CN1257169C - 双环咪唑－3－基－胺衍生物 - Google Patents
双环咪唑－3－基－胺衍生物 Download PDFInfo
- Publication number
- CN1257169C CN1257169C CNB008159866A CN00815986A CN1257169C CN 1257169 C CN1257169 C CN 1257169C CN B008159866 A CNB008159866 A CN B008159866A CN 00815986 A CN00815986 A CN 00815986A CN 1257169 C CN1257169 C CN 1257169C
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- CN
- China
- Prior art keywords
- imidazo
- amine
- pyridin
- butyl
- tert
- 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.)
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- 125000002619 bicyclic group Chemical group 0.000 title claims abstract description 7
- -1 bicyclic imidazol-3-yl-amines Chemical class 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- MXZANEWAFZMPKW-UHFFFAOYSA-N imidazol-1-amine Chemical compound NN1C=CN=C1 MXZANEWAFZMPKW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 276
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 70
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- 150000002527 isonitriles Chemical class 0.000 claims description 15
- GXOBXLHECBUGTD-UHFFFAOYSA-N n-butyl-2-(2-methylphenyl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NCCCC)=C1C1=CC=CC=C1C GXOBXLHECBUGTD-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- GFLHPLKXODRDKS-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=CN1 GFLHPLKXODRDKS-UHFFFAOYSA-N 0.000 claims description 7
- FBFJMRUHTKUKAN-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine Chemical compound COC1=C(OC)C(OC)=CC(C2=C(N3C=CC=CC3=N2)NC(C)(C)CC(C)(C)C)=C1 FBFJMRUHTKUKAN-UHFFFAOYSA-N 0.000 claims description 7
- DVAZTXNALBESBS-UHFFFAOYSA-N 2-(furan-2-yl)-n-(6-isocyanohexyl)imidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NCCCCCC[N+]#[C-])=C1C1=CC=CO1 DVAZTXNALBESBS-UHFFFAOYSA-N 0.000 claims description 7
- HDLUJJCNTDBGQQ-UHFFFAOYSA-N 2-anthracen-9-yl-n-tert-butylimidazo[1,2-a]pyrazin-3-amine Chemical compound C1=CC=C2C(C3=C(N4C=CN=CC4=N3)NC(C)(C)C)=C(C=CC=C3)C3=CC2=C1 HDLUJJCNTDBGQQ-UHFFFAOYSA-N 0.000 claims description 7
- YALISRCPDJICPH-UHFFFAOYSA-N 2-cyclohexyl-n-(6-isocyanohexyl)imidazo[1,2-a]pyrazin-3-amine Chemical compound N1=C2C=NC=CN2C(NCCCCCC[N+]#[C-])=C1C1CCCCC1 YALISRCPDJICPH-UHFFFAOYSA-N 0.000 claims description 7
- SMBRAFOTVLPARM-UHFFFAOYSA-N 3-[3-(tert-butylamino)imidazo[1,2-a]pyridin-2-yl]phenol Chemical compound N1=C2C=CC=CN2C(NC(C)(C)C)=C1C1=CC=CC(O)=C1 SMBRAFOTVLPARM-UHFFFAOYSA-N 0.000 claims description 7
- ONTGILWWXJESRJ-UHFFFAOYSA-N methyl 2-[[2-(furan-2-yl)imidazo[1,2-a]pyrazin-3-yl]amino]acetate Chemical compound N1=C2C=NC=CN2C(NCC(=O)OC)=C1C1=CC=CO1 ONTGILWWXJESRJ-UHFFFAOYSA-N 0.000 claims description 7
- IYWRAEJAOBUUER-UHFFFAOYSA-N n,2-ditert-butylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CC=CN2C(NC(C)(C)C)=C(C(C)(C)C)N=C21 IYWRAEJAOBUUER-UHFFFAOYSA-N 0.000 claims description 7
- CKFBCHGNXAGKQZ-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-2-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-amine Chemical compound COC1=CC=CC=C1C1=C(NC=2C(=CC=CC=2C)C)N2C=CN=CC2=N1 CKFBCHGNXAGKQZ-UHFFFAOYSA-N 0.000 claims description 7
- UHGOIFRYNLFZQJ-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine Chemical compound CC1=CC=CC(C)=C1NC1=C(C=2OC=CC=2)N=C2N1C=CC=C2 UHGOIFRYNLFZQJ-UHFFFAOYSA-N 0.000 claims description 7
- FXHHUSLVJMVCSM-UHFFFAOYSA-N n-(6-isocyanohexyl)-2-pyridin-2-ylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NCCCCCC[N+]#[C-])=C1C1=CC=CC=N1 FXHHUSLVJMVCSM-UHFFFAOYSA-N 0.000 claims description 7
- AXOJDRXNPHURRH-UHFFFAOYSA-N n-butyl-2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-3-amine Chemical compound N1=C2C=NC=CN2C(NCCCC)=C1C1=CC=CC(Cl)=C1Cl AXOJDRXNPHURRH-UHFFFAOYSA-N 0.000 claims description 7
- LIQUJNIYWJECJB-UHFFFAOYSA-N n-cyclohexyl-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine Chemical compound C1CCCCC1NC1=C(C=2OC=CC=2)N=C2N1C=CC=C2 LIQUJNIYWJECJB-UHFFFAOYSA-N 0.000 claims description 7
- UUOFQSYGSJLFSC-UHFFFAOYSA-N n-cyclohexyl-2-methylimidazo[1,2-a]pyridin-3-amine Chemical compound CC=1N=C2C=CC=CN2C=1NC1CCCCC1 UUOFQSYGSJLFSC-UHFFFAOYSA-N 0.000 claims description 7
- HFVIQGNMAGCUCK-UHFFFAOYSA-N n-cyclohexyl-n-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidin-3-yl]acetamide Chemical compound C=1C(C)=C(C)OC=1C=1N=C2N=CC=CN2C=1N(C(=O)C)C1CCCCC1 HFVIQGNMAGCUCK-UHFFFAOYSA-N 0.000 claims description 7
- SZEUAPUHWFRARK-UHFFFAOYSA-N n-cyclohexyl-n-[2-(5-methylfuran-2-yl)imidazo[1,2-a]pyridin-3-yl]acetamide Chemical compound C=1C=C(C)OC=1C=1N=C2C=CC=CN2C=1N(C(=O)C)C1CCCCC1 SZEUAPUHWFRARK-UHFFFAOYSA-N 0.000 claims description 7
- LBUVDABAAFTBPI-UHFFFAOYSA-N n-tert-butyl-2-methylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CC=CN2C(NC(C)(C)C)=C(C)N=C21 LBUVDABAAFTBPI-UHFFFAOYSA-N 0.000 claims description 7
- SZWLZKCBRXYYRA-UHFFFAOYSA-N n-tert-butyl-2-naphthalen-1-ylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CC=C2C(C3=C(N4C=CC=CC4=N3)NC(C)(C)C)=CC=CC2=C1 SZWLZKCBRXYYRA-UHFFFAOYSA-N 0.000 claims description 7
- SQAKXGCTMJBJCF-UHFFFAOYSA-N n-tert-butyl-2-pyridin-2-ylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NC(C)(C)C)=C1C1=CC=CC=N1 SQAKXGCTMJBJCF-UHFFFAOYSA-N 0.000 claims description 7
- YWIRAZUBMRYABL-UHFFFAOYSA-N n-tert-butyl-2-pyridin-3-ylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NC(C)(C)C)=C1C1=CC=CN=C1 YWIRAZUBMRYABL-UHFFFAOYSA-N 0.000 claims description 7
- KWXQPJCBTYCUGX-UHFFFAOYSA-N n-tert-butyl-2-pyridin-3-ylimidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NC(C)(C)C)=C1C1=CC=CN=C1 KWXQPJCBTYCUGX-UHFFFAOYSA-N 0.000 claims description 7
- ORDKAKDRMJQWGP-UHFFFAOYSA-N n-tert-butyl-2-thiophen-2-ylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NC(C)(C)C)=C1C1=CC=CS1 ORDKAKDRMJQWGP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- KBXQSAAAVZYHTC-UHFFFAOYSA-N 2-methyl-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrazin-3-amine Chemical compound C1=NC=CN2C(NC(C)(C)CC(C)(C)C)=C(C)N=C21 KBXQSAAAVZYHTC-UHFFFAOYSA-N 0.000 claims description 6
- UIIYLFFNBBRBGX-UHFFFAOYSA-N 2-pyridin-4-yl-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrazin-3-amine Chemical compound N1=C2C=NC=CN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=NC=C1 UIIYLFFNBBRBGX-UHFFFAOYSA-N 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- VBRCIDLFXIVZHW-UHFFFAOYSA-N methyl 2-[(2-cyclohexylimidazo[1,2-a]pyrimidin-3-yl)amino]acetate Chemical compound N1=C2N=CC=CN2C(NCC(=O)OC)=C1C1CCCCC1 VBRCIDLFXIVZHW-UHFFFAOYSA-N 0.000 claims description 6
- LJEAFEJKWFRIJU-UHFFFAOYSA-N methyl 2-[(2-methylimidazo[1,2-a]pyrazin-3-yl)amino]acetate Chemical compound C1=NC=CN2C(NCC(=O)OC)=C(C)N=C21 LJEAFEJKWFRIJU-UHFFFAOYSA-N 0.000 claims description 6
- HKCUKYRHQVXRFQ-UHFFFAOYSA-N n-tert-butyl-2-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound S1C(SC)=CC=C1C1=C(NC(C)(C)C)N2C=CC=NC2=N1 HKCUKYRHQVXRFQ-UHFFFAOYSA-N 0.000 claims description 6
- 150000001409 amidines Chemical class 0.000 claims description 5
- QIACGFKYKKFJLH-UHFFFAOYSA-N 2-(2-chloro-4-fluorophenyl)-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=C(F)C=C1Cl QIACGFKYKKFJLH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 2
- 230000036592 analgesia Effects 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 238000010490 three component reaction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 claims 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 87
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 32
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 27
- 239000000126 substance Substances 0.000 description 11
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 10
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 9
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- YVPXQMYCTGCWBE-UHFFFAOYSA-N 2-isocyano-2,4,4-trimethylpentane Chemical compound CC(C)(C)CC(C)(C)[N+]#[C-] YVPXQMYCTGCWBE-UHFFFAOYSA-N 0.000 description 6
- VBLHGASEDWPBTM-UHFFFAOYSA-N 2-(3-bromothiophen-2-yl)-n-cyclohexylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CSC(C2=C(N3C=CC=CC3=N2)NC2CCCCC2)=C1Br VBLHGASEDWPBTM-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 5
- 239000012346 acetyl chloride Substances 0.000 description 5
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- WJCPMQQLTJQIJK-UHFFFAOYSA-N 1,6-diisocyanohexane Chemical compound [C-]#[N+]CCCCCC[N+]#[C-] WJCPMQQLTJQIJK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
本发明涉及以碱或可药用盐形式的通式(I)的双环咪唑-3-基-胺。本发明还涉及制备本发明的双环咪唑-3-基胺化合物的方法和含有至少一种以碱或可药用盐形式的通式(I)的双环咪唑-3-基-胺作为活性成分的药物。
Description
本发明涉及取代的双环咪唑-3-基-胺化合物以及含有这些化合物的药物。
咪唑-3-基胺类的个别化合物具有有益的药理性质是已知的，例如一些特定的咪唑并[1，2-a]吡啶被描述为降血压活性物质(GB-B-1,135,893)、驱虫剂和抗真菌药物(J.Med.Chem.1972，15，982-985)和用于治疗炎症的抑制分泌作用的活性物质(EP-A-0 068 378)。EP-A-0266 890和J.Med.Chem.1987，30，2031-2046也描述了个别的咪唑并吡啶类物质的抗炎作用，特别是胃炎。此外，咪唑-3-基胺类的个别代表性物质的其他药理学作用还包括抗菌性(chem.Pharm.Bull.1992，40，1170)、抗病毒性(J.Med.Chem.1998，41，5108-5112)和作为苯二氮受体拮抗剂的作用(J.Heterocyclic Chem.1998，35，1205-1217)。
基于这些有益的作用，过去已经合成了各种取代的咪唑-3-基胺类化合物，特别是尝试了通过组合合成的方法增加可得到的取代的咪唑-3-基胺类化合物的数量。例如，C.Blackburn等人在TetrahedronLett，1998，39，5469-5472中描述了三组分固相合成法制备咪唑-3-基胺化合物，同时在Tetrahedron Lett，1998，39，3635-3638描述了平行合成咪唑-3-基胺化合物的三组分缩合法。K.Groebke等人发表在Synlett，1998，661-663中的的合成方法与后者的反应类似。H.Bienayme和K.Bouzid在Angew.Chem，1998，110(16)，2349-2352中描述了用于咪唑-3-基胺化合物组合合成的多组分反应，用此方法还制备了个别的咪唑-5-胺化合物。
但是，根据现有技术，在氨基的氮原子和咪唑环2-位上的可能取代基的范围是有限的。
因此，本发明提供以碱或可药用盐形式的通式I的双环咪唑-3-基-胺化合物
其中X和Y表示CH或N，条件是X和Y不能同时为N，
R1代表叔丁基、(CH2)nCN(n＝4、5或6)、任选取代的苯基、C4-C8-环烷基、CH2CH2R(R＝4-吗啉基)、1，1，3，3-四甲基丁基或CH2Ra，其中Ra为H、OH、C1-C8-烷基(直链或支链的)、任选取代的苯基、CO(OR’)(R’为直链C1-C4-烷基或支链的C1-C5-烷基)、PO(OR’)2(其中R’＝直链的C1-C4-烷基或支链的C1-C5-烷基)或Si(RxRyRz)(其中Rx、Ry、Rz各自独立是C1-C4-烷基(直链或支链)、C4-C8-环烷基和苯基)。
R2代表H、CORb，其中Rb是C1-C4-烷基(直链或支链)、C3-C8-环烷基(Adamantyl)、CH2CH2CO(ORc)，其中Rc是C1-C4-烷基(直链或支链)、金刚烷基、任选取代的苯基、任选取代的1-萘基或2-萘基和任选取代的2-吡啶基、3-吡啶基、4-吡啶基、噻唑基或呋喃基、CH2苯基、CH2CH2Rd，其中Rd为任选取代的苯基、或CONHR°，其中R°表示C1-C8-烷基(直链或支链)、C3-C8-环烷基或任选取代的苯基，
R3是甲基、乙基、叔丁基、C3-C8-环烷基、苯基，其任选在3、5或6-位单取代的或任选在4-位和另外在2-和/或3-位和/或5-位和/或6-位多取代的、苯氧基、任选取代的萘基、任选取代的吡咯、任选取代的吡啶基、任选取代的呋喃、任选取代的噻吩、任选取代的蒽、任选取代的菲或任选取代的喹啉，
条件是当R1为叔丁基、正丙基、正丁基、1，1，3，3-四甲基丁基、环己基、CH2CH2R(R＝4-吗啉基)、单取代的苯基、2，6-二甲基苯基或苄基，而且同时R2为H或-CO(甲基)时，R3不能是正丙基、环己基、未取代的苯基或在3-位上被甲酰氨基单取代的苯基，当R1为苄基且R3为甲基时，或者当R1为CH2C(O)叔丁基且R3为未取代的苯基时，R2不能是H。
根据本发明，优选这样一些化合物，其中
R2为H
R1选自：(CH2)nCN(n可以是4、5或6)、环己基、CH2CO(O甲基)、2，6-二甲基苯基、1，1，3，3-四甲基丁基、叔丁基、正丁基，和
R3选自：2-吡啶基、3-吡啶基、2-呋喃基、2-吡咯基、甲基、叔丁基、3-羟基苯基、3，4-二甲氧基苯基、2，3-二氯苯基、2，4二氯苯基、2-甲氧基苯基、2，3-二甲氧基苯基、3-溴苯基、4-溴-2-氟苯基、5-溴-2-氟苯基、3-溴-4-氟苯基、3-氯苯基、3，4-二氯苯基、3-氟苯基、3-甲苯基、3-苯氧基苯基、3-(4-氯苯氧基)苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2，4-二甲基苯基、2，5-二甲基苯基、2-溴苯基、2-氟苯基或2-(三氟甲基)-苯基。
本发明优选选自下列的双环咪唑-3-基-胺：
(6-异氰基己基)-(2-吡啶-2-基咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-(6-异氰基己基)-胺，
(2-环己基-咪唑并[1，2-a]吡嗪-3-基)-(6-异氰基己基)-胺，
(2，6-二甲基苯基)-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-环己基-咪唑并[1，2-a]嘧啶-3-基-氨基)-乙酸甲酯，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-吡啶-4-基咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
3-(3-叔丁基氨基-咪唑并[1，2-a]吡啶-2-基)-苯酚，
丁基-[2-(2，3-二氯-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
[(2-苯基-咪唑并[1，2-a]吡啶-3-基-氨基)-甲基]-磷酸二乙酯，
叔丁基-(2-叔丁基-咪唑并[1，2-a]吡啶-3-基)-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
(2，6-二甲基苯基)-[2-(2-甲氧基-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-吡啶-3-基咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
[2-(1H-吡咯-2-基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
环己基-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-3-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-噻吩-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
环己基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(5-甲基-呋喃-2-基)-咪唑并[1，2-a]吡啶-3-基]-乙酰胺，
叔丁基-[2-(5-甲基硫基(sulfanyl)-噻吩-2-基)咪唑并[1，2-a]嘧啶-3-基]-胺，
[2-(3-溴-噻吩-2-基)-咪唑并[1，2-a]吡啶-3-基]-环己基胺
乙酸-2-甲氧基-4-[3-(1，1，3，3-四甲基丁基氨基)-咪唑并[1，2-a]嘧啶-2-基]-苯基酯，
[2-(2-氯-4-氟-苯基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
(2-蒽-9-基-咪唑并[1，2-a]吡嗪-3-基)-叔丁基胺，
叔丁基-(2-萘-1-基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(4，5-二甲基-呋喃-2-基)-咪唑并[1，2-a]嘧啶-3-基]-乙酰胺或
(1，1，3，3-四甲基丁基)-[2-(3，4，5-三甲氧基苯基)-咪唑并[1，2-a]吡啶-3-基]-胺。
如果本发明双环咪唑-3-基-胺化合物中含有光学活性的碳原子的话，本发明也提供这些化合物的对映异构体或它们的混合物。
本发明进一步提供一种药物，它含有至少一种以碱或可药用盐形式的通式I的双环咪唑-3-基-胺作为活性物质，其中R1-R3、X、Y具有上述含义，所述盐优选为氢溴酸盐、硫酸盐、甲基磺酸盐、甲酸盐、乙酸盐、草酸盐、琥珀酸盐、酒石酸盐、苦杏仁酸盐、富马酸盐、乳酸盐、柠檬酸盐、谷氨酸盐和/或天冬氨酸盐、或者特别是盐酸盐。
令人惊奇地发现，本发明的化合物不仅对现有技术提到的适应症具有潜在的活性，而且也具有止痛作用。
本发明的药物特别优选含有至少一种选自下列的化合物或其可药用盐作为活性物质：
(6-异氰基己基)-(2-吡啶-2-基咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-(6-异氰基己基)-胺，
(2-环己基-咪唑并[1，2-a]吡嗪-3-基)-(6-异氰基己基)-胺，
(2，6-二甲基苯基)-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-环己基-咪唑并[1，2-a]嘧啶-3-基-氨基)-乙酸甲酯，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-吡啶-4-基咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
3-(3-叔丁基氨基-咪唑并[1，2-a]吡啶-2-基)-苯酚，
丁基-[2-(2，3-二氯-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
[(2-苯基-咪唑并[1，2-a]吡啶-3-基-氨基)-甲基]-磷酸二乙酯，
叔丁基-(2-叔丁基-咪唑并[1，2-a]吡啶-3-基)-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
(2，6-二甲基苯基)-[2-(2-甲氧基-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-吡啶-3-基咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
[2-(1H-吡咯-2-基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
环己基-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-3-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-噻吩-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
环己基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(5-甲基-呋喃-2-基)-咪唑并[1，2-a]吡啶-3-基]-乙酰胺，
叔丁基-[2-(5-甲基硫基-噻吩-2-基)咪唑并[1，2-a]嘧啶-3-基]-胺，
[2-(3-溴-噻吩-2-基)-咪唑并[1，2-a]吡啶-3-基]-环己基胺
乙酸-2-甲氧基-4-[3-(1，1，3，3-四甲基丁基氨基)-咪唑并[1，2-a]嘧啶-2-基]-苯基酯，
[2-(2-氯-4-氟-苯基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
(2-蒽-9-基-咪唑并[1，2-a]吡嗪-3-基)-叔丁基胺，
叔丁基-(2-萘-1-基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(4，5-二甲基-呋喃-2-基)-咪唑并[1，2-a]嘧啶-3-基]-乙酰胺或
(1，1，3，3-四甲基丁基)-[2-(3，4，5-三甲氧基苯基)-咪唑并[1，2-a]吡啶-3-基]-胺或者在药学上能接受的这些化合物的盐。
对此，特别优选的是本发明的双环咪唑-3-基胺化合物与一种或多种助剂用于制备治疗疼痛的药物的用途。
为制备相应的药物，除了至少一种本发明的活性物质外，还使用一种或多种助剂，优选载体材料、填料、溶剂、稀释剂、着色剂和/或粘结剂。助剂的选择及其用量取决于否该药物是口服、静注、腹膜内注射、皮内、肌内、鼻内、向颊还是局部施用。片剂、包衣片、胶囊、颗粒剂、滴剂、汁剂和糖浆剂形成的制剂适于口服，而溶液、悬浮液、易于重构的干粉及喷雾剂适用于非肠道、局部和吸入给药。以储库、溶解形式或以膏药形式，任选在加入透皮促进剂的情况下的本发明的活性物质是适合的经皮给药制剂。可口服或经皮的剂型可以缓释本发明的活性物质。
给患者施用的活性物质的量根据患者的体重、施用方式、指征和疾病的严重程度而变化。
本发明化合物的合成通过下述方法进行：通式II的脒，特别是从例如Acros、Avocado、Aldrich、Fluka、Laneaster、Maybridge、Merck、Sigma或TCI-Jp公司商购的2-氨基吡啶、2-氨基吡嗪和2-氨基嘧啶衍生物，与各种酮或优选醛III和异腈IV在20％的高氯酸的存在下进行三组分反应。R1-R3、X和Y具有式I化合物中给出的含义。
对此，为了顺利进行该反应重要的是将原料按脒II、醛III及异腈IV的顺序先后加入。该反应优选在二氯甲烷(DCM)中于0℃-40℃，特别是在10℃-20℃下进行。
为制备本发明的其中R2不是氢的化合物，将在上述反应中生成的化合物Ia优选先溶解在THF中，根据目的产物，与化合物R2Hal反应，其中Hal为溴、碘或特别是氯，例如任选取代的烷基氯、芳基氯或酰氯，或任选取代的异氰酸酯R°NCO在吗啉树脂的存在(例如Argonaut公司的聚苯乙烯-吗啉)下，在二氯甲烷中于10℃～40℃按下述反应路线反应2～24小时：
1.)R2Hal或R2NCO
聚合物结合的吗啉；
MC，T＝10-40℃，2-24h
2.)聚合物结合的三
(2-氨基乙基)胺
然后经过一聚合物键合的三(2-氨基乙基)胺(制造商：Novabiochem)或3-(3-巯基苯基)丙酰氨基甲基聚苯乙烯层过滤从反应混合物中除去过量的试剂，并优选在真空下离心浓缩滤液。整个操作可以在自动合成设备中连续进行。
可按本身已知的方法用生理可耐受的酸将式I化合物转化成盐，所述酸优选为氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、酒石酸、扁桃酸、富马酸、乳酸、柠檬酸、谷氨酸和/或天冬氨酸并且特别是盐酸。盐的形成优选在溶剂中进行，特别是在乙醚、二异丙基醚、乙酸烷基酯、丙酮或2-丁酮或这些溶剂的混合物中进行。为了制备盐酸盐可另外选择应用三甲基硅烷水溶液。
实施例：下列实施例用于说明本发明，但不限制本发明的范围。
一般合成规程1(自动合成)
本发明化合物的合成是在Zymark公司的自动合成设备中按下列一般合成规程进行的：
手工向带有螺口的玻璃圆底试管(直径16mm，长125mm)加入一个搅拌子并在盖的位置用带有隔膜的螺口盖密封。由机械手1将试管放置在控制温度为15℃的反应器区，机械手2依次移取加入下列试剂：
1.)1ml 0.1M脒溶液+20％HClO4的二氯甲烷溶液
2.)0.5ml 0.3M醛的二氯甲烷溶液
3.)0.575ml 0.2M异腈的二氯甲烷溶液。
在15℃下在一个搅拌区搅拌反应混合物660min，然后在过滤区过滤反应液。对此每次用1ml二氯甲烷和200μl水洗涤试管两次。
然后通过人工将带有试管的管架放入后处理区域。在此于涡旋混合器上向反应混合物中加入3ml 10％NaCl溶液和1.5ml二氯甲烷。然后在旋转反应器上充分混合反应混合物10分钟，通过慢慢降低转动速度形成清楚的相界面。该相界面是光学可分辨的并且移出有机相。下一步再向反应混合物加入1.5ml二氯甲烷，振摇溶液、离心并移出有机相。合并的有机相用2.4g MgSO4(粒状)干燥，在真空离心机中除去溶剂。
一般合成规程2(手工合成)
(等量是指基于所用的异腈等摩尔量)
在适宜的反应容器中，首先将1.15倍量的杂环胺悬浮或溶于二氯甲烷(每1mmol的异腈加2ml)中，顺序加入1.5倍量的醛、1倍量的异腈和最后加入高氯酸水溶液(20％；每1mmol的异腈加入0.098ml)，将该混合物在室温下搅拌20小时。
在后处理阶段，向反应液中加入饱和氯化钠溶液(每1mmol的异腈约加5ml)和二氯甲烷(每1mmol的异腈约加4ml)，将各层分离，用二氯甲烷再萃取有机相2次(每1mmol的异腈加入约2ml)，将合并萃取后的有机相分别用缓冲溶液(pH＝10，每1mmol的异腈约用2ml)和饱和氯化钠溶液(每1mmol的异腈约2ml)洗涤，用硫酸钠干燥、过滤、在真空下用旋转蒸发器浓缩并用真空油泵除去残留溶剂。
所有的化学原料与溶剂均通过商业途径获得，每个化合物都经过ESI-MS和/或NMR分析。
一般合成规程3(与乙酰氯的反应)
将根据一般合成规程1得到的化合物溶解在二氯甲烷中，加入4倍摩尔量的乙酰氯，在18℃下搅拌4小时。多余的乙酰氯和溶剂在40-60℃、真空下除去，每个化合物均用ESI-MS分析。
实施例1：
(6-异氰基-己基)-(2-吡啶-2-基-咪唑并[1，2-a]吡啶-3-基)-胺(1)
化合物1是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的1，6-二异氰基己烷溶液(0.2M，DCM)，0.500ml的吡啶-2-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为321.43，实测值M-H＝320.4(ESI-MS)。
实施例2：
(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-(6-异氰基己基)-胺(2)
化合物2是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的1，6-二异氰基己烷溶液(0.2M，DCM)，0.500ml的糠醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为310.40，实测值M-H＝309.4(ESI-MS)。
实施例3：
(2-环己基-咪唑并[1，2-a]吡嗪-3-基)-(6-异氰基己基)-胺(3)
化合物3是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的1，6-二异氰基己烷溶液(0.2M，DCM)，0.500ml的环己基甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为327.48，实测值M-H＝326.5(ESI-MS)。
实施例4：
(2，6-二甲基苯基)-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺(4)
化合物4是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的2，6-二甲基苯基异腈溶液(0.2M，DCM)，0.500ml的糠醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分于量计算值为303.37，实测值为304.4(ESI-MS)。
实施例5：
(2-呋喃-2-基-咪唑并[1，2-a]吡嗪-3基-氨基)-乙酸甲酯(5)
化合物5是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的异氰基乙酸甲酯溶液(0.2M，DCM)，0.500ml的糠醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为272.27，实测值为273.4(ESI-MS)。
实施例6：
(2-环己基-咪唑并[1，2-a]嘧啶-3-基-氨基)-乙酸甲酯(6)
化合物6是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的异氰基乙酸甲酯溶液(0.2M，DCM)，0.500ml的环己基甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为288.35，实测值M-H＝289.4(ESI-MS)。
实施例7：
(2-甲基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯(7)
化合物7是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的异氰基乙酸甲酯溶液(0.2M，DCM)，0.500ml的乙醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为220.23，实测值为221.3(ESI-MS)。
实施例8：
(2-吡啶-4-基咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺(8)
化合物8是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的1，1，3，3-四甲基丁基异氰化物(0.2M，DCM)，0.500ml的吡啶-4-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为323.44，实测值为324.4(ESI-MS)。
实施例9：
(2-甲基-咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺(9)
化合物9是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的1，1，3，3-四甲基丁基异氰化物(0.2M，DCM)，0.500ml的乙醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为260.39，实测值为261.4(ESI-MS)。
实施例10：
3-(3-叔丁基氨基-咪唑并[1，2-a]吡啶-2-基)-苯酚(10)
化合物10是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的叔丁基异腈溶液(0.2M，DCM)，0.500ml的3-羟基苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为281.36，实测值为282.3(ESI-MS)。
实施例11：
丁基-[2-(2，3-二氯-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺(11)
化合物11是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的正丁基异腈溶液(0.2M，DCM)，0.500ml的2，3-二氯苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为335.24，实测值为335.4(ESI-MS)。
实施例12：
[(2-苯基-咪唑并[1，2-a]吡啶-3-基-氨基)-甲基]-磷酸二乙酯(12)
化合物12是根据一般合成规程2由2-氨基吡啶溶液、二乙基异氰基甲基磷酸酯、苯甲醛和高氯酸(W＝20％)反应而制备的。化学结构通过NMR图谱确认。
实施例13：
叔丁基-(2-叔丁基-咪唑并[1，2-a]吡啶-3-基)-胺(13)
化合物13是根据一般合成规程2由2-氨基吡啶、叔丁基异腈、新戊醛(pivaldehyde)和高氯酸(W＝20％)反应而制备的。化学结构通过NMR图谱确认。
实施例14：
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺(14)
化合物14是根据一般合成规程由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的正丁基异腈溶液(0.2M，DCM)，0.500ml的2-甲基苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为280.38，实测值为281.3(ESI-MS)。
实施例15：
(2，6-二甲基苯基)-[2-(2-甲氧基-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺(15)
化合物15是根据一般合成规程1由1.0ml的氨基吡嗪溶液(0.1M，DCM)，0.575ml的2，6-二甲基苯基异氰化物溶液(0.2M，DCM)，0.500ml的2-甲氧基苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为344.42，实测值为345.4(ESI-MS)。
实施例16：
丁基-(2-邻甲基苯基-咪唑并[1，2-a]嘧啶-3-基)-胺(16)
化合物16是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的正丁基异腈溶液(0.2M，DCM)，0.500ml的2-甲基苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为280.38，实测值(为281.3ESI-MS)。
实施例17：
叔丁基-(2-吡啶-3-基咪唑并[1，2-a]嘧啶-3-基)-胺(17)
化合物17是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的叔丁基异腈溶液(0.2M，DCM)，0.500ml的吡啶-3-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为267.34，实测值为268.3(ESI-MS)。
实施例18：
叔丁基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺(18)
化合物18是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的叔丁基异腈溶液(0.2M，DCM)，0.500ml的乙醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为203.29，实测值为204.3(ESI-MS)。
实施例19：
[2-(1H-吡咯-2-基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺(19)
化合物19是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的1，1，3，3-四甲基丁基异氰化物溶液(0.2M，DCM)，0.500ml的吡咯-2-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为311.43，实测值为312.4(ESI-MS)。
实施例20：
环己基-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺(20)
化合物20是根据一般合成规程2由2-氨基吡啶、环己基异腈、糠醛和高氯酸(W＝20％)反应而制备的。其化学结构通过NMR图谱确认。
实施例21：
叔丁基-(2-吡啶-3-基-咪唑并[1，2-a]吡啶-3-基)-胺(21)
化合物21是根据一般合成规程2由2-氨基吡啶、叔丁基异腈、烟碱醛和高氯酸(W＝20％)反应而制备的。其化学结构通过NMR图谱确认。
实施例22：
叔丁基-(2-吡啶-2-基-咪唑并[1，2-a]吡啶-3-基)-胺(22)
化合物22是根据一般合成规程2由2-氨基吡啶、叔丁基异腈、2-吡啶甲醛和高氯酸(W＝20％)反应而制备的。化学结构通过NMR图谱确认。
实施例23：
叔丁基-(2-噻吩-2-基-咪唑并[1，2-a]吡啶-3-基)-胺(23)
化合物23是根据一般合成规程2由2-氨基吡啶溶液、叔丁基异腈溶液、噻吩-2-甲醛和高氯酸(W＝20％)反应而制备的。其化学结构通过NMR图谱确认。
实施例24：
环己基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺(24)
化合物24是根据一般合成规程2由2-氨基吡啶、环己基异腈、乙醛和高氯酸(W＝20％)反应而制备的。其化学结构通过NMR图谱确认。
实施例25：
N-环己基-N-[2-(5-甲基-呋喃-2-基)-咪唑并[1，2-a]吡啶-3-基]-乙酰胺(25)
化合物25是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的环己基异氰化物溶液(0.2M，DCM)，0.500ml的5-甲基康醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应，然后再照一般合成规程3方法与乙酰氯反应制得。分子量计算值为337.4，实测值为338.5，M-乙酰基为296.5(ESI-MS)。
实施例26：
叔丁基-[2-(5-甲基硫基-噻吩-2-基)咪唑并[1，2-a]嘧啶-3-基]-胺(26)
化合物26是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的叔丁基异氰化物溶液(0.2M，DCM)，0.500ml的5-甲硫基-噻吩-2-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为318.5，ESI-MS得到的分子离子峰质量数为319.2。
实施例27：
[2-(3-溴-噻吩-2-基)-咪唑并[1，2-a]吡啶-3-基]-环己胺(27)
化合物27是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的环己基异氰化物溶液(0.2M，DCM)，0.500ml的3-溴噻吩-2-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为376.3，ESI-MS得到的分子离子峰质量数为376.4/378.3。
实施例28：
乙酸-2-甲氧基-4-[3-(1，1，3，3-四甲基丁基氨基)-咪唑并[1，2-a]嘧啶-2-基]-苯基酯(28)
化合物28是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的1，1，3，3-四甲基丁基异氰化物溶液(0.2M，DCM)，0.500ml的乙酸-4-甲酰基-2-甲氧基苯基酯溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为410.5，实测值为411.3(ESI-MS)。
实施例29：
[2-(2-氯-4-氟-苯)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺(29)
化合物29是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的1，1，3，3-四甲基丁基异氰化物溶液(0.2M，DCM)，0.500ml的2-氯-4-氟苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为374.9，实测值为375.3(ESI-MS)。
实施例30：
(2-蒽-9-基-咪唑并[1，2-a]吡嗪-3-基)-叔丁基胺(30)
化合物30是根据一般合成规程1由1.0ml的2-氨基吡嗪溶液(0.1M，DCM)，0.575ml的叔丁基异氰化物溶液(0.2M，DCM)，0.500ml的蒽-9-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为366.5，实测值为367.3(ESI-MS)。
实施例31：
叔丁基-(2-萘-1-基-咪唑并[1，2-a]吡啶-3-基)-胺(31)
化合物31是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的叔丁基异氰化物溶液(0.2M，DCM)，0.500ml的萘-1-甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为315.4，实测值为316.3(ESI-MS)。
实施例32：
N-环己基-N-[2-(4，5-二甲基-呋喃-2-基)-咪唑并[1，2-a]嘧啶-3-基]-乙酰胺(32)
化合物32是根据一般合成规程1由1.0ml的2-氨基嘧啶溶液(0.1M，DCM)，0.575ml的环己基异氰化物溶液(0.2M，DCM)，0.500ml的4，5-二甲基糠醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应，得到的产物然后再根据一般合成规程3与乙酰氯反应而制备的。分子量计算值为352.4，实测值为353.4(ESI-MS)。
实施例33：
(1，1，3，3-四甲基丁基)-[2-(3，4，5-三甲氧基-苯基)-咪唑并[1，2-a]吡啶-3-基]-胺(33)
化合物33是根据一般合成规程1由1.0ml的2-氨基吡啶溶液(0.1M，DCM)，0.575ml的1，1，3，3-四甲基丁基异氰化物溶液(0.2M，DCM)，0.500ml的3，4，5-三甲氧基苯甲醛溶液(0.3M，DCM)和10微升高氯酸(W＝20％)反应而制备的。分子量计算值为411.5，实测值为412.3(ESI-MS)。
小鼠镇痛试验-扭曲试验
镇痛实验是考察对苯醌诱导的小鼠的扭曲动作的影响(根据I.C.Hendershot和J.Forsatin在J.Pharmacol.EXP.Ther.，125，237～240(1959)的方法修改)。使用的雄性NMRI小鼠，体重为25-30g，在小鼠静脉注射或皮下注射测试物质后10分钟后，给每组10只动物腹膜内注射0.02％的苯醌水溶液(每只0.3ml)，(苯基苯醌，Sigma公司，Deisenhofen，溶液中含5％的乙醇，水浴45℃保存)，每个笼子中放一只受试动物观察。给动物注射苯醌后5～20分钟内，通过按钮计数器记录由于疼痛而导致的剧烈动作(称之为扭曲反应＝身体强直，后肢伸展)的次数。只接受生理盐水的动物作为对照组，测试物质的剂量为静脉注射10mg/kg或皮下注射21.5mg/kg。按照下面的公式计算扭曲的抑制率(％抑制率)
测试的本发明化合物表现出镇痛作用，其结果列于下表
表 小鼠镇痛实验-扭曲试验
| 实施例号 | 皮下注射21.5mg/kg化合物的扭曲抑制率 | 静脉注射10mg/kg化合物的扭曲抑制率 |
| 12 | 90 | |
| 13 | 86(剂量为2.15mg/kg) | |
| 20 | 43 | |
| 21 | 80 | |
| 22 | 53 | |
| 23 | 62 | |
| 24 | 56 |
Claims (7)
1.通式I所示的双环咪唑-3-基-胺或其可药用盐形式，
其中
X和Y代表CH或N，条件是X和Y不能同时为N，
R1代表叔丁基、(CH2)nCN、未被取代的或者被甲基取代的苯基、C4-C8-环烷基、CH2CH2R、1，1，3，3-四甲基丁基或CH2Ra，其中n＝4、5或6，R＝4-吗啉基，Ra为H、OH、直链或支链的C1-C8-烷基、苯基、CO(OR’)、PO(OR’)2、或Si(RxRyRz)，其中R’＝直链的C1-C4-烷基或支链的C1-C5-烷基，Rx、Ry、Rz各自独立是直链或支链C1-C4-烷基、C4-C8-环烷基或苯基，
R2代表H、CORb、CH2CH2CO(ORc)、CH2苯基、CH2CH2Rd或代表CONHRe，其中Rb是直链或支链C1-C4-烷基或C3-C8-环烷基，Rc是直链或支链C1-C4-烷基、金刚烷基、未被取代的或者被甲基取代的苯基、1-萘基或2-萘基或2-吡啶基、3-吡啶基、4-吡啶基、噻唑基或呋喃基，Rd为苯基，Re表示直链或支链C1-C8-烷基、C3-C8-环烷基或苯基，
R3是甲基、乙基、叔丁基、C3-C8-环烷基、苯基，其未被取代或者被选自三氟甲基、甲氧基、甲基、氟、氯、溴、羟基、苯氧基、乙酰氧基和4-氯苯氧基的取代基在3、5或6-位单取代或在4-位和另外在2-和/或3-位和/或5-位和/或6-位多取代、苯氧基、萘基、吡咯、吡啶基、未被取代的或者被甲基取代的呋喃、未被取代的或者被甲硫基和/或溴取代的噻吩、蒽、菲或喹啉，
条件是当R1为叔丁基、正丙基、正丁基、1，1，3，3-四甲基丁基、环己基、CH2CH2R、单取代的苯基、2，6-二甲基苯基或苄基，其中R＝4-吗啉基，而且同时R2为H或-CO(甲基)时，R3不能是正丙基、环己基、未取代的苯基或在3-位上被甲酰氨基单取代的苯基，当R1为苄基且R3为甲基时，或者当R1为CH2C(O)叔丁基且R3为未取代的苯基时，R2不能是H。
2.根据权利要求1的双环咪唑-3-基-胺或其可药用盐形式，
其中R2为H，
R1选自(CH2)nCN，其中n可以是4、5或6、环己基、CH2CO(O甲基)、2，6-二甲基苯基、1，1，3，3-四甲基丁基、叔丁基或正丁基，和
R3选自：2-吡啶基、3-吡啶基、2-呋喃基、2-吡咯基、甲基、叔丁基、3-羟基苯基、3，4-二甲氧基苯基、2，3-二氯苯基、2，4-二氯苯基、2-甲氧基苯基、2，3-二甲氧基苯基、3-溴苯基、4-溴-2-氟苯基、5-溴-2-氟苯基、3-溴-4-氟苯基、3-氯苯基、3，4-二氯苯基、3-氟苯基、3-甲基苯基、3-苯氧基苯基、3-(4-氯苯氧基)苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2，4-二甲基苯基、2，5-二甲基苯基、2-溴苯基、2-氟苯基或2-(三氟甲基)-苯基。
3.根据权利要求1的双环咪唑-3-基-胺化合物或其可药用盐形式，其特征是所述化合物是
(6-异氰基己基)-(2-吡啶-2-基咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-(6-异氰基己基)-胺，
(2-环己基-咪唑并[1，2-a]吡嗪-3-基)-(6-异氰基己基)-胺，
(2，6-二甲基苯基)-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-环己基-咪唑并[1，2-a]嘧啶-3-基-氨基)-乙酸甲酯，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-吡啶-4-基咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
3-(3-叔丁基氨基-咪唑并[1，2-a]吡啶-2-基)-苯酚，
丁基-[2-(2，3-二氯-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
[(2-苯基-咪唑并[1，2-a]吡啶-3-基-氨基)-甲基]-磷酸二乙酯，
叔丁基-(2-叔丁基-咪唑并[1，2-a]吡啶-3-基)-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
(2，6-二甲基苯基)-[2-(2-甲氧基-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-吡啶-3-基咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
[2-(1H-吡咯-2-基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
环己基-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-3-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-噻吩-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
环己基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(5-甲基-呋喃-2-基)-咪唑并[1，2-a]吡啶-3-基]-乙酰胺，
叔丁基-[2-(5-甲基硫基-噻吩-2-基)咪唑并[1，2-a]嘧啶-3-基]-胺，
[2-(3-溴-噻吩-2-基)-咪唑并[1，2-a]吡啶-3-基]-环己基胺
乙酸-2-甲氧基-4-[3-(1，1，3，3-四甲基丁基氨基)-咪唑并[1，2-a]嘧啶-2-基]-苯基酯，
[2-(2-氯-4-氟-苯基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
(2-蒽-9-基-咪唑并[1，2-a]吡嗪-3-基)-叔丁基胺，
叔丁基-(2-萘-1-基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(4，5-二甲基-呋喃-2-基)-咪唑并[1，2-a]嘧啶-3-基]-乙酰胺或
(1，1，3，3-四甲基丁基)-[2-(3，4，5-三甲氧基苯基)-咪唑并[1，2-a]吡啶-3-基]-胺。
4.一种药物，它含有至少一种按照权利要求1通式I的双环咪唑-3-基-胺化合物或其可药用盐形式作为活性化合物，其中R1、R2、R3、X、Y具有如权利要求1给出的含义。
5.根据权利要求4的药物，其特征为它含有至少一种选自下列的双环咪唑-3-基-胺或这些化合物的可药用盐作为活性化合物：
(6-异氰基己基)-(2-吡啶-2-基咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-(6-异氰基己基)-胺，
(2-环己基-咪唑并[1，2-a]吡嗪-3-基)-(6-异氰基己基)-胺，
(2，6-二甲基苯基)-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
(2-呋喃-2-基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-环己基-咪唑并[1，2-a]嘧啶-3-基-氨基)-乙酸甲酯，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基-氨基)-乙酸甲酯，
(2-吡啶-4-基咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
(2-甲基-咪唑并[1，2-a]吡嗪-3-基)-(1，1，3，3-四甲基-丁基)-胺，
3-(3-叔丁基氨基-咪唑并[1，2-a]吡啶-2-基)-苯酚，
丁基-[2-(2，3-二氯-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
[(2-苯基-咪唑并[1，2-a]吡啶-3-基-氨基)-甲基]-磷酸二乙酯，
叔丁基-(2-叔丁基-咪唑并[1，2-a]吡啶-3-基)-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
(2，6-二甲基苯基)-[2-(2-甲氧基-苯基)-咪唑并[1，2-a]吡嗪-3-基]-胺，
丁基-(2-邻甲苯基-咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-吡啶-3-基咪唑并[1，2-a]嘧啶-3-基)-胺，
叔丁基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
[2-(1H-吡咯-2-基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
环己基-(2-呋喃-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-3-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-吡啶-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
叔丁基-(2-噻吩-2-基-咪唑并[1，2-a]吡啶-3-基)-胺，
环己基-(2-甲基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(5-甲基-呋喃-2-基)-咪唑并[1，2-a]吡啶-3-基]-乙酰胺，
叔丁基-[2-(5-甲基硫基-噻吩-2-基)咪唑并[1，2-a]嘧啶-3-基]-胺，
[2-(3-溴-噻吩-2-基)-咪唑并[1，2-a]吡啶-3-基]-环己基胺
乙酸-2-甲氧基-4-[3-(1，1，3，3-四甲基丁基氨基)-咪唑并[1，2-a]嘧啶-2-基]-苯基酯，
[2-(2-氯-4-氟-苯基)-咪唑并[1，2-a]嘧啶-3-基]-(1，1，3，3-四甲基-丁基)-胺，
(2-蒽-9-基-咪唑并[1，2-a]吡嗪-3-基)-叔丁基胺，
叔丁基-(2-萘-1-基-咪唑并[1，2-a]吡啶-3-基)-胺，
N-环己基-N-[2-(4，5-二甲基-呋喃-2-基)-咪唑并[1，2-a]嘧啶-3-基]-乙酰胺或
(1，1，3，3-四甲基丁基)-[2-(3，4，5-三甲氧基苯基)-咪唑并[1，2-a]吡啶-3-基]-胺。
6.根据权利要求1、2或3的至少一种双环咪唑-3-基-胺或其可药用盐形式在制备用于镇痛的药物中的用途。
7.通过脒II、醛III和异腈IV的三组分反应制备根据权利要求1、2或3的双环咪唑-3-基-胺或其可药用盐形式的方法，其特征是该化合物的合成是在二氯甲烷作为溶剂、在高氯酸的存在下，将原料按脒、醛、异腈的顺序依次加入，然后生成的产物任选与式R2Hal的化合物或异氰酸酯ReNCO反应，
其中，R1、R2、R3、Re、X和Y如权利要求1所定义，Hal为溴、碘或氯。
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| DE1999148438 DE19948438B4 (de) | 1999-10-08 | 1999-10-08 | Bicyclische Imidazo-3-aminderivate |
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| DE19948434A DE19948434A1 (de) | 1999-10-08 | 1999-10-08 | Substanzbibliothek enthaltend bicyclische Imidazo-5-amine und/oder bicyclische Imidazo-3-amine |
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