CN87107148A - 1,3-二取代咪唑盐 - Google Patents
1,3-二取代咪唑盐 Download PDFInfo
- Publication number
- CN87107148A CN87107148A CN198787107148A CN87107148A CN87107148A CN 87107148 A CN87107148 A CN 87107148A CN 198787107148 A CN198787107148 A CN 198787107148A CN 87107148 A CN87107148 A CN 87107148A CN 87107148 A CN87107148 A CN 87107148A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl group
- low alkyl
- amino
- dimethylamino
- 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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- 150000004693 imidazolium salts Chemical class 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 49
- 150000002460 imidazoles Chemical class 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 55
- -1 halide anions Chemical class 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229940015043 glyoxal Drugs 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000003968 arylidene group Chemical group [H]C(c)=* 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000000843 phenylene group Chemical class C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 229910020706 Co—Re Inorganic materials 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 24
- 150000003839 salts Chemical class 0.000 abstract description 13
- 230000000507 anthelmentic effect Effects 0.000 abstract description 2
- 230000001857 anti-mycotic effect Effects 0.000 abstract description 2
- 239000002543 antimycotic Substances 0.000 abstract description 2
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 239000002423 protozoacide Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 235000019441 ethanol Nutrition 0.000 description 32
- 150000002430 hydrocarbons Chemical group 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- 125000005843 halogen group Chemical group 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 239000004215 Carbon black (E152) Substances 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 229930195733 hydrocarbon Natural products 0.000 description 14
- 229920000642 polymer Polymers 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 150000001805 chlorine compounds Chemical class 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 7
- 150000004292 cyclic ethers Chemical class 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 150000003335 secondary amines Chemical class 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 241000239183 Filaria Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000243994 Litomosoides carinii Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000012876 carrier material Substances 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
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
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- 150000002576 ketones Chemical class 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
- QWWFWOOTFZWVSB-UHFFFAOYSA-N 2-phenylimidazol-1-amine Chemical compound NN1C=CN=C1C1=CC=CC=C1 QWWFWOOTFZWVSB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- 125000002837 carbocyclic group Chemical group 0.000 description 2
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- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 1
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- CRWNQZTZTZWPOF-UHFFFAOYSA-N 2-methyl-4-phenylpyridine Chemical compound C1=NC(C)=CC(C=2C=CC=CC=2)=C1 CRWNQZTZTZWPOF-UHFFFAOYSA-N 0.000 description 1
- ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 2-phenyl-1h-imidazole Chemical compound C1=CNC(C=2C=CC=CC=2)=N1 ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- XXRUQNNAKXZSOS-UHFFFAOYSA-N 5-(chloromethyl)-1,2,3-trimethoxybenzene Chemical compound COC1=CC(CCl)=CC(OC)=C1OC XXRUQNNAKXZSOS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
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- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 230000003204 osmotic effect Effects 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- 125000004149 thio group Chemical group *S* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- BJAARRARQJZURR-UHFFFAOYSA-N trimethylazanium;hydroxide Chemical compound O.CN(C)C BJAARRARQJZURR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
- C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D233/16—Radicals substituted by nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P33/10—Anthelmintics
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- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/22—Radicals substituted by oxygen atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
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- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/42—Sulfur atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
相应于通式I的,可作药用的新咪唑 碳酸氢盐,具有有价值的抗菌、抗真菌、杀原虫和(或)驱肠虫的性质。式I的咪唑碳酸氢盐,可通过简单和廉价的方法用于生产可药用的,特别是水溶性的盐类。
Description
本发明涉及一类新的具有如下通式的咪唑鎓碳酸氢盐:
其中,符号Q表示亚芳基或杂亚芳基,基团-NR1R2代表碱性氨基基团,R3表示氢,低级烷基,低级羟烷基,低级烷氧烷基,低级卤代烷基,低级烷硫基,低级烷氧基或基团-(A)n-Ra,R4表示饱和或部分不饱和的低级碳氢基团,碱性氨基基团或基团-N=CRc-Rb,-CHRcRd,-NH-CHRcRd,-NH-CO-Re或-CHRc-CO-Re,R5表示氢,低级烷基,低级羟烷基,低级烷氧烷基,低级卤代烷基,芳基或稠合苯环,R6表示氢或低级烷基,Ra和Rb各表示芳基、杂芳基或碱性氨基基团,Rc表示氢或低级烷基,Rd表示芳基或杂芳基,Re表示氢,饱和的或部分不饱和的经氧原子任意连接的低级碳氢基团;或者,经低级烷基任意连接的芳基,杂芳基或碱性氨基基团,A表示1,2-亚乙烯基或低级亚烷基,n表示数字0或1,虚线表示另外的一个双键。
与这些新化合物相应的可作药用的盐类具有有价值的药理性质。特别是它们具有抗菌,抗真菌,杀原虫和(或)抗蠕虫的性质。具有通式Ⅰ的上述化合物可以经简单和廉价的方法,用以制造可作药用的,特别是水溶性的盐类。
本发明的目的是:式Ⅰ化合物本身;它们的制备方法;制造相应的可作药用盐类的方法;以及应用这些化合物生产可作药用的相应的盐类。
术语“低级”是指最多具有7个碳原子,最好为4个碳原子的残基或化合物。术语“烷基”,单独用或结合用,如“烷基”,“烷氧基”,和“烷硫基”,是指直链或支链的饱和碳氢残基,如甲基,乙基,正丙基,异丙基,正丁基,仲丁基,异丁基和叔丁基。
术语“饱和或部分不饱和碳氢基团”是指开链和环状基团以及它们的结合体。饱和的或部分不饱和的低级碳氢基团的例子有:低级烷基如甲基,乙基,丙基,异丙基,仲丁基和异丁基;低级链烯基如2-丙烯基,2-丁烯基,3-丁烯基和2-甲基-2-丙烯基;被低级烷基任意取代的低级环烷基如环丙基,环戊基,2-甲基环戊基,环己基和3-甲基-环己基;被低级烷基任意取代的低级环烯基如3-环戊烯基,1-甲基-3-环戊烯基和3-环己烯基;被低级环烷基或环烯基取代的低级烷基或链烯基如环丙基甲基,环丙基乙基,环戊基甲基,环己基甲基,2-环己烯基甲基和3-环丙基-2-丙烯基。优选的低级碳氢基团是饱和的。低级烷基和低级环烷基,尤其是低级烷基,是特别好的低级碳氢基团。
术语“芳基”是指碳环芳香基团,优选的是单或双环的,即苯基和萘基,尤其是苯基。这些基团可被一个,两个或三个取代基任意取代,这些取代基包括碱性氨基,低级烷基,低级烷氧基,低级烷硫基,低级烷酰基,低级烷氧羰基,芳基(特别是苯基),卤素,三氟甲基,羟基,硝基和氰基。这些基团最好是未被取代的或被一,二或三个取代基所取代的,取代基包括低级烷基,低级烷氧基,低级烷硫基,卤素,硝基和二(低级烷基)氨基。
术语“亚芳基”是指带有两个自由价键的碳环芳香基团,优选的是单或双环基团,即亚苯基和亚萘基,尤其是1,4或1,2亚苯基,特别是1,4亚苯基。这些基团可被一或二个取代基所取代,取代基包括低级烷基,低级烷氧基,低级烷硫基,低级烷酰基,低级烷氧羰基,芳基(尤其是苯基),卤素,三氟甲基,羟基,硝基和氰基。它们最好是未被取代的。
术语“杂芳基”是指杂环芳香基团,优选的是单或双环基团,尤其是五-或六-元芳杂环,它们可以和苯环任意稠合,或者,被一个、二个或三个取代基任意取代,取代基包括碱性氨基,低级烷基,低级烷氧基,低级烷硫基,低级烷酰基,低级烷氧羰基,芳基(尤其是苯基),卤素,三氟甲基,羟基,硝基和氰基。五元芳香杂环最好含有一个氧原子或硫原子、或亚氨基作为杂环的成员;并且,可任意地再另有一个或二个氮原子。六元芳香杂环最好含有一个,二个或三个氮原子作为杂环的成员。
术语“杂亚芳基”是指带有两个自由价键的杂环芳香基团,优选的是单或双环基团,尤其是带有两个自由价键的五元和六元芳香杂环,它们可以是和苯环任意稠合的,或是被一个或二个取代基所取代的,取代基包括低级烷基,低级烷氧基,低级烷硫基,低级烷酰基,低级烷氧羰基,芳基(尤其是苯基),卤素,三氟甲基,羟基,硝基和氰基。
术语“卤素”是指氟、氯、溴、碘四种形式。
术语“碱性氨基基团”或“碱性氨基”是指具碱性的、未被取代的、或单一或双取代的氨基。碱性氨基基团可用通式-NRR′来表示。其中,R最好是氢或低级烷基,R′最好是氢或一个饱和或部分不饱和的低级碳氢基团,该基团可以被一个或两个低级烷氧基或羟基任意取代,或被氨基,低级烷氨基,低级二烷氨基,氧,低级烷氧羰基或低级亚烷二氧基任意取代;或者,R和R′连同氮原子一起表示一个四元到七元饱和的氮杂环,该杂环被一个或二个低级烷基任意取代,并且可含有一个氧或硫原子或基团>SO,>SO2,>CO,>CH-Rf或>N-Rg来代替亚甲基作为环的成员,其中,Rf代表羟基,低级烷酰基,低级烷氧羰基,氨基甲酰基,单一或双(低级烷基)氨基甲酰基,或者,饱和或部分不饱和的经氧原子任意连接的低级碳氢基团,并且这些低级碳氢基团可以被一个或二个低级烷氧基或羟基,或者被氨基,低级烷氨基,低级二烷氨基,氧,低级烷氧羰基或低级亚烷二氧基任意取代;Rg表示氢,低级烷酰基,低级烷氧羰基,氨基甲酰基,单一或双(低级烷基)氨基甲酰基,或饱和的或部分不饱和的低级碳氢基团,这些碳氢基团可以被一或二个低级烷氧基或羟基,或被氨基,低级烷氨基,低级二烷氨基,氧,低级烷氧羰基或低级亚烷基二氧基任意取代。
特别好的碱性氨基基团-NRR′是:R表示氢或低级烷基,R′表示饱和的低级碳氢基团,或者,R和R′连同氮原子一起表示一个四,五或六元饱和氮杂环,该氮杂环可被羟基,低级烷氧基,低级羟烷基或低级烷氧烷基任意取代,或者是表示一个六元的饱和氮杂环,该氮杂环可被一或二个低级烷基任意取代,并且,它含有氧或硫原子或亚氨基或低级烷亚氨基代替亚甲基。
尤其好的碱性氨基基团-NRR′是:R和R′各表示低级烷基或连同氮原子一起表示1-吡咯烷基,1-哌啶基,4-吗啉基,2,6-二甲基-4-吗啉基,4-硫代吗啉基或4-甲基-1-哌嗪基。
如果式Ⅰ化合物含有一个以上的碱性氨基基团,则它们可以是相同的,也可以是不同的。
术语“离去基团”首先是指卤原子如氯、溴、碘,低级烷基磺酰氧基如甲磺酰氧基以及芳香磺酰氧基如对甲苯磺酰氧基。
在具体的实施例中,本发明涉及到上述式Ⅰ的化合物,其中R3表示低级烷基。
在更具体的实施例中,本发明涉及到上述式Ⅰ的化合物,其中R3表示基团-(A)n-Ra。最好是,n表示数字0,并且Ra表示未被取代的苯基或被一个,二个或三个取代基取代的苯基,其中取代基包括低级烷基,低级烷氧基,低级烷硫基,卤素,硝基和二(低级烷基)氨基,更好的是,Ra表示未被取代的苯基或被低级烷基,低级烷氧基或卤素单取代的苯基,诸如苯基,对氯苯基,对甲苯基和间甲氧苯基;或者,n表示数字1,A表示1,2-亚乙烯基,并且Ra表示基团-NRR′,其中R和R′各表示氢或低级烷基,或连同氮原子一起表示五或六元饱和杂环,这些杂环被一或二个低级烷基任意取代,并且它们含有一个或二个氮原子,或者一个氮原子和一个氧或硫原子作为杂原子,在这种情况下,R和R′最好各自表示低级烷基,尤其是甲基,或连同氮原子一起表示4-吗啉基或1-哌啶基。
符号R5优先表示氢。
在一个较好的实施例中,R4表示基团-N=CR6-Q-NR1R2。
在另一个较好的实施例中,R4表示基团-N=CRc-Rb,其中,Rc优先表示氢,Rb优先表示未被取代的苯基或被一个、二个或三个取代基取代的苯基,取代基包括低级烷基,低级烷氧基,低级烷硫基,卤素和硝基。Rb特代表对硝基苯基。
符号Q优先表示被一个或二个取代基任意取代的1,4-亚苯基,取代基包括低级烷基和低级烷氧基。在一个特别好的实施例中,符号Q表示1,4-亚苯基。
R1和R2各优先表示低级烷基。在一个特别好的实施例中,R1和R2各表示甲基。
符号R6优先表示氢。
下文所列的咪唑鎓盐是由式Ⅰ所定的一类物质中优选的代表物:
1,3-双〔〔对-(二甲基氨基)苯亚甲基〕氨基〕-2-〔2-(二甲基氨基)乙烯基〕咪唑鎓碳酸氢盐,
1,3-双〔〔对-(二甲基氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐,
1,3-双〔〔对-(二甲基氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓碳酸氢盐,
1,3-双〔〔对-(二甲基氨基)苯亚甲基〕氨基〕-2-苯基咪唑鎓碳酸氢盐。
依据本发明,式Ⅰ新化合物可以通过用浓的碱金属碳酸氢盐水溶液处理通式Ⅱ的化合物来制备。
其中,R1,R2,R3,R4,R5,R6,Q和虚线具有前述含义,Y-表示阴离子。
优选使用饱和的碳酸氢盐溶液。钠为优选的碱金属。依据本发明,该方法也可以在与水不相混溶的有机溶剂中进行,尤其可考虑用如氯仿等卤代碳氢化合物。Y-最好是卤化物,尤其是氯化物,溴化物或碘化物。反应最好在室温进行。
依据本发明,咪唑鎓碳酸氢盐实际上不溶于反应介质,因而可以过滤分离。
如前所述,这些咪唑鎓碳酸氢盐可用于以简单和廉价的方法来生产相应的,可作药用的,特别是水溶性的盐类。将咪唑鎓碳酸氢盐转变成具有通式Ⅲ的相应的可作药用盐的方法是:将咪唑鎓碳酸氢盐用与所需可药用的阴离子相应的酸处理。水和低级醇如甲醇或其混合液可优选作为溶剂。反应最好在室温进行。
其中R1,R2,R3,R4,R5,R6,Q和虚线具有前述的含义,A-表示药学上可用的阴离子。
与药学上可用的阴离子相应的适宜的酸有:醋酸,苯磺酸,苯甲酸,酒石酸,氢溴酸,盐酸,柠檬酸,富马酸,苹果酸,马来酸,扁桃酸,甲磺酸,磷酸,琥珀酸,硫酸和对甲苯磺酸。
鉴于这样一个事实,即在反应产物中除了所期望的盐和水外,还有连续释放的二氧化碳,因此,不必使用大量过量的上述酸。通常,根据酸的强度无需过量用酸。
式Ⅱ的化合物可用以下方法制备:
a),使通式Ⅳa或通式Ⅳb化合物与通式Ⅴ的羰基化合物反应
其中,R3,R4,R5,虚线,Y-具有前述含义
其中,R1,R2,R6和Q具有前述含义
或者,
b),将通式Ⅵ的化合物与通式Ⅶ的化合物反应
其中,R1,R2,R3,R5,R6和Q具有前述含义
其中,R41表示饱和的或部分不饱和的低级碳氢基团,或基团-CHRcRd或-CHRc-CO-Re,X表示离去基团,Rc,Rd及Re具有
前述含义
或者.
c),使通式Ⅱa的化合物与通式Ⅷ的醛缩合
其中,R1,R2,R4,R5,R6,Q,Y-和虚线具有前述含义
其中,Ra具有前述含义
或者,
d),使通式Ⅱb的化合物与氨或碱性伯胺或仲胺进行反应。
其中,R1,R2,R4,R5,R6,Q,Y-和虚线具有前述含义,R″
表示低级烷基
以上方法a)-d)中,有些需用保护基对起始原料中的任何活性氨基和(或)羟基进行保护。对于本领域技术人员来说,这些情况是很容易识别的,同时,对他们来说,选择各自的合适的保护基团也不成问题。
依据方法变式a),胺与醛或酮的反应本身是已知的,并且为任何本领域技术人员所熟知。合适的溶剂有:如水,低级脂肪酸如醋酸和丙酸,低级醇如甲醇,乙醇,1-丙醇和2-丙醇,低级脂肪酸酯如乙酸乙酯,低级醚如乙醚,叔丁基甲基醚,乙二醇二甲醚,四氢呋喃和二噁烷,卤代低级碳氢化合物如二氯甲烷,氯仿,二氯乙烷,芳香碳氢化合物如苯,甲苯,二甲苯,乙腈,N,N-二甲基甲酰胺和二甲亚砜。反应温度并不关键,如反应可在大约0℃到所选择溶剂的回流温度范围内进行。然而,在室温进行反应为好。当与活性较小的式Ⅴ(R6为低级烷基)所示的酮进行反应时,最好用缩合剂如三乙基氧鎓四氟硼酸盐。
依据方法变式b),式Ⅱ化合物可通过将式Ⅵ的咪唑衍生物进行烷基化来制备,在式Ⅱ中,R4表示饱和的或部分不饱和的低级碳氢基团,或是基团-CHRcRd或-CHRc-CO-Re。该反应本身也是已知的,并且为任何本领域技术人员所熟知。合适的溶剂有:例如:卤代低级碳氢化合物如二氯甲烷,氯仿和二氯乙烷,开链或环醚如乙醚,叔丁基甲基醚,乙二醇二甲醚,四氢呋喃和二噁烷,低级脂肪酸酯如乙酸乙酯,低级醇如甲醇,乙醇,1-丙醇和2-丙醇,芳香碳氢化合物如苯,甲苯和二甲苯,乙腈,N,N-二甲基甲酰胺和二甲亚砜。诸如2-丙醇等低级醇或乙腈是优先应用的。反应温度并不关键,例如,反应可在约0℃到溶剂的回流温度范围内进行,最好在室温到约60℃范围。
依据方法变式c),式Ⅱ的化合物(其中R3表示基团-CH=CH-Ra)可通过将式Ⅱa的化合物与式Ⅷ的醛缩合来制备,同样,该反应本身是已知的,并且为本领域技术人员所熟知。在Ra表示芳基或杂芳基的情况下,反应最好在仲胺,尤其是环状胺如哌啶或吗啉中进行。合适的溶剂有:如低级醇如甲醇,乙醇,1-丙醇,2-丙醇,芳香碳氢化合物如苯和甲苯,开链或环醚如乙二醇二甲醚,四氢呋喃和二噁烷,卤代低级碳氢化合物如二氯甲烷,N,N-二甲基甲酰胺和二甲亚砜。反应最好在所选溶剂的回流温度进行。在一个较好的实施例中,用一种共沸剂作为溶剂,如芳香碳氢化合物或卤代低级碳氢化合物,反应中生成的水用分水器降去。
在Ra表示碱性氨基的情况下,式Ⅷ的醛最好用其相应的二(低级烷基)缩醛,在本例子中,前述的各种溶剂也同样适用。优先选用的溶剂有低级醇如1-丙醇,卤代低级碳氢化合物如二氯甲烷或二甲基甲酰胺,反应温度并不关键,反应可在大约室温到所选溶剂的回流温度范围内进行,然而,反应最好在大约室温到约100℃之间进行。
依据方法变式d),式Ⅱ的化合物(其中R3表示碱性氨基基团)可通过将式Ⅱb的化合物与氨或碱性伯或仲胺反应来制备。同样,此时反应本身是已知的,并为任何本领域技术人员所熟知。合适的溶剂有:例如,卤代低级碳氢化合物如二氯甲烷,开链和环醚如乙醚,叔丁基甲基醚,四氢呋喃,二噁烷,N,N-二甲基甲酰胺,乙腈和二甲亚砜。优选的溶剂为N,N-二甲基甲酰胺和乙腈。反应温度并不关键,例如该反应可在大约0℃到所选溶剂的回流温度范围内进行。然而,反应最好在室温进行。
例如,作为起始原料的式Ⅳa的化合物,可按照下列反应图解Ⅰ′来制备,其中,R3,R5,Y-和虚线具有前述含义。
反应图解Ⅰ
例如,式Ⅳa的化合物(其中,R3表示低级烷硫基)可按照下列反应图解Ⅱ来制备,其中,R5,R″,Y-和虚线具有前述含义,φ表示苯基。
反应图解Ⅱ
例如,式Ⅳa(其中,R3表示基团-CH=CH-Ra)的化合物可按照下列反应图解Ⅲ来制备,其中,R5,Ra,Y-,虚线和φ具有前述含义。
反应图解Ⅲ
例如,式Ⅳa(其中R3表示碱性氨基)的化合物可按照下列反应图解Ⅳ来制备,其中,R5,Y-,虚线和φ具有前述含义,R″表示碱性氨基基团。
反应图解Ⅳ
例如,式Ⅳa的化合物(其中,R3表示基团-A′-Ra″,A′表示低级亚烷基,Ra″表示碱性氨基基团)可按照下列反应图解Ⅴ来制备,其中,R5,Ra″,A′,φ,Y-和虚线具有前述含义,X′表示卤原子。
反应图解Ⅴ
式Ⅳb的化合物可按前述的反应图解Ⅰ-Ⅴ来制备,在每一例中,用式ⅩⅤ的相应化合物代替式Ⅹ的化合物作为起始原料。
其中,Rh表示氢,甲基,基团-A′-OH或R3和A′,R3,R4及
R5具有前述含义。
例如,式Ⅳb的化合物(其中,R4表示饱和的或部分不饱和的低级碳氢基团或基团-CHRcRd或-CHRc-CO-Re)可按照下列反应图解Ⅵ来制备,其中,R3,R41,R5,Y-,φ和虚线具有前述含义。
反应图解Ⅵ
制备式Ⅳb化合物(其中R4表示饱和的或部分不饱和的低级碳氢基团;或基团-CHRcRd或-CHRc-CO-Re,R3表示基团-SR″,-CH=CH-Ra,Ra″或-A′-Ra″)亦可按照前述的反应图解Ⅵ,将式Ⅹb,Ⅹc或Ⅹe′化合物(代替式Ⅹa的化合物)转变成相应的式ⅩⅦa化合物,并以其代替式Ⅻ化合物,按照反应图解Ⅱ,Ⅲ,Ⅳ和Ⅴ对它进一步加工。
以下对反应图解中涉及到的反应步骤A-G作较详细的解释,在每个反应图解中,反应本身是已知的,并为任何本领域技术人员所熟知。
Aa:此步反应为亲电性胺化反应,用O-(2,4-二硝基苯基)羟胺,O-均三甲基苯磺酰基羟胺或者胲基O-磺酸或其与无机碱成的盐作为胺化剂。最好用胲基O-磺酸的碱金属盐,例如,用其钠盐并在水溶液中进行此反应。在这种情况下,一般得到含式Ⅳa或Ⅺ的二胺及式Ⅹ单胺的混合物。这两种化合物可用已知的,且为本领域技术人员所熟悉的方法加以分离。下述的实例中包含了关于分离所得混合物的细节。
Ab:此步反应为亲电性胺化反应,用如O-二苯基氧膦基羟胺或O-均-三甲基苯磺酰基羟胺作为胺化剂。在与胺化剂反应之前,先用强碱将起始原料转化成碱金属盐。例如合适的碱有:低级碱金属烷氧化物如甲醇钠、乙醇钠及碱金属氢化物,如氢化钠。合适的溶剂有:如N-甲基吡咯烷酮,N,N-二甲基甲酰胺,低级醇,醚类如四氢呋喃,二甘醇二甲醚,二甘醇二乙醚,二甘醇二丁醚。优选的反应温度范围为大约0℃到100℃,反应最好在室温进行。
Ac:此步反应为亲电性胺化反应,用如O-二苯基氧膦基羟胺或O-均三甲基苯磺酰基羟胺作为胺化剂。合适的溶剂有:如,卤代低级碳氢化合物如氯仿,二氯甲烷,二氯乙烷,醚类如乙醚,四氢呋喃,低级醇如乙醇,乙腈,N,N-二甲基甲酰胺,二甲亚砜及上述溶剂的混合物。反应温度范围在约0℃至所选溶剂的回流温度,反应最好在室温进行。
B:在此步反应中,用苯甲醛将相应的起始原料转化为相应的醛亚胺。合适的溶剂有:例如低级脂肪酸如乙酸和丙酸,低级醇如甲醇,乙醇及2-丙醇,酸性水介质,卤代低级碳氢化合物如二氯甲烷,氯仿及二氯乙烷,开链及环醚如乙醚,二异丙基醚,叔丁基甲基醚,乙二醇二甲醚,二甘醇二乙醚,四氢呋喃及二噁烷,乙腈,N,N-二甲基甲酰胺及二甲亚砜。反应可在大约0℃到所选溶剂的回流温度范围内进行,反应最好在室温进行。
C:例如,在合适的溶剂如吡啶中,并有叔胺存在下,用元素态硫处理起始原料,可以引入所需的硫代基团。反应可在约室温到反应混合物的回流温度范围内进行。
D:例如,将起始原料用烷化剂诸如三(低级烷基)氧鎓四氟硼酸盐(如三甲基氧鎓四氟硼酸盐)处理,可进行所需的烷基化。合适的溶剂有:如卤代低级碳氢化合物如二氯甲烷,反应最好在室温进行。
E:此步反应为醛亚胺的水解。在一个较好的实施例中,用酸水溶液处理相应的起始原料,并用水蒸汽蒸馏除去得到的芳香醛。合适的酸有:例如,稀盐酸,稀氢溴酸及四氟硼酸。
F:此步反应为式Ⅻc的化合物与式Ⅷ的醛缩合。当Ra表示芳香基或杂芳基时,反应最好在仲胺,尤其是环胺如哌啶或吗啉存在下进行。合适的溶剂有:例如,低级醇如甲醇,乙醇,1-丙醇及2-丙醇,芳香碳氢化合物如苯及甲苯,开链及环醚如乙二醇二甲醚,四氢呋喃及二噁烷,卤代低级碳氢化合物如二氯甲烷,N,N-二甲基甲酰胺及二甲亚砜。反应最好在所选溶剂的回流温度进行。在一个较好的实施例中,用共沸剂如芳香碳氢化合物或卤代低级碳氢化合物作为溶剂,反应中生成的水用分水器除去。
当Ra表示一个碱性氨基时,或Ⅷ的醛最好用其相应的二(低级烷基)缩醛,前述的各种溶剂在此仍适用。优先用的溶剂有低级醇如1-丙醇,卤代低级碳氢化合物如二氯甲烷或二甲基甲酰胺。反应温度并不关键,反应可在大约室温到所选溶剂的回流温度范围内进行。然而,反应最好在约室温至约100℃进行。
G:此反应是式ⅩⅣb的化合物与氨或碱性的伯或仲胺反应。合适的溶剂有:例如卤代低级碳氢化合物如二氯甲烷,开链及环醚如乙醚,叔丁基甲基醚,四氢呋喃及二噁烷,N,N-二甲基甲酰胺,乙腈及二甲亚砜。优选的溶剂为N,N-二甲基甲酰胺和乙腈。反应温度并不关键,例如该反应可在约0℃至所选溶剂的回流温度范围内进行。然而,反应最好在室温进行。
H:此反应是式Ⅻe′的化合物与卤化剂如亚硫酰氯,三氯氧磷反应,最好用过量的卤化剂作溶剂。反应可在约0℃至反应混合物回流温度范围内进行。
I:此反应是式Ⅻe的化合物与氨或碱性的伯或仲胺反应。最好用丙酮或N,N-二甲基甲酰胺作为溶剂。反应可在约室温至反应混合物的回流温度范围内进行。
J:此步反应为相应的起始原料与上述式Ⅵ的化合物反应。合适的的溶剂有:例如卤代低级碳氢化合物如二氯甲烷,氯仿及二氯乙烷,开链及环醚如乙醚,二异丙基醚,乙二醇二甲醚,二甘醇二乙醚,四氢呋喃及二噁烷,乙腈及N,N-二甲基甲酰胺。该反应可在约0℃至所选溶剂的回流温度范围内进行。
用作起始原料的式Ⅵ化合物可类似于方法变式a)来制备,或类似于前述反应步骤B,以式Ⅹa的化合物与式Ⅴ的醛或酮反应来制备。
前面已经提到,相应于式Ⅰ化合物的,可作药用的盐类(即式Ⅲ的化合物),具有价值的药理性质。例如,它们显示抗寄生虫性质,对寄生原虫和蠕虫尤其有活性。它们对寄生蠕虫,特别是对线虫如丝虫活性尤为显著。这些药理性质可用试验方法测定,这些方法是已知的,并对任何本领域技术人员来说是熟悉的。
式Ⅲ化合物的杀丝虫活性可在已被棉鼠丝虫(Litomosoides carinii)感染了的棉鼠(Sigmodon hispidus)身上进行测定。棉鼠丝虫的感染是通过吸血螨(Bdellonyssus bacoti)传染的,微丝蚴在吸血螨体内发育成有传染性的蚴。棉鼠暴露在已被传染的螨中,任其叮咬而受到感染。14周后,感染组中的2-4只动物,以皮下注射待试化合物进行治疗。经待试化合物治疗42天之后,将实验动物解剖,将成年丝虫从胸腔内取出。把活的和死的或者被荚膜包围的蠕虫彼此分开并称重。杀丝虫的活性以每治疗组的微丝蚴死亡的百分率表示。然后使用不同剂量组的值采用概率单位分析法测出ED90值。ED90值是能使自胸腔取出的蠕虫有90%为死虫所需的剂量。在下列表格中,汇集了前述试验所得的结果,被测试物质系具有通式Ⅲ的一类化合物中的几个有代表性的成员。此外,该表的数据包括这些化合物中的一些化合物在小鼠一次口服给药情况下的急性毒性(毫克/千克)。
表
化合物 | ED90 mg/kg皮下注射 | LD50 mg/kg口服 |
ABCD | 1.00.50.85<1.0 | 312-625--1250-2500 |
化合物A为1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕氯化咪唑鎓。
化合物B为1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基氯化咪唑鎓。
化合物C为1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基氯化咪唑鎓。
化合物D为1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-苯基氯化咪唑鎓。
式Ⅲ的化合物可作药用,例如,以药物制剂的形式经肠内或肠胃外用药。它们可以片剂、包衣片,糖衣片,硬及软明胶胶囊、溶液,乳剂或悬浮剂的形式口服给药,以栓剂形式直肠给药,或以注射液的形式肠胃外给药。
该药物制剂的制备可以用任何本领域技术人员所熟悉的方法,即将所述的式Ⅲ化合物,任意与其它有治疗价值的物质连同合适的,无毒的,惰性的,对治疗适合的固态或液态载体物质一起,组成一个可用的盖制剂形式。如果需要的话,可加入常见的药用辅助剂。
作为载体物质,不仅无机载体物质,而且有机载体物质也同样适用。因此,例如乳糖,玉米淀粉或它们的衍生物,滑石粉,硬脂酸或其盐可用作片剂、包衣片、糖衣丸及硬胶囊的载体物质。对于软胶囊来说,合适的载体有:例如植物油,蜡,脂肪及半固态和液态的多元醇(然而,根据活性物质的性质,在软胶囊中无需载体)。对制造溶液和糖浆制剂,合适的载体物质是:如水,多元醇,蔗糖,转化糖及葡萄糖。对注射液,合适的载体物质为:如水,醇,多元醇,甘油及植物油。对栓剂,合适的载体物质有:如天然油或硬质油,蜡,脂肪及半固态或液态的多元醇。
作为药物辅助剂,可考虑通常的稳定剂,防腐剂,润湿剂,乳化剂,调味剂,改变渗透压的盐,缓冲物质,助溶剂,着色剂,涂层剂及抗氧化剂。
式Ⅲ化合物的剂量可在很宽的范围内变化,取决于所治疗的疾病,病人的年龄和个体状况以及给药的方式。当然在每一特定情况下调节到个体的需求量。为了预防及治疗由细菌、真菌及寄生虫引起的感染性疾病,对于成年病人,可考虑每日剂量为约0.01g至约4g,尤其是约0.05g至约2g。根据剂量大小,将每日剂量分成几个单位剂量给药较为适宜。
药物制品以含约10~1000mg式Ⅲ化合物较为合适,更合适的为50~500mg。
下列实例用以较详细地阐述本发明,然而,并不想以任何方式对本发明的范围加以限制。所有温度均以摄氏温度给出。
实例1
ⅰ)将0.22g(1.5mmol)的1,3-二氨基-2-甲基氯化咪唑鎓溶于5ml冰醋酸中,溶液用5ml溶有0.45g(3mmol)4-二甲氨基苯甲醛的冰醋酸溶液处理。搅拌2小时后,滤出黄色沉淀。经干燥后,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基氯化咪唑鎓,分解点264~266℃。用乙醚处理母液,从中得到第二份所需产品,所得物质用热水重结晶,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基氯化咪唑鎓,分解点270°。
ⅱ)在50°将2.02g1,3-二氨基-氯化咪唑鎓及4.5g 4-二甲氨基苯甲醛溶于100ml冰醋酸中,该溶液在室温搅拌15小时,产生黄色结晶。向其中加入100ml乙醚,抽滤该混合物,并用100ml乙醚洗涤,产物在60°干燥。用250ml乙醇重结晶,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕氯化咪唑鎓,熔点244°。
a)将3.28g(8mmol)的1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基氯化咪唑鎓悬浮于200ml氯仿及400ml饱和碳酸氢钠溶液中,并于室温搅拌18小时。滤出产品,用水洗涤,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓碳酸氢盐,熔点144~146°(分解)。
用类似的方法:
b)从1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕氯化咪唑鎓得到1,3-双〔〔对-〔二甲氨基)苯亚甲基〕氨基〕咪唑鎓碳酸氢盐,熔点103~104°(分解)。
实例2
ⅰ)将1.49g(10mmol)的4-二甲氨基苯甲醛加到15ml溶有0.88g(5mmol)1,3-二氨基-2-异丙基氯化咪唑鎓的冰醋酸溶液中。室温放置2天,加入乙醚后析出结晶,用乙醇重结晶,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基氯化咪唑鎓,熔点241°。
ⅱa)将2.16g(10mmol)的3,4,5-三甲氧基氯苄加到10ml溶有1.99g(10mmol)1-苯亚甲基氨基-2-乙基咪唑的乙腈溶液中,该混合物加热迴流28小时。滤出析出的结晶产品,用乙醚洗涤,得到1-苯亚甲基氨基-2-乙基-3-(3,4,5-三甲氧基苄基)氯化咪唑鎓,熔点205°。
ⅱb)将3.1g(7.45mmol)的1-苯亚甲基氨基-2-乙基-3-(3,4,5-三甲氧基苄基)氯化咪唑鎓溶于70ml水中,溶液用8ml 25%的盐酸处理,用水蒸汽蒸馏除去产生的苯甲醛。蒸发后,产品用乙醇/乙醚重结晶,得到1-氨基-2-乙基-3-(3,4,5-三甲氧基苄基)氯化咪唑鎓,熔点174°。
ⅱc)将1.9g(5.8mmol)1-氨基-2-乙基-3-(3,4,5-三甲氧基苄基)氯化咪唑鎓溶于38ml冰醋酸中,溶液用0.86g(5.8mmol)
对-二甲氨基苯甲醛处理,室温搅拌52小时,蒸发该溶液。产品用乙醇/乙醚重结晶,得到2-乙基-1-〔〔对-(二甲氨基)苯亚甲基〕氨基〕-3-(3,4,5-三甲氧基苄基)氯化咪唑鎓,熔点211°。
ⅲ)将含2.42g(10mmol)1-〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-乙基咪唑的溶液用2.42g(10mmol)对-二甲氨基苯甲酰甲基溴处理,在40°搅拌30分钟之后,加入乙醚,使产物结晶析出。用二氯甲烷/乙醚重结晶,得到3-〔对-(二甲氨基)苯甲酰甲基〕-1-〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-乙基溴化咪唑鎓,熔点274°。
a)将3.0g(6.8mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基氯化咪唑鎓悬浮于200ml饱和碳酸氢钠溶液中,室温搅拌18小时。滤出产品,先用水再用乙醚洗涤,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐,熔点124~126°(分解)。
用类似的方法:
b)从2-乙基-1-〔〔对-(二甲氨基)苯亚甲基〕氨基〕-3-(3,4,5-三甲氧基苄基)氯化咪唑鎓得到2-乙基-1-〔〔对-(二甲氨基)苯亚甲基〕-3-(3,4,5-三甲氧基苄基)咪唑鎓碳酸氢盐,熔点75°(分解)。
c)从3-〔对-(二甲氨基)苯甲酰甲基〕-1-〔〔对-(二甲氨基〕苯亚甲基〕氨基〕2-乙基溴化咪唑鎓得到3-〔对-(二甲氨基)苯甲酰甲基〕-3-〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-乙基咪唑鎓碳酸氢盐,熔点122°(分解)。
实例3
a)将1.3g(2.6mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐溶于10ml甲醇中,并向其中加入2ml冰醋酸。室温搅拌1.6小时后,将该溶液浓缩,加乙醚后析出产物结晶。用甲醇/乙醚重结晶二次,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓醋酸盐,熔点150~151°。
用类似的方法:
b)从1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓碳酸氢盐得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓醋酸盐,熔点159~162°。
实例4
a)将48mg(0.1mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐溶于4ml甲醇中,并向其中加入9.6mg(0.1mmol)甲磺酸。10分钟后将该溶液在室温减压浓缩。加入乙醚使产物结晶析出,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓甲磺酸盐,熔点238~239°。
用类似的方法:
b)从1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓碳酸氢盐得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基-咪唑鎓甲磺酸盐,熔点255~257°(分解)。
实例5
将25mg(0.05mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓醋酸盐悬浮于5ml饱和碳酸氢钠溶液中。搅拌3天后,滤出产品,用水洗涤,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐,熔点122~124°。
实例6
将100mg(0.2mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐悬浮于3ml水中,向其中加入2ml10%的溴化氢溶液。15分钟后滤出产品,用水洗涤。用乙醇重结晶。得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基溴化咪唑鎓,熔点241°(分解)。
实例7
ⅰ)将2.05g(5mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基氯化咪唑鎓与7.35g(50mmol)N,N-二甲基甲酰胺二乙缩醛在150ml1-丙醇中,于100℃搅拌45分钟,加入乙醚使产品沉淀,产品用二氯甲烷/甲醇结晶,用乙醇重结晶,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕氯化咪唑鎓,熔点246~248°。
a)将2.75g(5.7mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕-2-〔2-(二甲氨基)乙烯基〕氯化咪唑鎓悬浮于100ml饱和碳酸氢钠溶液中,并于室温搅拌16小时,滤出产品并用水洗涤,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕咪唑鎓碳酸氢盐,熔点160~161°。
实例8
将1.0g(1.9mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕咪唑鎓碳酸氢盐溶于20ml甲醇及3ml冰醋酸中,20分钟后,将该溶液于室温减压浓缩。加乙醚使产品结晶,用甲醇/乙醚重结晶3次,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕咪唑鎓醋酸盐,熔点182°(分解)。
实例9
ⅰ、a)用无水四氢呋喃洗涤32.8g(0.75mmol)氢化钠(含量55%,分散在油中)。在0℃向其中滴加1500ml溶有53.1g(0.37mol)2-苯基咪唑的N-甲基吡咯烷酮溶液。混合物于0℃搅拌半小时,后在室温搅拌约1.5小时(直至看不到有气体溢出)。此时向其中加入85g(0.36mol)O-二苯基氧膦基羟胺。将该混合物在室温搅拌20小时,随后向其中加入910ml水。该深色溶液于室温搅拌1小时,并用二氯甲烷提取七次,每次用300ml。提取液用硫酸钠干燥,然后进行蒸发。剩余的油状物置于一装有900g硅胶的柱子上,用二氯甲烷/乙醇(85∶15)洗脱1-氨基-2-苯基咪唑。
ⅰ、b)在2000ml溶有30.1g(0.188mol)1-氨基-2-苯基咪唑的二氯甲烷溶液中,加入43.8g(0.188mol)O-二苯基氧膦基羟胺。于室温搅拌3天后,再加入21.9g(0.094mol)O-二苯基氧膦基羟胺。一天以后将该混合物过滤,滤出物用二氯甲烷洗四次,每次150ml。残余物置于装有700ml阴离子交换树脂400(氯离子型)的柱子上,用水洗脱。蒸发洗脱液,残余物用乙醇处理再蒸发。用氢氧化钾在高真空系统下干燥后,得到1,3-二氨基-2-苯基氯化咪唑鎓。
ⅰ、c)将0.45g(2.1mmol)1,3-二氨基-2-苯基氯化咪唑鎓溶于6ml冰醋酸,向其中加入0.64g(4.3mmol)4-二甲氨基苯甲醛。搅拌24小时后,加入约1ml无水乙醚。一天后蒸发该混合物,将残余物置于装有25g硅胶的柱子上,用二氯甲烷/乙醇(98∶2)洗脱,用乙醇/乙醚结晶,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕2-苯基氯化咪唑鎓,熔点242°。
a)将95mg(0.2mmol)1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-苯基氯化咪唑鎓悬浮于10ml饱和碳酸氢钠溶液中,悬浮液于室温搅拌18小时。滤出产品1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-苯基咪唑鎓碳酸氢盐,用水和乙醚洗涤。随后将仍潮湿的产品溶于10ml甲醇中,并用2ml冰醋酸处理。在室温减压蒸发该溶液,残留物用甲醇/乙醚结晶,得到1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-苯基咪唑鎓醋酸盐,熔点167°。
实例A
采用已知的方法,用1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕咪唑鎓醋酸盐为活性物质,生产具有下列组成的片剂:
mg/片
活性物质 100
乳糖 192
玉米淀粉 80
水解玉米淀粉 20
硬脂酸钙 8
片重 400mg
下面列出的化合物也可作活性物质:
1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-苯基咪唑鎓醋酸盐;
1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓醋酸盐;
1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓甲磺酸盐;
1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓醋酸盐;
1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑甲磺酸盐。
Claims (26)
1、一种制备通式Ⅰ化合物的方法,
其中,符号Q表示亚芳基或杂亚芳基;基团-NR1R2表示碱性氨基基团;R3表示氢,低级烷基,低级羟烷基,低级烷氧烷基,低级卤代烷基,低级烷硫基,低级烷氧基或基团-(A)n-Ra;R4表示饱和或部分不饱和的低级碳氢基团,碱性氨基基团或基团-N=CRc-Rb,-CHRcRd,-NH-CHRcRd,-NH-Co-Re或-CHRc-CO-Re;R5表示氢,低级烷基,低级羟烷基,低级烷氧烷基、低级卤代烷基,芳基或稠合苯环;R6表示氢或低级烷基;Ra和Rb各表示芳基,杂芳基或碱性氨基基团;Rc表示氢或低级烷基;Rd表示芳基或杂芳基;Re表示氢,饱和或部分不饱和的经氧原子任意连接的低级碳氢基团,或者,经低级烷基任意连接的芳基,杂芳基或碱性氨基基团;A表示1,2-亚乙烯基或低级亚烷基;
n表示数字0或1;虚线表示另外一个双键。
该方法包括将通式Ⅱ的化合物用浓的碱金属碳酸氢盐水溶液处理。
其中R1,R2,R3,R4,R5,R6,Q及虚线具前述含意,Y表示一个阴离子。
2、根据权利要求1的方法,其中使用饱和碳酸氢盐溶液。
3、根据权利要求1或2的方法,其中使用碳酸氢钠溶液。
4、根据权利要求1-3中任意一项的方法,其中反应在有机溶剂存在下进行。
5、根据权利要求1-4中任意一项的方法,其中Y是一个卤化物阴离子。
6、根据权利要求1的方法,其中R3表示低级烷基。
7、根据权利要求1的方法,其中R3表示基团-(A)n-Ra。
8、根据权利要求7的方法,其中n表示数字0,Ra表示未取代的苯基或一个单、双或三取代的苯基,取代基有低级烷基,低级烷氧基,低级烷硫基,卤素,硝基及二(低级烷基)氨基。
9、根据权利要求8的方法,其中Ra表示未取代的苯基或被低级烷基,低级烷氧基或卤素单取代的苯基。
10、根据权利要求7的方法,其中n表示数字1,A表示1,2-亚乙烯基,Ra表示基团-NRR′,R和R′各自表示氢或低级烷基,或与氮原子一起表示五元或六元饱和杂环,该杂环可随意被一个或两个低级烷基取代且含有一个或两个氮原子或一个氮原子和一个氧或硫原子作为杂原子。
11、根据权利要求10的方法,其中R和R′各表示低级烷基或连同氮原子一起表示4-吗啉基或1-哌啶基。
12、根据权利要求1及6-11中任意一项的方法,其中R5表示氢。
13、根据权利要求1及6-12中任意一项的方法,其中R4表示基团-N=CR6-Q-NR′R2。
14、根据权利要求1及6-12中任意一项的方法,其中R4表示基团-N=CRc-Rb
15、根据权利要求14的方法,其中Rc表示氢。
16、根据权利要求14或15的方法,其中Rb表示未取代的苯基或单,双或三取代的苯基,取代基有低级烷基,低级烷氧基,低级烷硫基,卤素及硝基。
17、根据权利要求1及6-16中任意一项的方法,其中Q表示1,4-亚苯基,该亚苯基可被低级烷基及低级烷氧基单或双取代。
18、根据权利要求17的方法,其中Q表示1,4-亚苯基。
19、根据权利要求1及6-18中任意一项的方法,其中R1和R2各表示低级烷基。
20、根据权利要求1及6-19中任意一项的方法,其中R6表示氢。
21、根据权利要求1的方法,其中,制备1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-〔2-(二甲氨基)乙烯基〕咪唑鎓碳酸氢盐。
22、根据权利要求1的方法,其中,制备1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-异丙基咪唑鎓碳酸氢盐。
23、根据权利要求1的方法,其中,制备1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-甲基咪唑鎓碳酸氢盐。
24、根据权利要求1的方法,其中,制备1,3-双〔〔对-(二甲氨基)苯亚甲基〕氨基〕-2-苯基咪唑鎓碳酸氢盐。
26、如上文所述的本发明。
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CH395586 | 1986-10-03 |
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EP (1) | EP0266532A1 (zh) |
JP (1) | JPS6391374A (zh) |
KR (1) | KR880005090A (zh) |
CN (1) | CN87107148A (zh) |
AU (1) | AU598034B2 (zh) |
DK (1) | DK506787A (zh) |
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EP0200947B1 (de) * | 1985-04-26 | 1990-09-12 | F. Hoffmann-La Roche Ag | 1,3-Disubstituierte Imidazoliumsalze |
DK59888A (da) * | 1987-03-20 | 1988-09-21 | Hoffmann La Roche | Imidazolderivater |
US6410562B1 (en) | 1998-12-18 | 2002-06-25 | Eli Lilly And Company | Hypoglycemic imidazoline compounds |
US8367845B2 (en) * | 2006-04-21 | 2013-02-05 | The Trustees Of Boston University | Ionic viscoelastics and viscoelastic salts |
US9096540B2 (en) * | 2007-12-12 | 2015-08-04 | Basf Se | Method for the production of disubstituted imidazolium salts |
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US3050520A (en) * | 1960-03-31 | 1962-08-21 | Air Prod & Chem | Process of preparing 2-olefinic imidazoles |
US3577553A (en) * | 1969-01-29 | 1971-05-04 | Smith Kline French Lab | Compositions and methods for controlling coccidiosis in poultry employing triazole derivatives |
DE2127355A1 (en) * | 1970-06-03 | 1971-12-16 | Allen & Hanburys Ltd | Bis imidazolium cpds short acting neuromus cular blockers |
NL7311001A (zh) * | 1972-08-14 | 1974-02-18 | ||
DE2523103C3 (de) * | 1975-05-24 | 1979-11-29 | C.H. Boehringer Sohn, 6507 Ingelheim | Substituierte 2-[N-Progargyl-N-(2-chlorphenyl)amino] -imidazoline-^), deren Säureadditionssalze, Verfahren zu ihrer Herstellung und deren Verwendung |
EP0200947B1 (de) * | 1985-04-26 | 1990-09-12 | F. Hoffmann-La Roche Ag | 1,3-Disubstituierte Imidazoliumsalze |
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1987
- 1987-09-21 MW MW70/87A patent/MW7087A1/xx unknown
- 1987-09-22 EP EP87113797A patent/EP0266532A1/de not_active Withdrawn
- 1987-09-23 ZW ZW180/87A patent/ZW18087A1/xx unknown
- 1987-09-25 DK DK506787A patent/DK506787A/da not_active Application Discontinuation
- 1987-09-28 AU AU79038/87A patent/AU598034B2/en not_active Expired - Fee Related
- 1987-09-29 US US07/102,067 patent/US4808727A/en not_active Expired - Fee Related
- 1987-09-30 CN CN198787107148A patent/CN87107148A/zh active Pending
- 1987-10-02 JP JP62248218A patent/JPS6391374A/ja active Pending
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JPS6391374A (ja) | 1988-04-22 |
EP0266532A1 (de) | 1988-05-11 |
DK506787D0 (da) | 1987-09-25 |
AU598034B2 (en) | 1990-06-14 |
MW7087A1 (en) | 1988-05-11 |
DK506787A (da) | 1988-04-04 |
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