires C,46.83;H,5.04;N,15.52%);δ(360MHz,D2O)2.93(6H,s,2 of CH3);3.18(2H,t,J=7.6Hz,CH2);3.46(2H,t,J=7.6Hz,CH2);7.33(1H,s,Ar-H);7.48(1H,d,J=8.7Hz,Ar-H);7.65(1H,dd,J=8.7and1.5Hz,Ar-H);8.04(1H,d,J=1.5Hz,Ar-H).
实施例50
N,N-二甲基-2-[5-(5-(3-乙酰氨基甲基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,琥珀酸盐半水合物
所得琥珀酸盐半水合物理化数据:mp 65-70℃(hygroscopic);(Found:C,56.14;H,6.03;N,16.02.C17H21N5O2.0.8(C4H6O4).0.6H2O requires C,56.08;H,6.29;N,16.19%);δ(360MHz,D2O)2.16(3H,s,CH3);2.96(6H,s,2 of
CH3);3.15(2H,t,J=7.8Hz,CH2);3.45(2H,t,J=7.8Hz,CH2);4.50(2H,s,CH2);7.31(1H,s,Ar-H);7.45(1H,d,J=8.6Hz,Ar-H);7.61(1H,dd,J=8.6and1.5Hz,Ar-H);7.96(1H,d,J=1.5Hz,Ar-H).
实施例51
N,N-二甲基-2-[5-(5-(3-(2-乙酰氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,倍半草酸盐一水合物
所得倍半草酸盐一水合物理化数据:
mp 35℃(hygroscopic);(Found:C,51.76;H,5.73;N,14.17.C18H23N5O2.1.4(C2H2O4).0.9H2O requires C,51.65;H,5.75;N,14.47%).
实施例52
N,N-二甲基-2-[5-(5-(3-(4-氨基甲酰氨基苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,盐酸化物
所得盐酸化物理化数据:
mp 214-215℃;(Found:C,57.70;H,6.13;N,17.34.C22H24N6O2.1.25HCl.1.0C2H5OH requires C,58.10;H,6.35;N,16.94%).
实施例53
N,N-二甲基-2-[5-(5-(3-(2-叔丁氧基羰基氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐
所得草酸盐理化数据:
mp 184-185℃;(Found:C,55.97;H,6.38;N,14.18.C21H30N5O3.C2H2O4.0.3H2O requires C,55.82;H,6.44;N.14.15%).
实施例54
N,N-二甲基-2-[5-(5-(3-(4-N-甲基氨基甲酰苄基)-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,半草酸盐二水合物
所得半草酸盐二水合物理化数据:
mp 109-111℃;(Found:C,59.88;H,5.99;N,14.24.C23H25N5O2.0.5(C2H2O4).1.9H2O requires C,59.71;H,6.22;N,14.51%).
实施例55
N,N-二甲基-2-[5-(5-(3-(2-氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,倍半草酸盐半水合物
将三氟乙酸(25ml,0.133mol)加入N,N-二甲基-2-[5-(5-(3-(2-叔丁酯基氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺(0.5g,1.25mmol)的无水CH2Cl2(10ml)溶液中,于25℃下搅拌1小时,真空去溶剂,再加K2CO3水溶液(30ml),并用EtOAc(6×200ml)萃取,合并萃取液,干燥和蒸发后得标题胺(0.36g,96%),所得倍半草酸盐理化数据:
mp 220-221℃;(Found:C,50.81;H,5.78;N,15.49.C16H21N5O.1.6(C2H2O4)0.5H2O requires C,50.97;H,5.61;N,15.48%);δ(360MHz,D2O)2.95(6H,s,2 of CH3);3.22-3.29(4H,m,2 of CH2);3.52(4H,t,J=7.2Hz,2 of CH2);7.42(1H,s,Ar-H);7.61(1H,d,J=8.6Hz,Ar-H);7.86(1H,d,J=8.6Hz,Ar-H);8.32(1H,s,Ar-H).
实施例56
N,N-二甲基-2-[5-(5-(3-(2-甲磺酰基氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐,1.5水合物
在-30℃下,将甲磺酰氯(0.14ml,1.81mmol)的CH2Cl2(10ml)溶液滴加入搅拌着的前述胺(实施例55;0.36g,1.2mmol)的CH2Cl2(10ml)和吡啶(0.29ml;3.6mmol)溶液中,该溶液搅拌1小时,让其升至室温,真空去溶剂,残留物以CH2Cl2/EtOH/NH3(90∶8∶1)为洗提剂用硅凝胶色谱提纯,所得草酸盐理化数据:
mp<30℃(hygroscopic);(Found:C,46.15;H,5.71;N,14.16.C17H23N5SO3.C2H2O4.1.5H2O requires C,46.39;H,5.49;N,14.12%).δ(360MHz,D2O)2.94(6H,s,2 of CH3);2.99(2H,t,J=6.5Hz,CH2);3.09(3H,s,CH3);3.16-3.24(2H,m,CH2);3.48(2H,t,J=7.4Hz,CH2);3.55(2H,t,J=6.5Hz,CH2);7.35(1H,s,Ar-H);7.52(1H,d,J=8.6Hz,Ar-H);7.72(1H,dd,J=1.6and8.6Hz,Ar-H);8.13(1H,d,J=1.6Hz,Ar-H).
实施例57
N,N-二甲基-2-[5-(5-(3-(2-氨基甲酰氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,倍半草酸盐
在20℃下,将羰基二咪唑(0.26g,1.6mmol)加到实施例55(0.4g,1.53mmol)的无水THF(20ml)溶液中,该溶液升至室温后搅拌3小时,向溶液中通入氨气,鼓泡8小时,真空除去溶剂,残留物以CH2Cl2/EtOH/NH3(60∶8∶1)为洗提剂经硅凝胶色谱分离,得标题脲,所得倍半草酸盐理化数据:mp 81-82℃;(Found:C,49.25;H,5.44;N,16.42.C17H22N6O2.1.7(C2H2O4).0.5(MeOH)requires C,49.08;H,5.40;N,16.43%).
实施例58
N,N-二甲基-2-[5-(5-(3-(2-N-甲基氨基甲酰氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐
室温下,向实施例55(0.5g,1.67mmol)的CH2Cl2(30ml)溶液中滴加异氰酸甲酯(0.105g,1.84mmol)的CH2Cl2(10ml)溶液,该溶液搅拌1小时后真空去溶剂,制得草酸盐产物,其理化数据:mp:185-188℃;(实测值:C,53.27;H,5.92;N,18.66;C18H24N6O2·C2H2O4·0.25H2O,理论值:C,53.27;H,5.92;N,18.64%)。
实施例59
N,N-二甲基-2-[5-(5-(3-(2-甲酯基氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐
在0℃下,将三乙胺(0.60ml)和氯甲酸甲酯(0.33ml)加入实施例55(0.14g,0.45mmol)的无水CH2Cl2(7ml)溶液中,让反应混合物升温至室温后,搅拌16小时,碱化得到粗产品,用CH2Cl2/MeOH/NH3(80∶16∶1)作洗提剂在硅凝胶上色谱提纯,从粗产品所得到的草酸盐理化数据:
mp 175-181℃;(Found:C,53.28;H,5.46;N,15.45.C18H23N5O3.C2H2O4.0.1H2O requires C,53.47;H,5.65;N,15.59%).
实施例60
N,N-二甲基-2-[5-(5-(3-(2-乙酯基氨基)乙基-1,2,4-噁二唑)基)-1H-吲哚-3-基]乙胺,草酸盐
按实施例59的制备方法从实施例55胺和氯甲酸乙酯制备,所得草酸盐理化数据:
mp 169-172℃;(Found:C,54.09;H,5.91;N,14.94.C19H25N5O3.C2H2O4.0.2H2O requires C,54.23;H,5.94;N,15.06%).
实施例61
N,N-二甲基-2-[5-(2-(5-(3-氨基-1,2,4-噁二唑)基)乙基)-1H-吲哚-3-基]乙胺,草酸盐
按实施例6所述方法从N,N-二甲基-2-(5-(2-(乙酯基)乙基)-1H-吲哚-3-基)乙胺和羟基硫酸胍制备,所得草酸盐理化数据:mp 164-167℃;(Found:C,55.07;H,5.74;N,17.81.C16H21N5O0.1.1(C2H2O4)requires C,54.87;H,5.87;N,17.58%);δ(360MHz,D2O)2.89(6H,s,2 of CH3);3.21-3.14(6H,m,3 of CH2);3.42(2H,t,J=7.3Hz,CH2);7.12(1H,dd,J=1.6 and 8.4Hz,Ar-H);7.30(1H,s,Ar-H);7.38(1H,d,J=1.6Hz,Ar-H);7.45(1H,d,J=8.4Hz,Ar-H).
实施例62-82按通常的NaOEt/EtOH法从N,N-二甲基-2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺和适合的酰胺肟制备。
实施例62
N,N-二甲基-2-[5-(5-(3-N-甲氨基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐
所得草酸盐理化数据:mp 184℃(EtOH/Et2O);(Found:C,55.37;H,6.17;N,17.62.C16H21N5O.1.05(C2H2O4)requires C,55.19;H,5.91;N,17.78%);δ(360MHz,D6-DMSO)2.66(3H,d,J=5.0Hz,NHMe);2.78(6H,s,2 of CH3);3.03(2H,m,CH2);
3.23(2H,m,CH2);4.15(2H,s,CH2);6.54(1H,q,J=5.0Hz,NHMe);7.02(1H,d,J=8.3Hz,Ar-H);7.24(1H,s,Ar-H);7.32(1H,d,J=8.3Hz,Ar-H);7.51(1H,s,Ar-H);10.98(1H,s,indole NH).
实施例63
N,N-二甲基-2-[5-(5-(3-(4-氨基甲酰苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐-水合物
所得草酸盐-水合物理化数据:
mp 98-101℃;(Found:C,58.95;H,5.66;N,13.78.C23H25N5O2.C2H2O4.0.9H2O requires C,58.90;H,5.69;N,13.74%);δ(360MHz,D2O)2.82(6H,s,2 of CH3);3.04(2H,t,J=7.5Hz,CH2);3.31(2H,t,J=7.5Hz,CH2);4.01(2H,s,CH2);4.28(2H,s,CH2);7.08(1H,dd,J=1.4and8.4Hz,Ar-H);7.22(2H,d,J=8.2Hz,Ar-H);7.24(1H,s,Ar-H);7.39(1H,d,J=8.4Hz,Ar-H);7.48(1H,d,J=1.4Hz,Ar-H);7.58(2H,d,J=8.2Hz,Ar-H).
实施例64
N,N-二甲基-2-[5-(5-(3-(4-乙酰氨基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐半水合物
所得草酸盐半水合物理化数据:
mp 98-102℃;(Found:C,60.26;H,5.72;N,13.48.C24H27N5O2.C2H2O4.0.6H2O requires C,60.24;H,5.87;N,13.51%);δ(360MHz,D2O)2.11
(3H,s,CH3);2.77(6H,s,2 of CH3);2.99(2H,t,J=7.6Hz,CH2);3.25(2H,t,J=7.6Hz,CH2);3.89(2H,s,CH2);4.23(2H,s,CH2);7.06(1H,dd,J=1.5and8.4Hz,Ar-H);7.10(2H,d,J=8.5Hz,Ar-H);7.22(2H,d,J=8.5Hz,Ar-H);7.23(1H,s,Ar-H);7.39(1H,d,J=8.4Hz,Ar-H);7.41(1H,s,Ar-H).
实施例65
N,N-二甲基-2-[5-(5-(3-(4-甲氨基磺酰基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐
所得草酸盐理化数据:
mp 160-164℃;(Found:C,54.89;H,5.48;N,12.76.C23H27N5SO3.C2H2O4requires C,55.24;H,5.38;N,12.88%).
实施例66
N,N-二甲基-2-[5-(5-(3-(4-氨基甲酰氨基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐-水合物
所得草酸盐-水合物理化数据:
mp 176-177℃;(Found:C,57.10;H,6.04;N,15.97.C23H26N6O2.C2H2O4.1.0H2O requires C,57.03;H,5.74;N,15.96%).
实施例67
N,N-二甲基-2-[5-(5-(3-(4-甲磺酰基氨基苄基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐
所得草酸盐:
mp 156-159℃;(Found:C,54.64;H,5.35;N,12.70;S,6.13.C23H27N5SO3.C2H2O4.0.25H2O requires C,54.78;H,5.43;N,12.78;S,5.85%).
实施例68
N,N-二甲基-2-[5-(5-(3-(4-N-甲基氨基甲酰苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐半水合物
所得草酸盐半水合物:mp 205-207℃;(Found:C,59.65;H,5.71;N,14.22.C23H25N5O2.C2H2O4.0.5H2O requires C,59.75;H,5.62;N,13.94%);δ(360MHz,D2O)2.83(6H,s,2 of CH3);2.89(3H,s,CH3);3.01(2H,t,J=7.6Hz,CH2);3.29(2H,t,J=7.6Hz,CH2);4.14(2H,s,CH2);6.98(1H,d,J=8.4Hz,Ar-H);7.19(1H,s,Ar-H);7.34(1H,d,J=8.4Hz,Ar-H);7.44(1H,s,Ar-H);7.60(2H,d,J=8.4Hz,Ar-H);7.68(2H,d,J=8.4Hz,Ar-H).
实施例69
N,N-二甲基-2-[5-(5-(3-乙酰氨基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,琥珀酸盐半水合物
所得琥珀酸盐半水合物:mp 165℃;(Found:C,56.94;H,6.71;N,14.57.C15H23N5O2.C4H6O40.4H2O requires C,56.62;H,6.44;N,15.01%);δ(360MHz,D2O)2.04(3H,s,CH3);2.92(6H,s,2 of CH3);3.23(2H,t,J=7.3Hz,CH2);3.48(2H,t,J=7.3Hz,CH2);4.41(2H,s,CH2);4.46(2H,s,CH2);7.21(1H,dd,J=1.6and8.4Hz,Ar-H);7.35(1H,s,Ar-H);7.51(1H,d,J=8.4Hz,Ar-H);7.63(1H,s,Ar-H).
实施例70
N,N-二甲基-2-[5-(5-(3-甲磺酰基氨基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐半水合物
所得草酸盐半水合物:mp 148-150℃;(Found:C,47.90;H,5.52;N,14.37.C17H23N5SO3.C2H2O4.0.6H2O requires C,47.71;H,5.52;N,14.64%).
实施例71
N,N-二甲基-2-[5-(5-(3-氨基甲酰甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:mp 210℃(dec.);(Found:C,53.55;H,5.38;N,15.83.C13H21N4O2.1.2(C2H2O4)requires C,53.51;H,5.42;N,16.08%);δ(360MHz,D2O)2.90(6H,s,2 of CH3);3.21(2H,t,J=7.3Hz,CH2);3.47(2H,t,J=7.3Hz,CH2);3.80(2H,s,CH2);4.43(2H,s,CH2);7.22(1H,dd,J=1.6and8.4Hz,Ar-H);7.34(1H,s,Ar-H);7.51(1H,d,J=8.4Hz,Ar-H);7.63(1H,d,J=1.6Hz,Ar-H).
实施例72
N,N-二甲基-2-[5-(5-(3-(3-甲磺酰氨基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:mp 95-97℃(EtOH/Et2O):(Found:C,55.28;H,5.58;N,12.72%.C23H27N5SO3.C2H2O4requires C,55.14;H,5.55;N,12.86%);δ(360MHz,D2O)2.86(6H,s,NMe2);2.87(3H,s,MeSO2);3.13(2H,t,J=7.3Hz,CH2);3.39(2H,t,J=7.3Hz,CH2);4.03(2H,s,CH2);4.31(2H,s,CH2);7.07-7.14(4H,m,Ar-H);7.29-7.34(2H,m,Ar-H);7.43(1H,d,J=8.4Hz,Ar-H);7.52(1H,s,Ar-H).
实施例73
N,N-二甲基-2-[5-(5-(3-(3-乙酰氨基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:
mp 92-96℃(EtOH/Et2O);(Found:C,61.72;H,6.02;N,13.60.C24H27N5O2.C2H2O4requires C,61.53;H,5.76;N,13.80%).
实施例74
N,N-二甲基-2-[5-(5-(3-(4-氨基甲酰苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:
mp 217-219℃;(Found:C,59.15;H,5.38;N,14.23.C22H23N5O2.1.2(C2H2O4)requires C,58.91;H,5.15;N,14.08%).
实施例75
N,N-二甲基-2-[5-(5-(3-(3-氨基甲酰苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:mp 109-111℃;(Found:C,59.46;H,5.41;N,14.40.C22H23N5O2requires C,59.50;H,5.20;N,14.33%).
实施例76
N,N-二甲基-2-[5-(5-(3-(4-甲磺酰氨基苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:
mp 213-215℃;(Found:C,55.03;H,5.91;N,12.44.C22H25N5SO3.C2H2O4.0.4(Et2O)requires C,54.98;H,5.59;N,12.52%).
实施例77
N,N-二甲基-2-[5-(5-(3-(4-甲氨基磺酰基甲基苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:
mp 190-192℃;(Found:C,55.03;H,5.77;N,12.36.C23H27N5SO3.C2H2O4.0.5(EtOH)requires C,55.11;H,5.69;N,12.36%).
实施例78
N,N-二甲基-2-[5-(5-(3-(3-甲氨基磺酰基甲基苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.3水合物
所得草酸盐:
mp 199-210℃;(Found:C,54.54;H,5.41;N,12.65;S,5.80.C23H27N5SO3.C2H2O4.0.3H2O requires C,54.69;H,5.43;N,12.76;S,6.01%);δ(360MHz,D2O)2.69(3H,s,CH3);2.87(6H,s,2 of CH3);3.17(2H,t,J=7.5Hz,CH2);3.43(2H,t,J=7.5Hz,CH2);4.42(2H,s,CH2);4.48(2H,s,CH2);7.23(1H,d,J=8.5Hz,Ar-H);7.30(1H,s,Ar-H);7.49(1H,d,J=8.4Hz,Ar-H);7.53-7.57(2H,m,Ar-H);7.63(1H,s,Ar-H);7.90-7.92(2H,m,Ar-H).
实施例79
N,N-二甲基-2-[5-(5-(3-(4-氨基磺酰基甲基苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,1.5水合物
所得草酸盐水合物:
mp 210-212℃;(Found:C,51.72;H,5.43;N,12.49.C22H25N5SO3.C2H2O4.1.5H2O requires C,51.76;H,5.34;N,12.39%).
实施例80
N,N-二甲基-2-[5-(5-(3-(4-二甲基氨基磺酰甲基苯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.25水合物
所得草酸盐0.25水合物:
mp 208-210℃;(Found:C,56.63;H,5.74;N,12.91.C24H29N5SO3.0.75(C2H2O4)0.25H2O requires C,56.76;H,5.79;N,12.98%).
实施例81
N,N-二甲基-2-[5-(5-(3-叔丁酯基氨基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.25水合物
所得草酸盐0.25水合物:
mp 155-156℃;(Found:C,54.64;H,6.16;N,13.34.C21H29N5O3.1.25(C2H2O4).0.25H2O requires C,54.64;H,6.24;N,13.56%);δ(360MHz,D2O)1.38(9H,br s,3 of CH3);2.91(6H,s,2 of CH3);3.21(2H,t,J=7.4Hz,CH2);3.47(2H,t,J=7.4Hz,CH2);4.31(2H,br s,CH2);4.40(2H,s,CH2);7.20(1H,d,J=8.4Hz,Ar-H);7.34(1H,s,Ar-H);7.49(1H,d,J=8.4Hz,Ar-H);7.63(1H,s,Ar-H).
实施例82
N,N-二甲基-2-[5-(5-(3-(2-叔丁酯基氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.25水合物
所得草酸盐0.25水合物:
mp 137-142℃;(Found:C,56.64;H,6.84;N,13.69.C22H31N5O3.C2H2O4.0.2H2O requires C,56.84;H,6.64;N,13.81%).
实施例83
N,N-二甲基-2-[5-(5-(3-氨基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按实施例55所述方法从实施例81产品制备,所得草酸盐:
mp:109-110℃;m/e 300(M++1);δ(360MHz,D2O)2.92(6H,s,2 of CH3);3.24(2H,t,J=7.3Hz,CH2);3.50(2H,t,J=7.3Hz,CH2);4.37(2H,s,CH2);4.48(2H,s,CH2);7.23(1H,d,J=8.4Hz,Ar-H);7.36(1H,s,Ar-H);7.53(1H,d,J=8.4Hz,Ar-H);7.67(1H,s,Ar-H).
实施例84
N,N-二甲基-2-[5-(5-(3-甲酯基氨乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按实施例59所述方法从实施例83产品制备,所得草酸盐:
mp 132-133℃;(Found:C,53.50;H,5.62;N,15.46.C18H23N5O3.C2H2O4requires C,53.67;H,5.63;N,15.65%);δ(360MHz,D2O)2.90(6H,s,2 of CH3);3.21(2H,t,J=7.4Hz,CH2);3.46(2H,t,J=7.4Hz,CH2);3.66(3H,s,CH3);4.29(2H,s,CH2);4.40(2H,s,CH2);7.19(1H,dd,J=1.3and8.4Hz,Ar-H);7.34(1H,s,Ar-H);7.50(1H,d,J=8.4Hz,Ar-H);7.62(1H,s,Ar-H).
实施例85
N,N-二甲基-2-[5-(5-(3-N,N-二甲氨基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺琥珀酸盐半水合物
按实施例2所述的N-二甲基化方法从实施例83产品制备,所得琥珀酸盐半水合物:mp 135-137℃;(Found:C,57.83;H,7.19;N,15.16.C18H25N5O.1.1(C4H6O4)0.5H2O requires C,57.69;H,7.05;N,15.02%);δ(360MHz,D2O)2.86(6H,s,2 of CH3);2.94(6H,s,2 of CH3);3.26(2H,t,J=7.4Hz,CH2);3.51(2H,t,J=7.4Hz,CH2);4.38(2H,s,CH2);4.51(2H,s,CH2);7.25(1H,d,J=8.4Hz,Ar-H);7.38(1H,s,Ar-H);7.54(1H,d,J=8.4Hz,Ar-H);7.70(1H,s,Ar-H).
实施例86
N,N-二甲基-2-[5-(5-(3-(2-甲磺酰氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按实施例55和56的制备方法从实施例82产品制备,所得草酸盐:
mp 163-164℃(isopropyl alcohol/ether);(Found:C,49.72;H,5.74;N,14.37.C18H25N5SO3.C2H2O4requires C,49.89;H,5.65;N,14.54%)δ(360MHz,D2O)2.90(6H,s,2 of CH3);2.92(3H,s,CH3);2.96(2H,t,J=6.4Hz,CH2);3.21(2H,t,J=6.4Hz,CH2);3.44-3.49(4H,m,2 of CH2);4.40(2H,s,CH2);7.21(1H,dd,J=1.4and8.5Hz,Ar-H);7.34(1H,s,Ar-H);7.50(1H,d,J=8.5Hz,Ar-H);7.62(1H,s,Ar-H).
实施例87
N,N-二甲基-2-[5-(5-(3-(2-乙酯基氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按实施例55和60的制备方法从实施例82产品制备,所得草酸盐:
mp 120-124℃;(Found:C,54.90;H,6.29;N,14.62.C20H27N5O3.C2H2O4.0.2H2O requires C,55.15;H,6.19;N,14.62%).
实施例88
N,N-二甲基-2-[5-(5-(3-苯基羧氨基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺琥珀酸盐一水合物
-20℃下,将苯甲酰氯(0.14ml)加入实施例83(0.35g,1.2mmol)的THF(10ml)和吡啶(0.1ml)溶液中,使混合液升温至室温,搅拌16小时后除去溶剂,以CH2Cl2/EtOH/NH3(60∶8∶1)为洗提剂经硅凝胶色谱分离,所得琥珀酸盐:mp 72-74℃;(Found:C,60.70;H,6.14;N,13.76.C23H25N5O2.0.8(C4H6O4).1.05H2O requires C,60.77;H,6.22;N,13.52%).
实施例89
N,N-二甲基-2-[5-(5-(3-(2-苯基羰氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按实施例55和88的制备方法从实施例82产品制备,所得草酸盐:
mp 157-164℃;(Found:C,61.56;H,6.06;N,13.59.C24H27N5O2.C2H2O4requires C,61.53;H,5.76;N,13.80%).
实施例90
N,N-二甲基-2-[5-(5-(3-(2-n-苯基氨基甲酰氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐0.3水合物
在0℃下,将异氰酸苯酯(56.0μl,0.5mmol)滴加入搅拌的N,N-二甲基-2-[5-(5-(3-(2-氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺(0.15g,0.47mmol)的CH2Cl2(10mL)溶液中,使溶液升温至室温并搅拌1小时后真空去溶剂,以CH2Cl2/MeOH/NH3(40∶8∶1)为洗提剂用硅凝胶色谱提纯,所得草酸盐:
mp 155-162℃;(Found:C,59.10;H,5.77;N,15.67.C24H28N6O2.C2H2O4.0.3H2O requires C,59.15;H,5.84;N,15.92%).
实施例91
N,N-二甲基-2-[5-(5-(3-(2-N-叔丁基氨基甲酰氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,半水合物
按实施例55和90的制备方法,由实施例82产物,用异氰酸叔丁酯制备。所得草酸盐半水合物:
mp 135-140℃;(Found:C,56.21;H,6.99;N,16.27.C22H32N6O2.C2H2O4.0.5H2O requires C,56.35;H,6.90;N,16.43%).
实施例92
N-甲基-2-[5-(5-(3-氨基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺半琥珀酸盐,半水合物
1.N-苄基-2-[5-乙酯基甲基-1H-吲哚-3-基]乙胺
将新蒸出的苯甲醛(1.21g,11.37mmol)加到2-[5-乙酯基甲基-1H-吲哚-3-基]乙胺(2.8g,11.37mmol)的EtOH(45ml)溶液中,所得溶液在室温下搅拌22小时,室温下分批加入NaBH(0.434g,11.48mmol),10分钟加完。混合液再搅拌0.5小时后真空除去溶剂。残留物用水(20ml)溶解,用1N HCl(30ml)酸化。然后再用2N NaOH碱化,用EtOAc(4×70ml)萃取。合并的有机相用盐水(50ml)洗涤,干燥、浓缩。以CH2Cl2/EtOH(90∶10)为洗提剂硅凝胶色谱分离得标题产物(2.78g,73%)。
δ(360MHz,CDCl3)1.25(3H,t,J=7.1Hz,CH3);2.98(4H,s,2 of CH2);3.68(2H,s,CH2);3.81(2H,s,CH2);4.14(2H,q,J=7.1Hz,CH2);6.98(1H,d,J=2.2Hz,Ar-H);7.11(1H,dd,J=1.6and8.3Hz,Ar-H);7.20-7.32(6H,m,Ar-H);7.49(1H,d,J=0.7Hz,Ar-H);7.99(1H,br s,indole N-H).
2.N-甲基-N-苄基-2-[5-乙酯基甲基-1H-吲哚-3-基]乙胺。
向搅拌的前述胺(2.7g,8.02mmol)的无水DMF(80ml)溶液中依次加入K2CO3(2.06g,14.92mmol)和硫酸二甲酯(0.82ml,8.67mmol)。混合物在室温下搅拌4小时后加入HO(150ml),用EtOAc(2×125ml)萃取。合并的有机相溶液用盐水(50ml)洗涤,干燥(Na2SO4)并浓缩。残留物以CH2Cl2/EtOH(90∶10)为洗提剂用硅凝胶闪色谱提纯,得无色油状产物(1.7g,61%):
δ(250MHz,CDCl3)1.25(3H,t,J=7.1Hz,CH3);2.33(3H,s,CH3);2.71-2.78(2H,m,CH2);2.93-3.00(2H,m,CH2);3.60(2H,s,CH2);3.68(2H,s,CH2);4.15(2H,q,J=7.1Hz,CH2);6.99(1H,br s,Ar-H);7.11(1H,dd,J=1.7and8.4Hz,Ar-H);7.23-7.36(6H,m,Ar-H);7.41(1H,s,Ar-H);7.93(1H,br s,indole N-H).
3.N-甲基-2-[5-乙酯基甲基-1H-吲哚-3-基]乙胺
以10% Pd/C(1g)为催化剂在1个大气压下将前述苄胺(.16g)的乙醇(140ml)溶液氢化1小时,滤去催化剂,以EtOH(2×50ml)洗涤,真空除去溶剂得到标题N-甲胺(1.12g):
δ(250MHz,CDCl3)1.25(3H,t,J=7.1Hz,CH3);2.44(3H,s,CH3);2.86-2.99(4H,m,2 of CH2);3.70(2H,s,CH2);4.15(2H,q,J=7.1Hz,CH2);7.02(1H,d,J=2.0Hz,Ar-H);7.12(1H,dd,J=1.6and8.4Hz,Ar-H);7.30(1H,d,J=8.4Hz,Ar-H);7.52(1H,s,Ar-H);8.08(1H,br s,indole N-H).
4.N-甲基-2-[5-(5-(3-氨基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺半琥珀酸盐,半水合物
按实施例6所述方法从N-甲基-2-[5-乙酯基甲基-1H-吲哚-3-基]乙胺和羟基硫酸胍制备,所得半琥珀酸盐半水合物:mp 75-79℃(EtOH/Et2O);(Found:C,55.64;H,6.62;N,19.27%.C14H17N5O.0.65(C4H6O4).0.13(C2H6O).0.6H2O requires C,55.50;H,6.32;N,19.19%);δ(360MHz,D6-DMSO)2.47(3H,s,CH3);2.87-3.00(4H,m,2 of CH2);4.13(2H,s,CH2);6.13(2H,br s,NH2);7.01(1H,dd,J=1.5and8.3Hz,Ar-H);7.19(1H,d,J=1.8Hz,Ar-H);7.31(1H,d,J=8.3Hz,Ar-H);7.48(1H,s,Ar-H);10.89(1H,br s,indole N-H).
实施例93
N,N-二甲基-2-[5-(5-(3-(4-叔丁酯基)哌嗪-1,4-基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按常规方法从4-叔丁酯基-哌嗪酰胺肟和N,N-二甲基-2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺制备,所得草酸盐:
mp 179-180℃;(Found:C,56.48;H,6.56;N,14.87.C24H34N6O3.1.2(C2H2O4)requires C,56.36;H,6.52;N,14.94%);δ(360MHz,D2O)1.44(9H,s,3 of CH3);2.89(6H,s,2 of CH3);3.20(2H,t,J=7.3Hz,CH2);3.30-3.33(4H,m,2 of CH2);3.43-3.48(6H,m,3 of CH2);4.25(2H,s,CH2);7.18(1H,d,J=8.3Hz,Ar-H);7.33(1H,s,Ar-H);7.49(1H,d,J=8.3Hz,Ar-H);7.60(1H,s,Ar-H).
实施例94
N,N-二甲基-2-[5-(5-(3-(4-甲磺酰基)哌嗪-1,4-基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
按实施例55和56所述方法从实施例93产物制备,所得草酸盐:mp 191-192℃;(Found:C,50.56;H,5.70;N,15.78.C20H28N6SO3.C2H2O4requires C,50.56;H,5.79;N,16.08%);δ(360MHz,D2O)2.89(6H,s,2 of CH3);2.96(3H,s,CH3);3.17-3.25(6H,m,3 of CH2);3.40-3.49(6H,m,3 of CH2);4.24(2H,s,CH2);7.16(1H,d,J=8.4Hz,Ar-H);7.33(1H,s,Ar-H);7.48(1H,d,J=8.4Hz,Ar-H);7.60(1H,s,Ar-H).
实施例95
N,N-二甲基-2-[5-(5-(3-(4-甲酯基)哌嗪-1,4-基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.2水合物
按实施例55和59所述方法从实施例93产物制备,所得草酸盐:mp 204-205℃;(Found:C,54.41;H,5.81;N,16.51.C21H28N6O3.C2H2O4.0.2H2O requires C,54.58;H,6.05;N,16.60%).
实施例96
N,N-二甲基-2-[5-(5-(3-(4-N-甲基氨基甲酰基)哌嗪-1,4-基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.4水合物
按实施例55和58所述方法从实施例93产物制备,所得草酸盐0.4水合物:
mp 193-194℃;(Found:C,54.27;H,6.24;N,19.22.C21H29N7O2.0.4H2O requires C,54.30;H,6.30;N,19.13%).
实施例97
N,N-二甲基-2-[5-(5-(3-(4-乙酰基)哌嗪-1,4-基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.3水合物
按实施例55所述方法,将实施例93产物衍生出的中间产物Ac2O进行N-乙酰基化制得标题化合物,所得草酸盐:
mp 196-197℃;(Found:C,56.07;H,6.05;N,16.91.C21H28N6O2.C2H2O4.0.3H2O requires C,56.16;H,6.27;N,17.08%).
实施例98
N,N-二甲基-2-[5-(5-(3-(4-甲磺酰氨甲基)苯基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,半水合物
所得草酸盐半水合物:mp 196-198℃;(Found:C,54.16;H,5.65;N,12.51.C23H27N5SO3.C2H2O4.0.5H2O requires C,54.34;H,5.47;N,12.67%).
实施例99
N,N-二甲基-2-[5-(5-(3-苯磺酰氨甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺倍半草酸盐,
所得倍半草酸盐:mp 88-90℃;(Found:C,52.16;H,5.15;N,12.26.C22H25N5SO3.1.5(C2H2O4)requires C,52.26;H,4.91;N,12.19%).
实施例100
N,N-二甲基-2-[5-(5-(3-N-苄氨基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.25水合物
按常规的NaOEt/EtOH方法从N-苄氨基酰胺肟和N,N-二甲基-2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺制备,所得草酸盐
mp 168-169℃;(Found:C,61.20;H,5.89;N,14.93.C22H25N5O.C2H2O4.0.25H2O requires C,61.33;H,5.89;N,14.90%).
实施例101
N,N-二甲基-2-[5-(5-(3-吡啶-3-基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺二盐酸化物,一水合物
按常规方法从吡啶-3-基甲基酰胺肟和N,N-二甲-2-(5-乙酯基甲基-1H-吲哚-3-基)乙胺制备,所得二盐酸化物-水合物:
mp 150-152℃;(Found:C,56.02;H,6.01;N,15.01.C23H23N5O.2HCl.1H2O.0.1(iPA)requires C,55.81;H,6.11;N,15.28%).
实施例102
N,N-二甲基-2-[5-(5-(3-(6-甲氧基)吡啶-3-基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺,草酸盐,0.25水合物
所得草酸盐0.25水合物:mp 146-148℃;(Found:C,59.24;H,5.70;N,14.19.C22H25N5O2.C2H2O4.0.25H2O requires C,59.31;H,5.70;N,14.41%).
实施例103
2-[5-(5-(3-(4-乙酰胺基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:mp 140℃;(Found:C,59.68;H,5.68;N,13.81.C22H23N5O2.C2H2O4.0.6(C2H5OH)requires C,59.65;H,5.75;N,13.85%).
实施例104
2-[5-(5-(3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:mp 110-112℃;(Found:C,52.48;H,5.07;N,12.77;S,6.14.C21H23N5SO3.1.25(C2H2O4).0.3(C2H5OH)requires C,52.46;H,5.01;N,12.65;S,5.79%).
实施例105和106是通过2-[5-(2-乙酯基)乙基)-1H-吲哚-3-基]乙胺与适当的酰胺肟反应得到的。
实施例105
2-[5-(2-(5-(3-(4-乙酰氨基苄基)-1,2,4-噁二唑)基)乙基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐 mp121-127℃;(Found:C,59.09;H,5.56;N,13.54.C23H25N5O2.1.3(C2H2O4)requires C,59.07;H,5.34;N,13.45%).
实施例106
2-[5-(2-(5-(3-(4-甲氧基苄基)-1,2,4-噁二唑)基)乙基)-1H-吲哚-3-基]乙胺倍半草酸盐
所得草酸盐:mp 136-138℃;(Found:C,58.70;H,4.85;N,11.00.C22H24N4O2.1.5(C2H2O4)requires C,58.94;H,4.95;N,11.00%).
实施例107
N,N-二甲基-2-[5-(2-(5-甲基-1,3-噁唑)基)-1H-吲哚-3-基]乙胺倍半草酸盐
1.2-[5-羧基-1H-吲哚-3-基]N,N-二甲基乙胺
将2-[5-乙酯基-1H-吲哚-3-基]N,N-二甲基乙胺(1.4g,5.4mmol)和氢氧化锂(0.45g,10.8mmol)的乙醇(40ml)溶液在60℃下加热8小时,然后室温下搅拌过夜,真空除去乙醇,粗产物用色谱提纯(洗提剂为20∶15∶5∶1,乙醚∶乙醇∶水∶氨),用乙醚沉淀后,将酸(0.94g,75%)白色固体分离出来。
δ(360MHz,D6-DMSO)2.86(6H,s),3.09(2H,t,J=7Hz),3.33(2H,t,J=7Hz),7.22(1H,s),7.46(1H,d,J=9Hz),7.78(1H,dd,J=9and2Hz),8.12(1H,s).
2.2-[5-丙炔基羧酰胺基-1H-吲哚-3-基]N,N-二甲基乙胺
在0℃下,2-[5-羧基-1H-吲哚-3-基]N,N-二甲基乙胺(0.2g,0.86mmol),1-羟基苯三唑(0.14g,1.0mmol),N-甲基吗啉(0.2ml,1.7mmol)和炔丙胺(71μl,1.0mmol)的二氯甲烷∶二甲基甲酰胺(1∶1)(25ml)溶液中分批加入1-(3-二甲基氨丙基)-3-乙基-碳化二亚胺盐酸化物。溶液搅拌18小时后水洗(1×50ml),将有机层分离,水层用更多的二氯甲烷(4×20ml)洗涤。有机层合并,真空蒸发。残留物粗品经色谱分离(洗提剂为40∶8∶1二氯甲烷∶乙醇∶氨)得到标题化合物(88mg,38%)。水相蒸发后经色谱分离后(洗提剂为40∶8∶1的二氯甲烷∶乙醇∶氨),得到所期望的含少量碳化二亚胺脲杂质的炔(100mg,48%)。
δ(360MHz,CDCl3)2.33(7H,m),2.65(2H,t,J=7Hz),2.92(2H,t,J=7Hz),4.32(2H,dd,J=7and1Hz),6.50(1H,brt),7.02(1H,s),7.24(1H,d,J=9Hz),7.54(1H,dd,J=9and1Hz),8.09(1H,s),8.79(1H,brs).
3.N,N-二甲基-2-[5-(2-(5-甲基-1,3-噁唑)基)-1H-吲哚-3-基]乙胺倍半草酸盐
将2-[5-丙炔基羧酰氨基-1H-吲哚-3-基]N,N-二甲基乙胺(88mg,0.33mmol)和醋酸汞(7mg,0.02mmol)的乙酸(4ml)溶液回流3小时,然后将溶液冷却至环境温度,真空蒸发,向残留物中加饱和碳酸钾溶液(10ml),混合物用二氯甲烷(5×20ml)萃取,有机层合并,干燥(MgSO4),蒸发,残留物经色谱分离(洗提剂为60∶8∶1,二氯甲烷∶乙醇∶氨)得浅黄色油状噁唑(50mg,57%),所得倍半草酸盐:
mp 164-166℃.(Found:C,55.86;H,5.52;N,10.07,C16H19N3O.1.6(C2H2O4)requires C,55.78,H,5.41,N,10.16%);δ(360MHz,D2O)2.49(3H,s),2.93(6H,s),3.25(2H,t,J=7Hz),3.51(2H,t,J=7Hz),7.30(1H,s),7.43(1H,s),7.61(1H,d,J=9Hz),7.72(1H,dd,J=9and1Hz),8.20(1H,d,J=1Hz).m/z(EI),269(M+),225,211,181,168,155,129,115,81,69.
实施例108
N,N-二甲基-2-[5-(2-(5-甲基-1,3-噁唑)基)乙基)-1H-吲哚-3-基]乙胺酒石酸盐
按上一实施例的三步法由2-[5-(2-乙酯基)乙基)-1H-吲哚-3-基]N,N-二乙基乙胺制备
mp 55-60℃.Formula:C18H23N3O.(C4H6O6).0.6H2O.Analysis:Calc:C,57.66;H,6.64;N,9.17.Found:C,57.94;H,7.22;N,8.82δ(360MHz,D2O)δ2.06(3H,s),2.92(6H,s),3.15(6H,m),3.44(2H,t,J=7Hz),4.39(2H,s),6.62(1H,s),7.09(1H,dd,J=8and2Hz),7.30(1H,s),7.38(1H,s),7.43(1H,d,J=8Hz).
实施例109
4-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]N-甲基哌啶草酸盐
将吲哚-5-羰酸(1.0g,6.2mmol),1-甲基-4-哌啶酮(1.4ml,11.2mmol)和氢氧化钾(2M溶液,30ml)的混合溶液加热回流5小时,室温下搅拌过夜,然后,真空蒸发去溶剂,残留物经色谱分离(洗提剂为20∶15∶5∶1,乙醚∶乙醇∶水∶氨)得到4-[5-羧基-1H-吲哚-3-基]N-甲基哌啶-3-烯(1.0g,63%)。
在氮气氛中,于0℃下向搅拌着的甲醇∶乙醇(2∶1,200ml)溶液中滴加亚硫酰氯(1.1ml,15mmol),在0℃下分批加入酸(1.0g,3.9mmol),使溶液升温至室温,搅拌过夜,溶液加热回流2小时,然后让其冷却至环境温度。真空蒸发混合物得相应甲酯∶乙酯(2∶1)的盐酸盐(0.97g,80%)。
在Pd/C(600mg)的存在下,将4-[5-羧基-1H-吲哚-3-基]N-甲基哌啶-3-烯盐酸化物(0.5g,1.6mmol)的甲酯∶乙酯(2∶1)的乙醇(50ml)溶液在30p.s.i.氢化四小时后滤去催化剂,真空蒸发去乙醇。残留物粗品经色谱提纯(以80∶8∶1,二氯甲烷∶乙醇∶氨为洗提剂)得到粘性油状的4-[5-羰基-吲哚-3-基]N-甲基哌啶的甲酯∶乙酯(2∶1)(255mg,58%)。
将钠金属(0.19g,8.5mmol)加入处于搅拌下的羟基硫酸胍(0.57g,2.1mmol)乙醇(10ml)悬浮液中,30分钟后加入上述酯(255mg,0.91mmol)的乙醇(5ml)溶液,混合物加热回流72小时,然后将混合物冷却至环境温度,真空除去溶剂,残留物经色谱提纯(以40∶8∶1,二氯甲烷∶乙醇∶氨为洗提剂)得期望的粘性油产品4-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]N-甲基哌啶(12mg,4.5%),含有产品与原料的柱馏分合并后,蒸发并经制备薄层色谱分离(以40∶8∶1二氯甲烷∶乙醇∶氨为洗提剂)得期望的粘性油状氨基噁二唑(10mg,3.5%)。
mp 186-188℃Formula:C16H19N5O.1.2(CO2H)2.0.8H2O.Analysis:Found:C,52.39;H,5.55;N,17.09 Calc.C,52.64;H,5.52;N,16.68;δ(360MHz,D2O)δ1.87(2H,m),2.22(2H,m),2.94(4H,m),3.13(2H,m),3.63(2H,m),7.18(1H,s),7.38(1H,d,J=9Hz),7.53(1H,dd,J=9and1Hz),7.94(1H,d,J=1Hz).m/z(FAB)298(M+1),185,93,75.
实施例110
4-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]N-甲基哌啶草酸盐
第一步:4-[5-甲酯基甲基-1H-吲哚-3-基]N-甲基哌啶
将1-甲基-4(甲酰基甲基)哌啶(2.3g,16mmol)和4-(乙酯基甲基)苯肼盐酸化物(3.7g,16mmol)的甲醇∶水(20∶1)(25ml)溶液在室温下搅拌1小时。然后加入聚磷酸(7g),在氮气氛下加热回流5小时,溶液冷却至环境温度后用饱和碳酸氢钠溶液碱化至pH值为9。用二氯甲烷(2×20ml)萃取,合并有机相,干燥(MgSO),蒸发后得棕色残留物。将其进行色谱分离(洗提剂为50∶8∶1二氯甲烷∶乙醇∶氨)得黄色固体4-[5-甲酯基甲基-1H-吲哚-3-基]N-甲基哌啶(1.8g,39%)。
mp 105-107℃.δ(360MHz,CDCl3)δ1.85(2H,m),2.16(4H,m),2.36(3H,s),2.81(1H,m),3.00(2H,m),3.70(3H,s),3.73(2H,s),6.97(1H,d,J=2Hz),7.10(1H,dd,J=8and Hz),7.31(1H,d,J=8Hz),7.53(1H,s),7.97(1H,brs).
第2步:4-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]N-甲基哌啶草酸盐
将钠(0.4g,17mmol)在氮气氛下溶于乙醇(30ml)中并搅拌,加入羟基硫酸胍(1.53g,5.8mmol),室温下搅拌20分钟后,分批加酯(0.5g,1.7mmol),加热5回流1.5小时,溶液冷却至室温,过滤,滤液真空蒸发,残留物以50∶8∶1二氯甲烷∶乙醇∶氨为洗提剂经柱分离得标题氨基噁二唑(313mg,60%),所得草酸盐:
mp 116-120℃.Formula:C17H21N5O.1.2(CO2H)2.0.2H2O.0.34(C4H10O).Analysis:Calc:C,55.76;H,6.12;N,15.63.Found:C,55.63;H,6.31;N,15.86.δ(360MHz,D6-DMSO)δ1.95(2H,m),2.10(2H,m),2.76(3H,s),3.05(3H,m),3.42(2H,m),4.13(2H,s),6.13(2H,s),7.00(1H,d,J=8Hz),7.15(1H,s),7.31(1H,d,J=8Hz),7.54(1H,s),10.90(1H,s).m/z(EI)311(M+),271,156,97,70.
实施例111
4-[5-(3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]N-甲基哌啶草酸盐
mp 122-124℃;δ(360MHz,D6-DMSO)1.91(2H,m),2.08(2H,m),2.76(3H,s),3.01(6H,m),3.42(2H,m),3.99(2H,s),4.32(2H,s),7.02(1H,dd,J=8and2Hz),7.14(3H,m),7.23(2H,d,J=9Hz),7.31(1H,d,J=8Hz),7.56(1H,s),10.92(1H,s).
实施例112
4-[5-(3-(3-吡啶基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]N-甲基哌啶草酸盐,
mp 94-96℃.δ(360MHz,D6-DMSO)δ1.92(2H,m),2.10(2H,m),2.80(3H,s),3.05(3H,m),3.45(2H,m),4.11(2H,s),4.32(2H,s),7.00(1H,d,J=8Hz),7.16(1H,s),7.31(1H,d,J=9Hz),7.35(1H,m),7.56(1H,s),7.70(1H,d,J=8Hz),8.46(1H,m),8.52(1H,s),10.93(1H,s).
实施例113
N,N-二甲基-2-[5-(5-(3-吡啶基-4-基甲基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,一水合物
所得草酸盐一水合物 mp<50℃(hygroscopic);(Found:C,58.52;H,5.71;N,14.60.C21H23N5O.1.05(C2H2O4).1H2O requires C,58.53;H,5.76;N,14.78%).
实施例114
N,N-二甲基-2-[5-(5-(3-(4-叔丁酯基)乙撑-1,4-氨基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐
所得草酸盐:
mp 120-122℃;(Found:C,55.42;H,6.59;N,15.91.C22H32N6O3.C2H2O4requires C,55.59;H,6.61;N,16.21%).
实施例115
2-[5-(5-(3-(羧氨基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸氢盐
第1步:2-[5-(5-(3-乙酯基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]-N-(叔丁酯基)乙胺
向放有4A分子筛(3g)的2-[5-羧甲基-1H-吲哚-3-基]-N-(叔丁酯基)乙胺(3g,9.4mmol)的四氢呋喃(100ml)溶液中加入三乙胺(2.62ml,18.8mmol)。溶液在氮气氛和室温下搅拌1小时,然后冷却至-10℃,加氯甲酸异丁酯(2.45ml,18.8mmol)。在-10℃下搅拌15分钟后,加入(乙酯基)甲酰胺肟(1.87g,14,2mmol)的四氢呋喃(10ml)溶液,使反应混合物升温至室温搅拌2.5小时,悬浮液经Hyflo过滤,滤液于真空蒸发,得黄色固体,将其溶于1,4-二烷(25ml)中,在4A分子筛(3g)的存在和氮气氛下加热回流2天,经Hyflo过滤后,真空蒸发滤液并用硅凝胶色谱分离(梯度洗脱,洗脱剂成分先是3∶1石油醚∶乙酸乙酯,后是1∶1石油醚∶乙酸乙酯),得期望之黄色胶状二唑酯。
δ(360MHz,CDCl3)1.42(3H,t,J=7.1Hz),1.43(9H,s),2.92(2H,t,J=6.8Hz),3.44(2H,m),4.40(2H,s),4.48(2H,q,J=7.1Hz),7.04(1H,s),7.15(1H,dd,J=1.6,8.3Hz),7.32(1H,d,J=8.3Hz),7.54(1H,s),8.13(1H,s).m/z(EI),414(M+),358,297,212,143,115,91.
第2步,2-[5-(5-(3-羧氨基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺
将二唑酯(0.19g,0.46mmol)的乙醇(30ml)溶液冷却至0℃(冰水浴),通入氨气鼓泡15分钟,真空蒸发溶剂得黄色胶状2-[5-(5-(3-(羧氨基)-1,2,4-噁二唑)基甲基-1H-吲哚-3-基]-N-(叔丁酯基)乙胺(0.17g)。将粗品在氮气氛下溶于无水二氯甲烷(20ml)中,冷却至0℃,加入三氟乙酸(1ml,13.0mmol),使溶液升温至室温,在氮气氛下搅拌3小时,真空除去溶剂,残留物加入甲苯(2×5ml)得浅橙色胶状共沸混合物,将其进行硅凝胶色谱分离(以20∶15∶5∶1,乙醚∶乙醇∶水∶氨洗脱)。得期望之beige胶状噁二唑酰胺(95mg,72%)。
所得草酸盐:m.p.184-186℃.Formula:C14H15N5O2.0.8(CO2H)2.0.2(CH3OH).Analysis:Calc:C,52.17;H,4.82;N,19.25.Found:C,51.99;H,5.09;N,19.25.δ(360MHz,D6-DMSO)2.90(2H,t,J=6.8Hz),2.99(2H,t,J=6.8Hz),4.44(2H,s),7.06(1H,dd,J=1.4,8.3Hz),7.23(1H,s),7.34(1H,d,J=8.3Hz),7.51(1H,s),8.04(1H,br s),8.24(1H,br s),10.96(1H,br s).m/z(FAB)286(M+1).
实施例116-118是按实施例115第2步的方法用适当的胺制备的。
实施例116
2-[5-(5-(3-(N-甲基羧酰胺基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸氢盐
m.p.113-115℃;Formula:C15H17N5O2(CO2H)2.0.5(H2O).0.15(Et2O).Analysis:Calc:C,51.62;H,5.29;N,17.10.Found:C,51.58;H,5.15;N,17.07.δ(360MHz,D6-DMSO)2.76(3H,d,J=4.7Hz),2.96(2H,t,J=7.1Hz),3.06(2H,t,J=7.1Hz),4.45(2H,s),7.07(1H,dd,J=1.4,8.3Hz),7.25(1H,s),7.35(1H,d,J=8.3Hz),7.51(1H,s),8.85(1H,br d,J=4.5Hz),11.01(1H,br s).m/z(FAB)300(M+1).
实施例117
2-[5-(5-(3-(N-吡咯烷基羧酰胺基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸氢盐
m.p.182-185℃.δ(360MHz,D6-DMSO)1.86(4H,m),2.95(2H,t,J=7.4Hz),3.05(2H,t,J=7.4Hz),3.47(2H,t,J=6.9Hz),3.54(2H,t,J=6.9Hz),4.45(2H,s),7.08(1H,d,J=7.0Hz),7.25(1H,s),7.35(1H,d,J=8.3Hz),7.53(1H,s),11.0(1H,br s).
实施例118
2-[5-(5-(3-(N-氮杂环丁烷基羧酰胺基)-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸氢盐
m.p.114-117℃;δ(360MHz,D6-DMSO)2.28(2H,quin,J=7.8Hz),2.95(2H,t,J=7.1Hz),3.05(2H,t,J=7.1Hz),4.06(2H,t,J=7.8Hz),4.40(2H,t,J=7.8Hz),4.44(2H,s),7.07(1H,dd,J=1.6,8.3Hz),7.25(1H,s),7.35(1H,d,J=8.3Hz),7.52(1H,s),11.00(1H,br s).
实施例119
N,N-二甲基-2-[5-(5-(3-(4-苯磺酰基)哌嗪-1,4-基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,0.3水合物
按实施例55和56所述方法从实施例93产物制备,所得草酸盐:mp 210-211℃;(Found:C,54.15;H,5.26;N,13.81.C25H30N6SO3.1.2(C2H2O4).0.3H2O requires C,54.12;H,5.47;N,13.82%).
实施例120
N,N-二甲基-2-[5-(5-(3-吡咯烷氧基羰基氨基)乙基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,半水合物
按实施例55和57的制备方法由实施例82产物用吡咯烷制备,所得草酸盐半水合物:
mp 132-135℃;(Found:C,56.63;H,6.23;N,16.38.C22H30N6O.C2H2O4.0.5H2O requires C,56.57;H,6.53;N,16.49%).
实施例121
N,N-二甲基-2-[5-(5-(3-(4-甲磺酰基)乙撑-1,4-二氨基-1,2,4-噁二唑)基甲基)-1H-吲哚-3-基]乙胺草酸盐,半水合物
所得草酸盐半水合物:
mp 178-181℃;(Found:C,47.43;H,5.49;N,16.82.C18H26N6SO3.C2H2O4.0.5H2O requires C,47.52;H,5.78;N,16.62%).
实施例122
N,N-二甲基-2-[5-(5-(3-氨基-1,2,4-噻二唑)基甲基)-1H-吲哚-3-基]乙胺
1.N,N-二甲基-2-[5-(4-甲氧基苄基)氧羰基甲基-1H-吲哚-3-基]乙胺
向处于冷却(-70℃)和搅拌中的4-甲氧基苄醇(6.3g,45.6mmol)的无水THF(50ml)溶液滴加正丁基锂(1.6M的己烷溶液,20ml)0.2小时加完,在-70℃下过5分钟后,滴加N,N-二甲基-2-(5-甲酯基甲基-1H-吲哚-3-基]乙胺(2.5g,9.6mmol)的THF(20ml)溶液,5分钟加完。使所得溶液升温至室温搅拌1小时,真空除去溶剂,残留物溶解在无水甲苯(100ml)中,再次浓缩,残留物加水(50ml)以Et O(2×150ml)萃取,合并有机相溶液,用盐水(50ml)洗涤一次,干燥(Na2SO4)并浓缩,残留油状物经闪色谱分离(CH2Cl2/Me OH/NH3,90∶10∶1,硅凝胶)得标题化合物(3.1g,89%)。δ(360MHz,CDCl3)2.33(6H,s,NMe2);2.59-2.65(2H,m,CH2);2.87-2.94(2H,m,CH2);3.74(2H,s,Ar-CH2);3.80(3H,s,OMe);5.07(2H,s,Ar-CH2-O);6.83-6.88(2H,m,Ar-H);6.99(1H,d,J=2.5Hz,Ar-H);7.10(1H,dd,J=1.7and8.4Hz,Ar-H);7.23-7.29(3H,m,Ar-H);7.48(1H,s,Ar-H);8.04(1H,brs,indole-NH).
2.N,N-二甲基-2-[5-(4-甲氧基苄基)氧羰基甲基-1-叔丁酯基-吲哚-3-基]乙胺
向上述酯(3.4g,9.27mmol)的无水CH3CN(25ml)溶液中依次加入碳酸氢二叔丁酯(2.63g,12.06mmol)和4-DAMP(0.11g),室温下搅拌1小时,真空去溶剂,以闪色谱提纯残留物(硅凝胶,CH2Cl2/MeOH,95∶5)得标题化合物(3.33G,77%)。δ(360MHz,CDCl3)1.66(9H,s,3 of CH3);2.32(6H,s,N(Me)2);2.58-2.65(2H,m,CH2);2.80-2.88(2H,m,CH2);3.74(2H,s,Ar-CH2-CO);3.80(3H,s,OMe);5.07(2H,s,Ar-CH2-O);6.84-6.89(2H,m,Ar-H);7.18-7.28(3H,m,Ar-H);7.38(1H,s,Ar-H);7.41(1H,d,J=1.2Hz,Ar-H);8.03(1H,br d,J=8.1Hz,Ar-H).
3.N,N-二甲基-2-[5-(5-(3-氨基-1,2,4-噻二唑)基甲基)-1H-吲哚-3-基]乙胺
向上述酯(0.3g,0.64mmol)的无水DMF(4ml)溶液中加入NaH(60%的油分散体64mg),混合物在室温下搅拌15分钟后加入3-氨基-5-氯-1,2,4-噻二唑(0.17g,1.27mmol)的无水DMF(1ml)溶液,1小时后加水(50ml),产物以CH2Cl2(2×70ml)萃取,除去溶剂后得到的残留物以CH2Cl2/MeOH(10%)为洗提剂经硅凝胶色谱分离得白色泡沫体64mg(17%)。
δ(250MHz,CDCl3)1.65(9H,s,3 of CH3);2.32(6H,s,N(Me)2);2.57-2.64(2H,m,CH2);2.78-2.84(2H,m,CH2);3.78(3H,s,OMe);4.83(2H,s,NH2);5.08(1H,d,J=11.9Hz,Ar-CH2-O);5.19(1H,d,J=11.9Hz,Ar-CH2-O);5.35(1H,s,Ar-CH-CO);6.79-6.84(2H,m,Ar-H);7.16-7.21(2H,m,Ar-H);7.28(1H,dd,J=1.9and8.7Hz,Ar-H);7.41(1H,s,Ar-H);7.50(1H,d,J=1.7Hz,Ar-H);8.06(1H,d,J=8.3Hz,Ar-H).
将上述产物(5mg)的CH2Cl2(0.8ml)<H2O(30μl)和TFA(130μl)溶液在室温下搅拌1小时,真空去溶剂,剩余残留物溶解于无水甲苯(1.5ml)和MeOH(0.3ml)中,再次浓缩,残留物溶解于MeOH中,回流0.5分钟,真空去溶剂,残留物用制备厚层色谱提纯(硅凝胶,CH2Cl2/Me OH/NH3;80∶20∶1.5)得N,N-二甲基-2-[5-(5-(3-氨基-1,2,4-噻二唑)基甲基)-1H-吲哚-3-基]乙胺(1mg)。
δ(250MHz,CDCl3)2.50(6H,s,N(Me)2);2.80-2.88(2H,m,CH2);3.05-3.10(2H,m,CH2);4.36(2H,s,CH2);4.88(2H,br s,NH2);7.09(1H,d,J=2.5Hz,Ar-H);7.13(1H,dd,J=1.7and8.4Hz,Ar-H);7.34(1H,d,J=8.4Hz,Ar-H);7.55(1H,s,Ar-H);8.08(1H,br s,indole-NH).
实施例123
片剂的制备
分别含有1.0,2.0,25.0,26.0,50.0和100.0mg下列化合物的药片
N,N-二甲基-2-[5-[5-(3-氨基-1,2,4-噁二唑)基甲基]-1H-吲哚-3-基]乙胺半琥珀酸盐水合物
2-[5-(3-(5-苄基-1,2,4-噁二唑)基]-1H-吲哚-3-基]乙胺马来酸氢盐
N,N-二甲基-2-[5-(2-(5-甲基-1,3-噁唑)基)-1H-吲哚-3-基]乙胺倍半草酸盐
4-[5-(3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]N-甲基哌啶草酸盐
含1-25mg活性化合物剂量的片剂含量(mg)
活性化合物 1.0 2.0 25.0
微晶纤维素 49.25 48.75 37.25
改性食用玉米淀粉 49.25 48.75 37.25
硬脂酸镁 0.50 0.50 0.50
含26-100mg活性化合物剂量的片剂
活性化合物 26.0 50.0 100.0
微晶纤维素 52.0 100.0 200.0
改性食用玉米淀粉 2.21 4.25 8.5
硬脂酸镁 0.39 0.75 1.5
所有活性化合物,纤维素和部分玉米淀粉相混合,制成含10%玉米淀粉的粒状物,将其过筛,干燥并与剩下的玉米淀粉以及硬脂酸镁相混合。所得粒剂压成每片含1.0mg,2.0mg,25.0mg,26.0mg,50.0mg和100mg活性成分的片剂。
Claims (8)
1、制备式Ⅰ化合物或其盐或其前体药物的方法,式(Ⅰ)如下:
其中虚线圆表示五元环上任意位置的两个不相邻双键;
W,X,Y和Z分别独立地代表氧,硫,氮或碳,但W,X,Y和Z之一必须代表氧或硫,且W,X,Y和Z中至少有一个代表碳;
A代表氢,烃基,囟素,氰基,三氟甲基,硝基,-ORx,-OCORx,-ONRxRy,-SRx,-NRxRy,-NRxORy,-NRxNRxRy,-NRxCORy,-NRxCO2Ry,-NRxSO2Ry,-NRzCVNRxRy,-CORx,-CO2Rx或-CONRxRy;
E代表一个键或含有1~4个碳原子的直链或支链烷撑;
F代表结构式为
的基团,
其中R1代表-CH2.CHR4.NRxRy或如下结构的基团
其中,虚线代表一个任意的化学键。
R2,R3,R4和R5独立地代表氢,1-6C烷基,2-6C烯基或2-6C炔基;
Rx和Ry独立地代表氢或烃基,或Rx和Ry一起代表2-6C烯基;
Rz代表氢或烃基;
V代表氧,硫或式为=N.G的基团;
G代表烃基或吸电子基,
该方法包括:
(A)使式为Rc-CO2H的活性羧酸衍生物与式Ⅲ或式Ⅳ的化合物或其盐反应,
式Ⅲ和式Ⅳ如下:
其中,Rc与Rd之一是式A基团,另一个是式-E-F基团,定义按上文;或
(B)将下述式Ⅺ化合物环化:
其中,Rc和Rd按上文定义,Re为氢或烷基,或
(C)将氰硫化物Rc-C≡N+-S-与腈Rd-CN环化加成,式中Rc和Rd按上文定义;
(D)将氨基硫脲RcCSNHNHCONRsRt脱氢,然后用常规方法接上Rd基团,上式中Rc按上文定义,Rs和Rt为氢或烷基,或
(E)使二胺
与氯化硫反应,其中Rc和Rd按上文定义,或
(F)使式Ⅻ酰胺或硫代酰胺与式Ⅷα-囟代酮反应,式Ⅻ与式Ⅷ如下:
其中U为氧或硫,Hal代表囟素,Rc和Rd按上文定义,或
(G)将式XIV化合物:
与能产生阴离子的试剂反应,脱除氧原子相邻的质子,接着将得到的阴离子物与能提供基团Rc亲电物反应,其中RC和Rd按上文定义;
(H)将式XV化合物与能提供阴离子-RC的试剂反应,式XV如下
其中W,X,Y,Z,RC和Rd按上文定义,Hal代表囟素;或
(I)将式XVI化合物
(其中W,X,Y,Z,A和E按上文定义)与式Ⅶ化合物或其羰基保护或反应,接着,需要时按规范方法通过N-烷基化引进上文定义的R3基团,式Ⅶ如下:
式中R2按上文定义,R″对应上文定义的R′基团或代表-CH2.CHR4D基团,其中R4按上文定义,D代表易取代基。
2、按权利要求1所述制备式ⅡA化合物及其盐和前体药物的方法:
其中
Z1代表氧或硫;
n为0,1,2或3;
A1代表1-6C烷基,2-6C烯基,2-6C炔基;3-7C环烷基,芳基,芳基(1-6C)烷基,3-7C杂环烷基,杂芳基或杂芳基(1-6C)烷基,其中的任一基团都可被任意取代;或氢,囟素,氰基,三氟甲基,硝基,1-6C烷氧基,1-6C烷硫基,-NRxRy或-CONRxRy;
R12,R13和R14各自代表氢,1-6C烷基,2-6C烯基或2-6C炔基;
Rx和Ry各自代表氢或烃基,或Rx、Ry一起代表2-6C烯基。
3、按权利要求1所述制备式ⅡB化合物及其盐和前体药物的方法:
其中
Y1代表氧或硫;
n为0,1,2或3;
A1按权利要求2定义;
R22,R23和R24各自代表氢,1-6C烷基,2-6C烯基或2-6C炔基;
Rx和Ry各自代表氢或烃基,或Rx与Ry一起代表2-6C亚烷基。
6、按权利要求1所述制备下列化合物和其盐和前体药物的方法:
2-[5-(3-苄基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苄基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-苄基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-苯基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-(2-甲氧基苄基)-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苄基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-[2-(3-苄基-1,2,4-噁二唑-5-基)乙基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-二苯甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-苯基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(2-甲氧基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-苄基-1,2,4-噁二唑-5-基)丙基]-1H-吲哚-3-基]乙胺;
2-[5-(3-苯乙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(5-苄基-1,2,4-噁二唑-3-基)-1H-吲哚-3-基]乙胺;
2-[5-(5-苄基-1,2,4-噁二唑-3-甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氧基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[2-(3-苄基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(1-萘基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-甲基)-1,2,4-噁二唑-5-基)丙基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-环丙基-1,2,4-噁二唑-5-基)丙基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-甲氧基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲氧基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-苯丙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-环丙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-(3-乙基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-三氟甲基苄基)-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[2-(3-氨基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
2-[5-[2-(3-二甲氨基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
2-[5-(5-甲基-1,2,4-噁二唑-3-基)-1H-吲哚-3-基]乙胺;
2-[5-(5-甲基-1,2,4-噁二唑-3-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(5-苄基-1,2,4-噁二唑-3-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲氧基甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲氨基羰基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲氨基羰基苯基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲氨基磺酰基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲磺酰苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(3-甲磺酰基氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-氨基羰基氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-乙酰氨基甲基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(2-乙酰氨基乙基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基甲基-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-乙酰氨基甲基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-乙酰氨基乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基氨基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-(叔丁酯基氨基)乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨羰基苄基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲磺酰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-氨基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氨基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氨基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氧基羰基氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-乙酯氨乙基)-1,2,4-噁二唑-5-基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[2-(3-氨基-1,2,4-噁二唑-5-基)乙基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲基氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基磺酰基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基氨基苄基)-1,2,4-噁二唑-3-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰基氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基羰基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-乙酰氨基甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲磺酰氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基羰基甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-乙酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基羰基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-氨基羰基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰氨基苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-甲氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-二甲氨基磺酰基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(叔丁酯基氨基)甲基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-(叔丁酯基氨基)乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-甲酯基氨甲基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-二甲氨基甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲磺酰氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-乙酯基氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苯甲酰基氨甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-苯甲酰基氨乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-叔丁氨基羰基氨基乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-叔丁氨基羰基氨基乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N-甲基-2-[5-(3-氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-(叔丁酯基)哌嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲酯基派嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲氨基羰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-乙酰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-甲磺酰基氨基甲苯基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苯磺酰氨甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-苄氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(3-吡啶基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲氧基吡啶-5-基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[2-[3-(4-乙酰氨基苄基)-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-3-基]乙胺;
2-[5-[2-[3-(4-甲氧基苄基)-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(5-甲基-1,3-噁唑-2-基)-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[2-(5-甲基-1,3-噁唑-2-基)乙基]-1H-吲哚-3-基]乙胺;
1-甲基-4-[5-(3-氨基-1,2,4-噁二唑-5-基)-1H-吲哚-3-基]哌啶;
1-甲基-4-[5-(3-氨基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]哌啶;
1-甲基-4-[5-[3-(4-甲磺酰氨基苄基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]哌啶;
1-甲基-4-[5-[3-(3-吡啶基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]哌啶;
N,N-二甲基-2-[5-[3-(4-吡啶基)甲基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-(叔丁氧基羰基氨基)乙基)氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-(3-氨基羰基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-(3-甲氨基羰基-1,2,4-噁二唑-5-基甲基)-1H-吲哚-3-基]乙胺;
2-[5-[3-(吡咯烷-1-基)羰基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
2-[5-[3-(氮杂环丁烷-1-基)羰基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(4-苯磺酰基哌嗪-1-基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-吡咯烷-1-基羰基氨基)乙基)-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-[3-(2-甲磺酰氨乙基)氨基-1,2,4-噁二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
N,N-二甲基-2-[5-(3-氨基-1,4-噻二唑-5-基甲基]-1H-吲哚-3-基]乙胺;
7、制备药用组合物的方法,其特征在于:将按上述任一权利要求制得的化合物与药学上可接受载体或赋形剂混合。
8、按权利要求1至6所述的任一方法制备的化合物用于制药,该药在临床上用于有关疾病的防治,它是5-HT,类受体的选择性特效药。
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GB909001018A GB9001018D0 (en) | 1990-01-17 | 1990-01-17 | Therapeutic agents |
GB9001018.2 | 1990-01-17 | ||
GB909008587A GB9008587D0 (en) | 1990-04-17 | 1990-04-17 | Therapeutic agents |
GB9008587.9 | 1990-04-17 |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4833153A (en) * | 1985-11-08 | 1989-05-23 | Glaxo Group Limited | Indole derivatives |
GB8724912D0 (en) * | 1987-10-23 | 1987-11-25 | Wellcome Found | Indole derivatives |
NZ227841A (en) * | 1988-02-12 | 1991-08-27 | Merck Sharp & Dohme | Heterocyclic compounds with at least two non-condensed five membered rings and pharmaceutical compositions |
-
1991
- 1991-01-07 IL IL96891A patent/IL96891A0/xx unknown
- 1991-01-10 EP EP91300180A patent/EP0438230B1/en not_active Expired - Lifetime
- 1991-01-10 AT AT91300180T patent/ATE152110T1/de not_active IP Right Cessation
- 1991-01-10 DE DE69125731T patent/DE69125731T2/de not_active Expired - Fee Related
- 1991-01-15 PT PT96477A patent/PT96477A/pt not_active Application Discontinuation
- 1991-01-15 CA CA002034189A patent/CA2034189A1/en not_active Abandoned
- 1991-01-16 KR KR1019910000593A patent/KR910014373A/ko not_active Application Discontinuation
- 1991-01-16 CS CS9186A patent/CS8691A2/cs unknown
- 1991-01-16 FI FI910228A patent/FI910228A/fi unknown
- 1991-01-16 NO NO91910187A patent/NO910187L/no unknown
- 1991-01-16 IE IE013991A patent/IE910139A1/en unknown
- 1991-01-16 HU HU91128A patent/HU910128D0/hu unknown
- 1991-01-16 AU AU69440/91A patent/AU6944091A/en not_active Abandoned
- 1991-01-17 CN CN91100380A patent/CN1053429A/zh active Pending
- 1991-01-17 JP JP3216736A patent/JPH06100558A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110461838A (zh) * | 2017-03-07 | 2019-11-15 | 豪夫迈·罗氏有限公司 | 噁二唑瞬时受体电位通道抑制剂 |
Also Published As
Publication number | Publication date |
---|---|
NO910187L (no) | 1991-07-18 |
IL96891A0 (en) | 1992-03-29 |
FI910228A (fi) | 1991-07-18 |
PT96477A (pt) | 1991-10-15 |
NO910187D0 (no) | 1991-01-16 |
IE910139A1 (en) | 1991-07-17 |
DE69125731T2 (de) | 1997-11-27 |
DE69125731D1 (de) | 1997-05-28 |
EP0438230B1 (en) | 1997-04-23 |
JPH06100558A (ja) | 1994-04-12 |
ATE152110T1 (de) | 1997-05-15 |
HU910128D0 (en) | 1991-08-28 |
EP0438230A3 (en) | 1992-02-12 |
CA2034189A1 (en) | 1991-07-18 |
EP0438230A2 (en) | 1991-07-24 |
FI910228A0 (fi) | 1991-01-16 |
CS8691A2 (en) | 1991-09-15 |
AU6944091A (en) | 1991-07-25 |
KR910014373A (ko) | 1991-08-31 |
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