CN1402726A - 双环咪唑-5-基胺衍生物 - Google Patents
双环咪唑-5-基胺衍生物 Download PDFInfo
- Publication number
- CN1402726A CN1402726A CN00816365A CN00816365A CN1402726A CN 1402726 A CN1402726 A CN 1402726A CN 00816365 A CN00816365 A CN 00816365A CN 00816365 A CN00816365 A CN 00816365A CN 1402726 A CN1402726 A CN 1402726A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- imidazo
- amine
- thiazole
- tertiary butyl
- 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.)
- Granted
Links
- 125000002619 bicyclic group Chemical group 0.000 title claims abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 362
- -1 1,1,3,3-tetramethyl butyl Chemical group 0.000 claims description 237
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 116
- 239000002585 base Substances 0.000 claims description 93
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 34
- 150000001412 amines Chemical class 0.000 claims description 31
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 8
- 229940015043 glyoxal Drugs 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 150000002527 isonitriles Chemical class 0.000 claims description 7
- 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 6
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 6
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 6
- 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 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 150000002460 imidazoles Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003233 pyrroles Chemical class 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 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 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
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 150000001409 amidines Chemical class 0.000 claims description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 4
- VOAOLXRAFKPMKK-UHFFFAOYSA-N 5-(2-bromophenyl)-n-(2,4,4-trimethylpentan-2-yl)-1h-imidazo[1,2-b][1,2,4]triazol-6-amine Chemical compound N1=C2N=CNN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=CC=C1Br VOAOLXRAFKPMKK-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- MTCCDFOSSZMGBE-UHFFFAOYSA-N C(CCC)NC1=C(N=C2SC=CN21)C2=C(C(=CC=C2)OC)OC Chemical group C(CCC)NC1=C(N=C2SC=CN21)C2=C(C(=CC=C2)OC)OC MTCCDFOSSZMGBE-UHFFFAOYSA-N 0.000 claims description 3
- CDHQUMZPAFAAKP-UHFFFAOYSA-N CCCCNc1c(nc2nc[nH]n12)-c1ccccc1C Chemical group CCCCNc1c(nc2nc[nH]n12)-c1ccccc1C CDHQUMZPAFAAKP-UHFFFAOYSA-N 0.000 claims description 3
- GHIVFHPAIHYGFJ-UHFFFAOYSA-N CCCCNc1c(nc2nc[nH]n12)-c1ccncc1 Chemical group CCCCNc1c(nc2nc[nH]n12)-c1ccncc1 GHIVFHPAIHYGFJ-UHFFFAOYSA-N 0.000 claims description 3
- CALPRJLPEBKDKV-UHFFFAOYSA-N CCCCNc1c(nc2sccn12)-c1ccc(C)cc1 Chemical group CCCCNc1c(nc2sccn12)-c1ccc(C)cc1 CALPRJLPEBKDKV-UHFFFAOYSA-N 0.000 claims description 3
- NHSHRKVBWXLUPF-UHFFFAOYSA-N CCCCNc1c(nc2sccn12)-c1ccccc1F Chemical group CCCCNc1c(nc2sccn12)-c1ccccc1F NHSHRKVBWXLUPF-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- BZNYNBXTIVGBCG-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-6-pyridin-4-ylimidazo[2,1-b][1,3]thiazol-5-amine Chemical compound CC1=CC=CC(C)=C1NC1=C(C=2C=CN=CC=2)N=C2N1C=CS2 BZNYNBXTIVGBCG-UHFFFAOYSA-N 0.000 claims description 3
- UDXYXCDIVWOLNF-UHFFFAOYSA-N n-butyl-n-[5-(2-chloro-6-fluorophenyl)-1h-imidazo[1,2-b][1,2,4]triazol-6-yl]acetamide Chemical compound N1=C2N=CNN2C(N(C(C)=O)CCCC)=C1C1=C(F)C=CC=C1Cl UDXYXCDIVWOLNF-UHFFFAOYSA-N 0.000 claims description 3
- TYQLVLQKPSSXOW-UHFFFAOYSA-N n-cyclohexyl-6-(2,4-dimethylphenyl)imidazo[2,1-b][1,3]thiazol-5-amine Chemical compound CC1=CC(C)=CC=C1C1=C(NC2CCCCC2)N2C=CSC2=N1 TYQLVLQKPSSXOW-UHFFFAOYSA-N 0.000 claims description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=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
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 2
- OXVRMGODULTPFQ-UHFFFAOYSA-N CCCCNc1c(nc2nc[nH]n12)-c1ccccc1F Chemical group CCCCNc1c(nc2nc[nH]n12)-c1ccccc1F OXVRMGODULTPFQ-UHFFFAOYSA-N 0.000 claims description 2
- DEBUQFLRRFSRRK-UHFFFAOYSA-N CCCCNc1c(nc2nc[nH]n12)-c1cccnc1 Chemical group CCCCNc1c(nc2nc[nH]n12)-c1cccnc1 DEBUQFLRRFSRRK-UHFFFAOYSA-N 0.000 claims description 2
- UQWMZTGSJFXAGC-UHFFFAOYSA-N CCCCNc1c(nc2sccn12)-c1ccccc1C Chemical group CCCCNc1c(nc2sccn12)-c1ccccc1C UQWMZTGSJFXAGC-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- QENGPZGAWFQWCZ-UHFFFAOYSA-N Methylthiophene Natural products CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- VUNKPGIOBGHERL-UHFFFAOYSA-N n,6-dicyclohexylimidazo[2,1-b][1,3]thiazol-5-amine Chemical compound C1CCCCC1NC1=C(C2CCCCC2)N=C2N1C=CS2 VUNKPGIOBGHERL-UHFFFAOYSA-N 0.000 claims description 2
- XBFSPBUEYSJBMN-UHFFFAOYSA-N n-tert-butyl-n-[6-(2-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetamide Chemical compound N1=C2SC=CN2C(N(C(=O)C)C(C)(C)C)=C1C1=CC=CC=C1C XBFSPBUEYSJBMN-UHFFFAOYSA-N 0.000 claims description 2
- BNPBSQNAZYSWGG-UHFFFAOYSA-N n-tert-butyl-n-[6-(4-methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]acetamide Chemical compound N1=C2SC=CN2C(N(C(=O)C)C(C)(C)C)=C1C1=CC=C(C)C=C1 BNPBSQNAZYSWGG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 238000010490 three component reaction Methods 0.000 claims description 2
- ASOWYKWRXJKJCT-UHFFFAOYSA-N CCCCNc1c(nc2cc[nH]n12)-c1ccccc1 Chemical group CCCCNc1c(nc2cc[nH]n12)-c1ccccc1 ASOWYKWRXJKJCT-UHFFFAOYSA-N 0.000 claims 1
- AHQSXQKSDUDVLT-UHFFFAOYSA-N CCCCNc1c(nc2sccn12)C1CCCCC1 Chemical group CCCCNc1c(nc2sccn12)C1CCCCC1 AHQSXQKSDUDVLT-UHFFFAOYSA-N 0.000 claims 1
- 235000003140 Panax quinquefolius Nutrition 0.000 claims 1
- 240000005373 Panax quinquefolius Species 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- BNAPFJXCQUISEE-UHFFFAOYSA-N n-cyclohexyl-6-pyridin-4-ylimidazo[2,1-b][1,3]thiazol-5-amine Chemical compound C1CCCCC1NC1=C(C=2C=CN=CC=2)N=C2N1C=CS2 BNAPFJXCQUISEE-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 172
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 57
- 239000000463 material Substances 0.000 description 54
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 33
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 27
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 13
- 239000012346 acetyl chloride Substances 0.000 description 13
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 11
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 8
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- UHJKVIKRLZEECP-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-6-pyridin-3-ylimidazo[2,1-b][1,3]thiazol-5-amine Chemical compound CC1=CC=CC(C)=C1NC1=C(C=2C=NC=CC=2)N=C2N1C=CS2 UHJKVIKRLZEECP-UHFFFAOYSA-N 0.000 description 4
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 2
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- OXSWYVKHUZAGOI-UHFFFAOYSA-N 5-(2,4-dimethylphenyl)-n-(2,4,4-trimethylpentan-2-yl)-1h-imidazo[1,2-b][1,2,4]triazol-6-amine Chemical compound CC1=CC(C)=CC=C1C1=C(NC(C)(C)CC(C)(C)C)N2NC=NC2=N1 OXSWYVKHUZAGOI-UHFFFAOYSA-N 0.000 description 2
- RXEGTWSFOIRZJH-UHFFFAOYSA-N 5-(2,5-dimethylphenyl)-n-(2,4,4-trimethylpentan-2-yl)-1h-imidazo[1,2-b][1,2,4]triazol-6-amine Chemical compound CC1=CC=C(C)C(C2=C(N3NC=NC3=N2)NC(C)(C)CC(C)(C)C)=C1 RXEGTWSFOIRZJH-UHFFFAOYSA-N 0.000 description 2
- GUABFMPMKJGSBQ-UHFFFAOYSA-N 5-methyl-1,3-thiazol-2-amine Chemical compound CC1=CN=C(N)S1 GUABFMPMKJGSBQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LNZSAJMJBKSJJJ-UHFFFAOYSA-N CCCCNc1c(nc2nc[nH]n12)-c1cc(C)ccc1C Chemical group CCCCNc1c(nc2nc[nH]n12)-c1cc(C)ccc1C LNZSAJMJBKSJJJ-UHFFFAOYSA-N 0.000 description 2
- AXXJVMOIQXARKV-UHFFFAOYSA-N CCCCNc1c(nc2nc[nH]n12)-c1cccc(OC)c1OC Chemical group CCCCNc1c(nc2nc[nH]n12)-c1cccc(OC)c1OC AXXJVMOIQXARKV-UHFFFAOYSA-N 0.000 description 2
- DRTXUUPCQAJZRJ-UHFFFAOYSA-N CCCCNc1c(nc2sccn12)-c1ccc(OC)c(OC)c1 Chemical group CCCCNc1c(nc2sccn12)-c1ccc(OC)c(OC)c1 DRTXUUPCQAJZRJ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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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
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Abstract
本发明涉及新的通式(I)的双环咪唑-5-基胺衍生物,其中X表示CR5、N或S,并且在X表示S的情况下,Y表示CR6或N,在其它所有情况下Y表示N。
Description
本发明涉及取代的双环咪唑-5-基胺和含有这些化合物的药物。
双环咪唑-5-基-胺类的个别代表描述于EP-A-0 518 033。对此总涉及这样一些化合物,其在未稠合的咪唑环氮原子上带有一个经短的烷基桥连接的芳族取代基。这些相应的化合物在EP-A-0 518 033中被描述为强的血管紧张素拮抗剂,其可用于治疗循环系统疾病如高血压的药物中。
后来人们也进行了制备未稠合的咪唑环氮原子上未取代的双环咪唑-5-基胺的尝试,但这些尝试没有(K.Groebke等,Synlett 1998,661)或只取得了很小的成果(H.Bienayme,K.Bouzid,Angew.Chem.1998,110(16),2349)。
因此,本发明的目的是提供双环咪唑-5-基胺,在其未稠合的咪唑环氮原子上是未取代的,和含有这些化合物的药物。
本发明因此提供通式I的双环咪唑-5-基胺和其可药用盐,
其中
R1为C(CH3)2、(CH2)6CN、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表示氢、C1-C8-烷基(支化的或未支化的),任选取代的苯基、CO(OR′)(其中R′=C1-C8-烷基(支化的或未支化的))、PO(OR”)2(其中R”=C1-C4-烷基(支化的或未支化的))或Si(RxRyRz)(其中Rx、Ry和Rz各自相互独立为C1-C8-烷基(支化的或未支化的)、C4-C8-环烷基或苯基),
R2为氢、CORb,其中Rb为氢、C1-C8-烷基(支化的或未支化的)、C3-C8-环烷基、CH2CH2CO(OR′)(其中R′=C1-C8-烷基(支化的或未支化的))、金刚烷基(Adamantyl)、任选取代的苯基、任选取代的1-萘基、2-萘基、2-吡啶基、3-吡啶基、4-吡啶基、噻唑基或糠酰基,CH2Rc,其中Rc为氢、C1-C8-烷基(支化的或未支化的)或任选取代的苯基、CH2CH2Rd,其中Rd为任选取代的苯基、或CONHRe,其中Re为苯基,
R3为C1-C8-烷基(支化的或未支化的)、C3-C8环烷基、任选取代的苯基、任选取代的1-萘基、2-萘基、喹啉、蒽、菲、苯并噻吩、苯并糠基、任选取代的吡咯、2-吡啶基、3-吡啶基、4-吡啶基、任选取代的糠基或任选取代的噻吩,
X为CR5、N或S并且Y在X为S时表示CR6或N并且在其它所有情况下表示N,其中结构单元中的虚线表示在X表示S时,Y经过双键与带有R4的C-原子相连,并且在其它所有情况下X或Y基团之一经过双键与带有R4的C-原子相连并且另一个基团另外带有一个氢,
R4、R5和R6各自独立为氢、C1-C8烷基(支化的或未支化的)、氟、氯、溴、CF3、CN、NO2、NHRf,其中Rf为氢、C1-C8-烷基(支化的或未支化的)、或任选取代的苯基、SRg,其中Rg为氢、C1-C8-烷基(支化的或未支化的)、苯基、吡啶、苄基或芴基、ORh,其中Rh为C1-C8-烷基(支化的或未支化的)、任选取代的苯基或CO(OR′)(R′=C1-C8-烷基(支化的或未支化的))、CO(OR′)或CH2CO(OR′),其中R′在每一情况下具有上述给出的含义、或在基团CH2CO(OR′)的情况下也表示氢,或任选取代的苯基。
排除的化合物是其中或者同时R1为C(CH3)3,R2为氢,R3为未取代的苯基,X为S和Y为N或者CR6,其中R6=氢或CH2-CO2-乙基,或同时R1为C(CH3)3,R2为氢,R3为未取代的苯基,Y为NH和X为N或CR5,其中R5=CO2乙基。
在R3为取代的苯基的情况下,其优选选自4-乙酰氨基苯基、2-溴苯基、3-溴苯基、4-溴苯基、4-溴-2-氟苯基、5-溴-2-氟苯基、3-溴-4-氟苯基、4-叔丁基苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、4-氰基苯基、2,3-二氯苯基、2,4-二氯苯基、3,4-二氯苯基、2,3-二甲氧基苯基、3,4-二甲氧基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-己基苯基、3-羟基苯基、2-甲氧基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-硝基苯基、3-苯氧基苯基、4-(1-吡咯烷基)苯基(4-(1-pyrrolidino)phenyl)、2-(三氟甲基)苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、3,4,5-三甲氧基苯基、3-(4-氯苯氧基)苯基和4-乙酰氧基-3-甲氧基苯基。
在R3为取代的1-萘基的情况下,其优选选自4-二甲基氨基萘基、2-乙氧基萘基和4-甲氧基萘基。
在R3为取代的吡咯基的情况下,其优选选自2-(1-(苯基磺酰基)-吡咯)、2-(N-甲基吡咯)、2-(N-(3,5-二氯苯基)-吡咯)和2-(1-(4-氯苯基)吡咯)。
在R3为取代的糠基的情况下,其优选选自2-(5-乙酰氧基甲基糠基)、2-(5-甲基糠基)、2-(5-硝基糠基)、2-[5-(3-硝基苯基)糠基]、2-[5-(2-硝基-苯基)糠基]、2-(5-溴糠基)、2-[5-(4-氯苯基)糠基]、2-(4,5-二甲基糠基)、2-[5-(2-氯苯基)糠基]、2-(5-乙基糠基)和2-[5-(1,3-dioxalan)糠基]。
在R3为取代的噻吩基的情况下,其优选选自2-(5-氯噻吩基)、2-(5-甲基噻吩基)、2-(5-乙基噻吩基)、2-(3-甲基噻吩基)、2-(4-溴噻吩基)、2-(5-硝基噻吩基)、5-(2-羧基噻吩基)、2-[4-(苯基乙基)噻吩基]、2-[5-(甲基硫基)噻吩基]、2-(3-溴噻吩基)、2-(3-苯氧基噻吩基)和2-(5-溴噻吩基)。
除这些化合物外,本发明还优选这样一些化合物,其中
在Rb代表取代的苯基的情况下,其选自3,5-双(三氟甲基)苯基、2-溴苯基、2-氟苯基、五氟苯基、2,4-二氟苯基、2,6-二氟苯基、2-氯苯基、2,4-二氯苯基、2-乙酰基苯基、2-甲氧基苯基、2,6-二甲氧基苯基、2-(三氟甲基)苯基、2-甲基苯基、3-溴苯基、3-氟苯基、3-氯苯基、3,4-二氯苯基、3-甲氧基苯基、3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、3,5-二甲氧基苯基、3-(三氟甲基)苯基、3-甲氧基苯基、4-溴苯基、4-氟苯基、4-氯苯基、4-甲氧基苯基、4-(三氟甲基)苯基、4-叔丁基苯基、4-甲基苯基、2-碘苯基、4-碘苯基、4-氰基苯基、2-硝基苯基、3-硝基苯基、3,5-二硝基苯基、4-硝基苯基、3,5-二氯苯基、2,5-二氟苯基、2,4二甲氧基苯基、3-硝基-4-甲基苯基、2,5-二氯苯基、2,3-二氟苯基、4-(三氟甲氧基)-苯基、2-(三氟甲氧基)苯基和3-(三氟甲氧基)-苯基,
在Rc代表取代的苯基的情况下,其选自2-氟苯基、2-氯苯基、2-甲基苯基、2-(三氟甲基)-苯基、2-溴苯基、3-甲氧基苯基、3-硝基苯基、3-氯苯基、3-氟苯基、3-苯氧基苯基、3-(三氟甲氧基)苯基、3-溴苯基、3-氯苯基、3-甲基苯基、4-叔丁基苯基、4-氟苯基、4-氯苯基、4-乙烯基苯基、4-(三氟甲氧基)苯基、3,5-二甲氧基苯基、3,5-二氟苯基、3,5-二(三氟甲基)苯基、3,5-二氟苯基、3,5-二甲基苯基、2,3-二氯苯基、2,3-二甲基苯基、2,3-二氟苯基、3-氯-2-氟苯基、2-氯-4-氟苯基、2,4-二(三氟甲基)苯基、2,4-二氯苯基、2,4-二氟苯基、2,4-二甲基苯基、2,5-二氯苯基、2,5-二甲基苯基、2,5-二氟苯基、3,4-二氯苯基、3,4-二氟苯基、3,4-二甲基苯基、2,3,4-三氟苯基、2,3,6-三氟苯基、2,4,5-三氟苯基、2,4,6-三甲基苯基和五氟苯基,以及
在Rd代表取代的苯基的情况下,其选自3-氯苯基、4-氯苯基、4-羧基苯基、4-乙酰基苯基、4-甲氧基-苯基、4-氟苯基、4-硝基苯基和4-羟基苯基。
本发明特别优选的双环咪唑-5-基-胺选自
叔丁基-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-呋喃-2-基咪唑并[2,1-b]噻唑-5-基)胺、
(5-叔丁基氨基-6-呋喃-2-基咪唑并[2,1-b]噻唑-3-基)-乙酸、
叔丁基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)胺、
叔丁基-(5-吡啶-3-基咪唑[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(5-吡啶-4-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-环己基咪唑并[2,1-b]噻唑-5-基)胺、
叔丁基-(5-甲基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-甲基咪唑并[2,1-b]噻唑-5-基)-胺、
环己基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
环己基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)胺、
(5-环己基氨基-6-吡啶-2-基咪唑并[2,1-b]噻唑-3-基)-乙酸、
环己基-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)胺、
环己基-(6-环己基咪唑并[2,1-b]噻唑-5-基)胺、
(6-环己基-5-环己基氨基咪唑并[2,1-b]噻唑-3-基)-乙酸、
(5-环己基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸、
(2,6-二甲基苯基)-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
(2,6-二甲基-苯基)-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、
(2,6-二甲基-苯基)-(6-吡啶-3-基咪唑并[2,1-b]噻唑-5-基)-胺、
(2,6-二甲基-苯基)-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)-胺、
(6-环己基咪唑并[2,1-b]噻唑-5-基氨基)-乙酸甲酯、
(6-甲基咪唑并[2,1-b]噻唑-5-基氨基)-乙酸甲酯、
叔丁基-(2-苯基-5H-咪唑并[1,2-b]吡唑-3-基)胺、
3-(5-叔丁基氨基咪唑并[2,1-b]噻唑-6-基)-苯酚、
叔丁基-[6-(3,4-二甲氧基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2,3-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2,3-二氯-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2,4-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2,4-二氯-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2-甲氧基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2-甲氧基-苯基)-咪唑并[2,1-b]噻唑5-基]-胺、
[5-叔丁基氨基-6-(2-甲氧基-苯基)-咪唑并[2,1-b]噻唑-3-基]-乙酸、
叔丁基-(5-邻甲苯基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)-胺、
叔丁基-[5-(2,3-二甲氧基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2,3-二甲氧基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-(6-对甲苯基咪唑并[2,1-b]噻唑-5-基)-胺、
(5-叔丁基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸、
N-叔丁基-N-(6-苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺、
N-叔丁基-N-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺、
丁基-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2-氟苯基)-咪唑并[1,2-b][1,2,4]三唑]-6-基]-胺、
叔丁基-[6-(2-氟苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
环己基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
[5-(2-溴苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基](1,1,3,3-四甲基-丁基)-胺、
N-[4-(6-环己基氨基咪唑并[1,2-b][1,2,4]三唑-5-基)-苯基]-乙酰胺、
叔丁基-[5-(2,5-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
环己基-[6-(2,4-二甲基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
环己基-[6-(2,5-二甲基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
N-叔丁基-N-(6-对甲苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺、
[5-(2,4-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基-丁基)-胺、
[5-(2,5-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基-丁基)-胺、
N-丁基-N-[5-(2-氯-6-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-乙酰胺和
N-丁基-N-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-乙酰胺。
如果本发明的双环咪唑-5-基胺包含光学活性碳原子,本发明也提供这些化合物的对映体或其混合物及其可药用盐。
本发明还提供包含至少一种以碱或可药用盐形式的通式I的双环咪唑-5-基胺作为活性化合物的药物,其中,R1-R6、X和Y具有上述含义,所述盐优选氢溴酸、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/或天冬氨酸的盐或特别是盐酸盐。
本发明的药物特别优选包含至少一种选自下列的以碱或可药用盐形式的双环咪唑-5-基胺作为活性化合物:
叔丁基-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-呋喃-2-基咪唑并[2,1-b]噻唑-5-基)胺、
(5-叔丁基氨基-6-呋喃-2-基咪唑[2,1-b]噻唑3-基)-乙酸、
叔丁基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、
叔丁基-(5-吡啶-3-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(5-吡啶-4-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-环己基咪唑并[2,1-b]噻唑-5-基)胺、
叔丁基-(5-甲基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-甲基咪唑并[2,1-b]噻唑-5-基)-胺、
环己基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
环己基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、
(5-环己基氨基-6-吡啶-2-基咪唑并[2,1-b]噻唑-3-基)-乙酸、
环己基-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)胺、
环己基-(6-环己基咪唑并[2,1-b]噻唑-5-基)-胺、
(6-环己基-5-环己基氨基咪唑并[2,1-b]噻唑-3-基)-乙酸、
(5-环己基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸、
(2,6-二甲基-苯基)-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
(2,6-二甲基-苯基)-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、
(2,6-二甲基-苯基)-(6-吡啶-3-基咪唑并[2,1-b]噻唑-5-基)-胺、
(2,6-二甲基-苯基)-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)-胺、
(6-环己基咪唑并[2,1-b]噻唑-5-基氨基)-乙酸甲酯、
(6-甲基咪唑并[2,1-b]噻唑-5-基氨基)-乙酸甲酯、
叔丁基-(2-苯基-5H-咪唑并[1,2-b]吡唑-3-基)胺、
3-(5-叔丁基氨基咪唑并[2,1-b]噻唑-6-基)-苯酚、
叔丁基-[6-(3,4-二甲氧基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2,3-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2,3-二氯-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2,4-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2,4-二氯-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2-甲氧基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2-甲氧基-苯基)-咪唑并[2,1-b]噻唑5-基]-胺、
[5-叔丁基氨基-6-(2-甲氧基-苯基)-咪唑并[2,1-b]噻唑-3-基]-乙酸、
叔丁基-(5-邻甲苯基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
叔丁基-(6-邻甲苯基咪唑并[2,1-b]噻唑-6-基)-胺、
叔丁基-[5-(2,3-二甲氧基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2,3-二甲氧基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-(6-对甲苯基咪唑并[2,1-b]噻唑-5-基)-胺、
(5-叔丁基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸、
N-叔丁基-N-(6-苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺、
N-叔丁基-N-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)-乙酰胺、
丁基-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-[5-(2-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
叔丁基-[6-(2-氟苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
叔丁基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
环己基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、
[5-(2-溴苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基](1,1,3,3-四甲基-丁基)-胺、
N-[4-(6-环己基氨基咪唑并[1,2-b][1,2,4]三唑-5-基)-苯基]-乙酰胺、
叔丁基-[5-(2,5-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、
环己基-[6-(2,4-二甲基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
环己基-[6-(2,5-二甲基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、
N-叔丁基-N-(6-对甲苯基咪唑并[2,1-b]噻唑-5-基)-乙酰胺、
[5-(2,4-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基-丁基)-胺、
[5-(2,5-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑6-基]-(1,1,3,3-四甲基-丁基)-胺、
N-丁基-N-[5-(2-氯-6-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-乙酰胺和
N-丁基-N-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-乙酰胺。
已证实本明化合物是疼痛相关的人类α肾上腺素能受体α2-亚型的配体。因此特别优选的是本发明的双环咪唑-5-基胺与一种或多种助剂一起用于制备治疗疼痛的药物。
为制备合适的药物,除了用至少一种本发明的活性化合物外,还使用载体材料、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、糖浆剂的制剂适于口服,溶液、悬浮液、易于重构的干粉及喷雾剂适合于非肠道、局部和吸入施用。以储库、溶解形式或以膏药形式、任选加入促进皮肤渗透的试剂的本发明的活性化合物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化合物。
给患者施用的本发明活性化合物的量随患者的体重、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、Lancaster、Maybridge、Merck、Sigma或TCI-Jp公司商购的3-氨基吡唑-、3-氨基-1,2,4-三唑-、2-氨基-、1,3,4-噻二唑-和2-氨基噻唑衍生物,与不同的醛III和异腈IV在20%的高氯酸的存在下进行三组分反应。这里R1-R3、X和Y具有上述式I化合物给出的含义。
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优选先溶解在二氯甲烷或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ReNCO,按下述反应方案在吗啉树脂的存在(例如Argonaut公司的聚苯乙烯-吗啉)下,在二氯甲烷中于10℃~40℃反应2~24小时:
然后通过用一聚合物键合的三(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。整个操作也可以容易地在自动合成设备中进行。
可按本身已知的方法用生理可耐受的酸将式I化合物转化成其可药用盐,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,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。另外在水溶液中的三甲基硅烷也适于制备盐酸盐。
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。
合成是在Zymark公司的自动合成设备中按下列通用合成规程进行的:
用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.)0.5ml0.3M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。在旋转反应器上充分混合这些组分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。
对于其中按上述方法得到的化合物进一步与乙酰氯反应的实施例,按下列通用合成规程进行操作:
将按上述通用合成规程得到的产物溶于二氯甲烷中,加入4摩尔当量的乙酰氯并在18℃下搅拌混合物4小时。在真空下于40-60℃除去过量的乙酰氯和溶剂。
所用试剂和溶剂是商购的。用ESI-MS和/或NMR分析每一种物质。实施例1叔丁基-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(1)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)糠醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物1。ESI-MS表征得到分子量为:262
实施例2叔丁基-(6-呋喃-2-基咪唑并[2,1-b]噻唑-5-基)胺(2)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)糠醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物2。ESI-MS表征得到分子量为:262
实施例3(5-叔丁基氨基-6-呋喃-2-基咪唑并[2,1-b]噻唑3-基)-乙酸(3)
按通用合成规程由1.0ml(0.1mmol)(2-氨基噻唑-4-基)乙酸溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)糠醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物3。ESI-MS表征得到分子量为:320
实施例4叔丁基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(4)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物4。ESI-MS表征得到分子量为:257实施例5叔丁基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)胺(5)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物5。ESI-MS表征得到分子量为:273
实施例6叔丁基-(5-吡啶-3-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(6)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)3-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物6。ESI-MS表征得到分子量为:257
实施例7叔丁基-(5-吡啶-4-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(7)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)4-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物7。ESI-MS表征得到分子量为:257
实施例8叔丁基-(6-环己基咪唑并[2,1-b]噻唑-5-基)胺(8)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)环己基甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物8。ESI-MS表征得到分子量为:278实施例9叔丁基-(5-甲基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(9)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)乙醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物9。ESI-MS表征得到分子量为:194
实施例10叔丁基-(6-甲基咪唑并[2,1-b]噻唑-5-基)-胺(10)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)乙醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物10。ESI-MS表征得到分子量为:210
实施例11环己基-(5-吡啶-2-基咪唑[1,2-b][1,2,4]三唑-6-基)-胺(11)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物11。ESI-MS表征得到分子量为:283
实施例12环己基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)胺(12)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物12。ESI-MS表征得到分子量为:299实施例13(5-环己基氨基-6-吡啶-2-基咪唑并[2,1-b]噻唑-3-基)-乙酸(13)
按通用合成规程由1.0ml(0.1mmol)(2-氨基噻唑-4-基)乙酸溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)3-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物13。ESI-MS表征得到分子量为:357
实施例14环己基-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)胺(14)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)3-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物14。ESI-MS表征得到分子量为:299
实施例15环己基-(6-环己基咪唑并[2,1-b]噻唑-5-基)胺(15)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)环己基甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物15。ESI-MS表征得到分子量为:304
实施例16(6-环己基-5-环己基氨基咪唑并[2,1-b]噻唑-3-基)-乙酸(16)
按通用合成规程由1.0ml(0.1mmol)(2-氨基噻唑-4-基)乙酸溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)环己基甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物16。ESI-MS表征得到分子量为:318实施例17(5-环己基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸(17)
按通用合成规程由1.0ml(0.1mmol)(2-氨基噻唑-4-基)乙酸溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)乙醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物17。ESI-MS表征得到分子量为:250
实施例18(2,6-二甲基苯基)-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(18)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)2,6-二甲基苯基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)糠醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物18。ESI-MS表征得到分子量为:292
实施例19(2,6-二甲基苯基)-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺(19)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)2,6二甲基苯基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物19。ESI-MS表征得到分子量为:321
实施例20(2,6-二甲基-苯基)-(6-吡啶-3-基咪唑并[2,1-b]噻唑-5-基)-胺(20)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)2,6-二甲基苯基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)3-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物20。ESI-MS表征得到分子量为:321
实施例21(2,6-二甲基苯基)-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)-胺(21)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)2,6-二甲基苯基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)4-吡啶甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物21。ESI-MS表征得到分子量为:321
实施例22(6-环己基咪唑并[2,1-b]噻唑-5-基氨基)乙酸甲酯(22)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)异氰基乙酸甲酯溶液(0.2M,DCM)、0.500ml(0.15mmol)环己基甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物22。ESI-MS表征得到分子量为:294
实施例23(6-甲基咪唑并[2,1-b]噻唑-5-基氨基)-乙酸甲酯(23)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)异氰基乙酸甲酯溶液(0.2M,DCM)、0.500ml(0.15mmol)乙醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物23。ESI-MS表征得到分子量为:226
实施例24叔丁基-(2-苯基-5H-咪唑并[1,2-b]吡唑-3-基)胺(24)
按通用合成规程由1.0ml(0.1mmol)3-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物24。ESI-MS表征得到分子量为:255
实施例253-(5-叔丁基氨基咪唑并[2,1-b]噻唑-6-基)-苯酚(25)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)3-羟基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物25。ESI-MS表征得到分子量为:288
实施例26叔丁基-[6-(3,4-二甲氧基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(26)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)3,4-二甲氧基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物26。ESI-MS表征得到分子量为:332
实施例27叔丁基-[5-(2,3-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺(27)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,3-二氯苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物27。ESI-MS表征得到分子量为:324
实施例28叔丁基-[6-(2,3-二氯苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(28)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,3-二氯苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物28。ESI-MS表征得到分子量为:340
实施例29叔丁基-[5-(2,4-二氯苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺(29)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,4-二氯苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物29。ESI-MS表征得到分子量为:324
实施例30叔丁基-[6-(2,4-二氯苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(30)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,4-二氯苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物30。ESI-MS表征得到分子量为:340
实施例31叔丁基-[5-(2-甲氧基苯基)咪唑[1,2-b][1,2,4]三唑-6-基]-胺(31)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-甲氧基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物31。ESI-MS表征得到分子量为:286实施例32叔丁基-[6-(2-甲氧基苯基)咪唑[1,2-b]噻唑-5-基]-胺(32)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-甲氧基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物32。ESI-MS表征得到分子量为:302
实施例33[5-叔丁基氨基-6-(2-甲氧基苯基)-咪唑并[2,1-b]噻唑-3-基]-乙酸(33)
按通用合成规程由1.0ml(0.1mmol)(2-氨基噻唑-4-基)乙酸溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-甲氧基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物33。ESI-MS表征得到分子量为:321
实施例34叔丁基-(5-邻甲苯基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(34)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物34。ESI-MS表征得到分子量为:270
实施例35叔丁基-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)-胺(35)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物35。ESI-MS表征得到分子量为:321实施例36叔丁基-[5-(2,3-二甲氧基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺(36)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,3-二甲氧基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物36。ESI-MS表征得到分子量为:316
实施例37叔丁基-[6-(2,3-二甲氧基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(37)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,3-二甲氧基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物37。ESI-MS表征得到分子量为:332
实施例38叔丁基-(6-对甲苯基咪唑并[2,1-b]噻唑-5-基)-胺(38)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)4-甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物38。ESI-MS表征得到分子量为:286
实施例39(5-叔丁基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸(39)
按通用合成规程由1.0ml(0.1mmol)(2-氨基噻唑-4-基)乙酸溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)乙醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物39。ESI-MS表征得到分子量为:M-CO2 224.3
实施例40N-叔丁基-N-(6-苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺(40)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)并与乙酰氯反应得到了化合物40,其中过量的乙酰氯在真空下除去。ESI-MS表征得到分子量为:315.3,M-乙酰基272.1
实施例41N-叔丁基-N-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺(41)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)并与乙酰氯反应得到了化合物41,其中过量的乙酰氯在真空下除去。ESI-MS表征得到分子量为:M-乙酰基286.3
实施例42丁基-[6-(4-叔丁基苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-胺(42)
按通用合成规程由1.0ml(0.1mmol)5-甲基-噻唑-2-基-胺溶液(0.1M,DCM)、0.575ml(0.115mmol)正丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)4-叔丁基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物42。ESI-MS表征得到分子量为:342.3
实施例43叔丁基-[5-(2-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺(43)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-氟苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物43。ESI-MS表征得到分子量为:274.1
实施例44叔丁基-[6-(2-氟苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(44)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-氟苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物44。ESI-MS表征得到分子量为:290.2
实施例45叔丁基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(45)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)1-萘基甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物45。ESI-MS表征得到分子量为:306.2
实施例46环己基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺(46)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)1-萘基甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物46。ESI-MS表征得到分子量为:332.3
实施例47[5-(2-溴苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基-丁基)-胺(47)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)1,1,3,3-四甲基丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-溴苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物47。ESI-MS表征得到分子量为:390.3/392.2
实施例48N-[4-(6-环己基氨基咪唑并[1,2-b][1,2,4]三唑-5-基)-苯基]-乙酰胺(48)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)N-(4-甲酰基苯基)-乙酰胺溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物48。ESI-MS表征得到分子量为:337.1
实施例49叔丁基-[5-(2,5-二甲基苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺(49)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,5-二甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物49。ESI-MS表征得到分子量为:284.2
实施例50环己基-[6-(2,4-二甲基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(50)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,4-二甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物50。ESI-MS表征得到分子量为:326.3实施例51环己基-[6-(2,5-二甲基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺(51)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)环己基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,5-二甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物51。ESI-MS表征得到分子量为:326.3
实施例52N-叔丁基-N-(6-对甲苯基咪唑并[2,1-b]噻唑-5-基)乙酰胺(52)
按通用合成规程由1.0ml(0.1mmol)2-氨基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)叔丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)4-甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)并与乙酰氯反应得到了化合物52,其中过量的乙酰氯在真空下除去。ESI-MS表征得到分子量为:327.4,M-乙酰基286.3
实施例53[5-(2,4-二甲基苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基-丁基)-胺(53)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)1,1,3,3-四甲基丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,4-二甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物53。ESI-MS表征得到分子量为:340.2
实施例54[5-(2,5-二甲基苯基)-咪唑并[1,2-b][1,2,4]-三唑-6-基]-(1,1,3,3-四甲基丁基)-胺(54)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)1,1,3,3-四甲基丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2,5-二甲基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)在物质库中合成了化合物54。ESI-MS表征得到分子量为:340.2
实施例55N-丁基-N-[5-(2-氯-6-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-乙酰胺(55)
按通用合成规程由1.0ml(0.1mmol)3-氨基-1,2,4-三唑溶液(0.1M,DCM)、0.575ml(0.115mmol)正丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)2-氯-6-氟-苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)并与乙酰氯反应得到了化合物55,其中过量的乙酰氯在真空下除去。ESI-MS表征得到分子量为:350.4
实施例56N-丁基-N-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-乙酰胺(56)
按通用合成规程由1.0ml(0.1mmol)2-氨基-5-甲基噻唑溶液(0.1M,DCM)、0.575ml(0.115mmol)正丁基异腈溶液(0.2M,DCM)、0.500ml(0.15mmol)4-叔丁基苯甲醛溶液(0.3M,DCM)和10μl高氯酸(w=20%)并与乙酰氯反应得到了化合物56,其中过量的乙酰氯在真空下除去。ESI-MS表征得到分子量为:384.5
本发明化合物被证明为与疼痛相关的人类α肾上腺素能受体的α2-亚型的配体。与人类α-肾上腺素能受体的α2-亚型的亲和性通过高通量筛选常用的SPA-分析法进行,如在John P.Devlin,HighThroughput Screening,Marcel Dekker Inc.1997,第307-316页中所述。该文献在此引入作为参考并被视为本公开的一部分。下列亲和性在10μM浓度下测定的:
α2-亲和性,10μM | |
实施例39 | 35% |
实施例40 | 77% |
实施例41 | 50% |
实施例42 | 36% |
实施例43 | 34% |
实施例44 | 38% |
实施例45 | 41% |
实施例46 | 46% |
实施例47 | 42% |
实施例48 | 36% |
实施例49 | 38% |
实施例50 | 36% |
实施例51 | 39% |
实施例52 | 51% |
实施例53 | 43% |
实施例54 | 56% |
实施例55 | 39% |
实施例56 | 46% |
Claims (7)
1.通式(I)的双环咪唑-5-基胺和其可药用盐,其中R1为C(CH3)3、(CH2)6CN、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为氢、C1-C8-烷基(支化的或未支化的)、任选取代的苯基、CO(OR′)(其中R′=C1-C8-烷基(支化的或未支化的))、PO(OR")2(其中R"=C1-C4-烷基(支化的或未支化的))或Si(RxRyRz)(其中Rx、Ry和Rz各自独立为C1-C8烷基(支化的或未支化的)、C4-C8-环烷基或苯基),R2为氢、CORb,其中Rb为氢、C1-C8-烷基(支化的或未支化的)、C3-C8环烷基、CH2CH2CO(OR′)(其中R′=C1-C8-烷基(支化的或未支化的))、金刚烷基、任选取代的苯基、任选取代的1-萘基、2-萘基、2-吡啶基、3-吡啶基、4-吡啶基、噻唑基或糠酰基、CH2Rc,其中Rc为氢、C1-C8-烷基(支化的或未支化的)或任选取代的苯基、CH2CH2Rd,其中Rd为任选取代的苯基、或CONHRe,其中Re为苯基,R3为C1-C8-烷基(支化的或未支化的)、C3-C8环烷基、任选取代的苯基、任选取代的1-萘基、2-萘基、喹啉、蒽、菲、苯并噻吩、苯并糠基、任选取代的吡咯、2-吡啶基、3-吡啶基、4-吡啶基、任选取代的糠基或任选取代的噻吩,X为CR5、N或S并且Y在X表示S的情况下为CR6或N并且在其它所有情况下表示N,R4、R5和R6各自相互独立为氢、C1-C8-烷基(支化的或未支化的)、氟、氯、溴、CF3、CN、NO2、NHRf,其中Rf为氢、C1-C8-烷基(支化的或未支化的)、或任选取代的苯基、SRg,其中Rg为氢、C1-C8-烷基(支化的或未支化的)、苯基、吡啶、苄基或芴基、ORh,其中Rh为C1-C8-烷基(支化的或未支化的)、任选取代的苯基或CO(OR′)(R′=C1-C8-烷基(支化的或未支化的))、CO(OR′)或CH2CO(OR′),其中R′在每一种情况下具有上述含义或在基团CH2CO(OR′)的情况下还表示氢、或任选取代的苯基,除外的化合物是其中同时R1为C(CH3)3、R2为氢、R3为未取代的苯基、X为S和Y为N或CR6,其中R6=氢或CH2-CO2-乙基,或同时R1为C(CH3)3、R2为氢、R3为未取代的苯基、Y为NH和X为N或CR5,其中R5=CO2乙基。
2. 按照权利要求1的双环咪唑-5-基-胺,其特征为对于R3为取代的苯基的情况下,其选自:4-乙酰氨基苯基、2-溴苯基、3-溴苯基、4-溴苯基、4-溴-2-氟苯基、5-溴-2-氟苯基、3-溴-4-氟苯基、4-叔丁基苯基、2-氯-4-氟苯基、2-氯-6-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、4-氰基苯基、2,3-二氯苯基、2,4-二氯苯基、3,4-二氯苯基、2,3-二甲氧基苯基、3,4-二甲氧基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-己基苯基、3-羟基苯基、2-甲氧基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-硝基苯基、3-苯氧基苯基、4-(1-吡咯烷基)苯基、2-(三氟甲基)苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、3,4,5-三甲氧基苯基、3-(4-氯苯氧基)苯基和4-乙酰氧基-3-甲氧基苯基,对于R3为取代的1-萘基的情况下,其选自:4-二甲基氨基萘基、2-乙氧基萘基、4-甲氧基萘基,对于R3为取代的吡咯基的情况下,其选自:2-(1-(苯基磺酰基)吡咯)、2-(N-甲基吡咯)、2-(N-(3,5-二氯苯基)吡咯)和2-(1-(4-氯苯基)吡咯),对于R3为取代的糠基的情况下,其选自:2-(5-乙酰氧基甲基糠基)、2-(5-甲基糠基)、2-(5-硝基糠基)、2-[5-(3-硝基苯基)糠基]、2-[5-(2-硝基苯基)糠基]、2-(5-溴糠基)、2-[5-(4-氯苯基)糠基]、2-(4,5-二甲基糠基)、2-[5-(2-氯苯基)糠基]、2-(5-乙基糠基)和2-[5-(1,3-dioxalan)糠基],和对于R3为取代的噻吩基的情况下,其选自:2-(5-氯噻吩基)、2-(5-甲基噻吩基)、2-(5-乙基噻吩基)、2-(3-甲基噻吩基)、2-(4-溴噻吩基)、2-(5-硝基噻吩基)、5-(2-羧基噻吩基)、2-[4-(苯基乙基)噻吩基]、2-[5-(甲基硫基)噻吩基]、2-(3-溴噻吩基)、2-(3-苯氧基噻吩基)和2-(5-溴噻吩基)。
3.按照权利要求1或2的双环咪唑-5-基胺,其特征为,对于Rb为取代的苯基的情况下,其选自:3,5-双(三氟甲基)苯基、2-溴苯基、2-氟苯基、五氟苯基、2,4-二氟苯基、2,6-二氟苯基、2-氯苯基、2,4-二氯苯基、2-乙酰基-苯基、2-甲氧基苯基、2,6-二甲氧基苯基、2-(三氟甲基)苯基、2-甲基苯基、3-溴苯基、3-氟苯基、3-氯苯基、3,4-二氯苯基、3-甲氧基苯基、3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、3,5-二甲氧基苯基、3-(三氟甲基)苯基、3-甲氧基苯基、4-溴苯基、4-氟苯基、4-氯苯基、4-甲氧基苯基、4-(三氟甲基)苯基、4-叔丁基苯基、4-甲基苯基、2-碘苯基、4-碘苯基、4-氰基苯基、2-硝基苯基、3-硝基苯基、3,5-二硝基苯基、4-硝基苯基、3,5-二氯苯基、2,5-二氟苯基、2,4-二甲氧基苯基、3-硝基-4-甲基苯基、2,5-二氯苯基、2,3-二氟苯基、4-(三氟甲氧基)-苯基、2-(三氟甲氧基)-苯基和3-(三氟甲氧基)苯基,对于Rc为取代的苯基的情况下,其选自:2-氟苯基、2-氯苯基、2-甲基苯基、2-(三氟甲基)苯基、2-溴苯基、3-甲氧基苯基、3-硝基苯基、3-氯苯基、3-氟苯基、3-苯氧基苯基、3-(三氟甲氧基)苯基、3-溴苯基、3-氯苯基、3-甲基苯基、4-叔丁基苯基、4-氟苯基、4-氯苯基、4-乙烯基苯基、4-(三氟甲氧基)苯基、3,5-二甲氧基苯基、3,5-二氟苯基、3,5-二(三氟甲基)苯基、3,5-二氟苯基、3,5-二甲基苯基、2,3-二氯苯基、2,3-二甲基苯基、2,3-二氟苯基、3-氯-2-氟苯基、2-氯-4-氟苯基、2,4-二(三氟甲基)苯基、2,4-二氯苯基、2,4-二氟苯基、2,4-二甲基苯基、2,5-二氯苯基、2,5-二甲基苯基、2,5-二氟苯基、3,4-二氯苯基、3,4-二氟苯基、3,4-二甲基苯基、2,3,4-三氟苯基、2,3,6-三氟苯基、2,4,5-三氟苯基、2,4,6-三甲基苯基和五氟苯基,对于Rd为取代的苯基的情况下,其选自:3-氯苯基、4-氯苯基、4-羧基苯基、4-乙酰基苯基、4-甲氧基苯基、4-氟苯基、4-硝基苯基、4-羟基苯基。
4.一种药物,其含有至少一种按照权利要求1的通式I的、以碱或其可药用盐形式存在的双环咪唑-5-基胺作为活性化合物,其中,R1~R6、X和Y具有按照权利要求1中给出的含义。
5.按照权利要求4的药物,其特征在于包含至少一种选自下列的双环咪唑-5-基胺或者其可药用盐作为活性化合物:叔丁基-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、叔丁基-(6-呋喃-2-基咪唑[2,1-b]噻唑-5-基)-胺、(5-叔丁基氨基-6-呋喃-2-基咪唑并[2,1-b]噻唑-3-基)-乙酸、叔丁基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、叔丁基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、叔丁基-(5-吡啶-3-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、叔丁基-(5-吡啶-4-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、叔丁基-(6-环己基咪唑并[2,1-b]噻唑-5-基)-胺、叔丁基-(5-甲基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、叔丁基-(6-甲基咪唑并[2,1-b]噻唑-5-基)胺、环己基-(5-吡啶-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、环己基-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、(5-环己基氨基-6-吡啶-2-基咪唑并[2,1-b]噻唑-3-基)-乙酸、环己基-(6-吡啶-4-基咪唑并[2,1-b]噻唑5-基)-胺、环己基-(6-环己基咪唑并[2,1-b]噻唑-5-基)-胺、(6-环己基-5-环己基氨基咪唑并[2,1-b]噻唑-3-基)-乙酸、(5-环己基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸、(2,6-二甲基-苯基)-(5-呋喃-2-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、(2,6-二甲基苯基)-(6-吡啶-2-基咪唑并[2,1-b]噻唑-5-基)-胺、(2,6-二甲基苯基)-(6-吡啶-3-基咪唑并[2,1-b]噻唑-5-基)-胺、(2,6-二甲基-苯基)-(6-吡啶-4-基咪唑并[2,1-b]噻唑-5-基)-胺、(6-环己基咪唑并[2,1-b]噻唑-5-基氨基)乙酸甲酯、(6-甲基咪唑并[2,1-b]噻唑-5-基氨基)乙酸甲酯、叔丁基-(2-苯基-5H-咪唑并[1,2-b]吡唑-3-基)-胺、3-(5-叔丁基氨基咪唑并[2,1-b]噻唑-6-基)苯酚、叔丁基-[6-(3,4-二甲氧基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、叔丁基-[5-(2,3-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、叔丁基-[6-(2,3-二氯-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、叔丁基-[5-(2,4-二氯-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、叔丁基-[6-(2,4-二氯苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、叔丁基-[5-(2-甲氧基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、叔丁基-[6-(2-甲氧基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、[5-叔丁基氨基-6-(2-甲氧基苯基)-咪唑并[2,1-b]噻唑-3-基]-乙酸、叔丁基-(5-邻甲苯基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、叔丁基-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)-胺、叔丁基-[5-(2,3-二甲氧基苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、叔丁基-[6-(2,3-二甲氧基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、叔丁基-(6-对甲苯基-咪唑并[2,1-b]噻唑-5-基)-胺、(5-叔丁基氨基-6-甲基咪唑并[2,1-b]噻唑-3-基)-乙酸、N-叔丁基-N-(6-苯基咪唑并[2,1-b]噻唑-5-基)-乙酰胺、N-叔丁基-N-(6-邻甲苯基咪唑并[2,1-b]噻唑-5-基)-乙酰胺、丁基-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-胺、叔丁基-[5-(2-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、叔丁基-[6-(2-氟苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、叔丁基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、环己基-(5-萘-1-基咪唑并[1,2-b][1,2,4]三唑-6-基)-胺、[5-(2-溴苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基-丁基)-胺、N-[4-(6-环己基氨基咪唑并[1,2-b][1,2,4]三唑-5-基)-苯基]-乙酰胺、叔丁基-[5-(2,5-二甲基苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-胺、环己基-[6-(2,4-二甲基-苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、环己基-[6-(2,5-二甲基苯基)-咪唑并[2,1-b]噻唑-5-基]-胺、N-叔丁基-N-(6-对甲苯基-咪唑并[2,1-b]噻唑-5-基)-乙酰胺、[5-(2,4-二甲基-苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基丁基)-胺、[5-(2,5-二甲基苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-(1,1,3,3-四甲基丁基)-胺、N-丁基-N-[5-(2-氯-6-氟苯基)-咪唑并[1,2-b][1,2,4]三唑-6-基]-乙酰胺、和N-丁基-N-[6-(4-叔丁基-苯基)-2-甲基咪唑并[2,1-b]噻唑-5-基]-乙酰胺。
6.至少一种按照权利要求1、2或3的双环咪唑-5-基胺与一种或多种助剂用于制备治疗疼痛的药物的用途。
7.通过脒、醛和异腈的三组分反应制备按照权利要求1、2或3的双环咪唑-5-基胺的方法,其特征在于这些化合物的合成在二氯甲烷作为溶剂和在高氯酸存在下进行,其中原料按脒、醛和异腈的顺序依次加入,然后生成的产物任选与化合物R2Hal或异氰酸酯ReNCO反应。
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AR078521A1 (es) | 2009-10-08 | 2011-11-16 | Eisai R&D Man Co Ltd | Compuesto pirazolotiazol |
IN2014DN00200A (zh) | 2011-07-13 | 2015-06-05 | Cytokinetics Inc | |
EP2855489B1 (en) | 2012-04-26 | 2017-01-04 | Bristol-Myers Squibb Company | Imidazothiadiazole and imidazopyridazine derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
PL2841437T3 (pl) | 2012-04-26 | 2017-12-29 | Bristol-Myers Squibb Company | Pochodne imidazotiadiazolu i imidazopirazyny jako inhibitory receptora 4 (par4) aktywowanego proteazą do leczenia agregacji płytek |
EP2847200B1 (en) | 2012-04-26 | 2017-03-29 | Bristol-Myers Squibb Company | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
US9617279B1 (en) | 2014-06-24 | 2017-04-11 | Bristol-Myers Squibb Company | Imidazooxadiazole compounds |
US9598419B1 (en) | 2014-06-24 | 2017-03-21 | Universite De Montreal | Imidazotriazine and imidazodiazine compounds |
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CN1637000B (zh) * | 2003-10-07 | 2014-08-27 | 三星显示有限公司 | 含有咪唑环的化合物和有机电致发光显示器件 |
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