NO322754B1 - Bicykliske imidazo-3-yl-aminderivater, legemiddel inneholdende disse, deres anvendelse for fremstilling av et legemiddel samt en fremgangsmate for fremstilling av derivatene. - Google Patents
Bicykliske imidazo-3-yl-aminderivater, legemiddel inneholdende disse, deres anvendelse for fremstilling av et legemiddel samt en fremgangsmate for fremstilling av derivatene. Download PDFInfo
- Publication number
- NO322754B1 NO322754B1 NO20021565A NO20021565A NO322754B1 NO 322754 B1 NO322754 B1 NO 322754B1 NO 20021565 A NO20021565 A NO 20021565A NO 20021565 A NO20021565 A NO 20021565A NO 322754 B1 NO322754 B1 NO 322754B1
- Authority
- NO
- Norway
- Prior art keywords
- imidazo
- amine
- pyridin
- butyl
- phenyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 39
- 125000002619 bicyclic group Chemical group 0.000 title claims description 16
- 239000003814 drug Substances 0.000 title claims description 12
- 229940079593 drug Drugs 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 10
- 150000001412 amines Chemical class 0.000 title description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 198
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 74
- -1 phenoxy, 4-Cl-phenoxy Chemical group 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 150000002527 isonitriles Chemical class 0.000 claims description 16
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- 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 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000001409 amidines Chemical class 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 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
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 6
- 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 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 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 5
- 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 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 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 4
- 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 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-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
- 239000004480 active ingredient Substances 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 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 4
- 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 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
- 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 4
- 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 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 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 4
- 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 4
- 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 4
- 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 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- 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 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 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 3
- 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 3
- 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 3
- 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 3
- 230000036407 pain Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 238000010490 three component reaction Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 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
- 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
- 101100448208 Human herpesvirus 6B (strain Z29) U69 gene Proteins 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
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 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 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 86
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 52
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000007429 general method Methods 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 8
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 8
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 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
- 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
- 239000013543 active substance Substances 0.000 description 5
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WJCPMQQLTJQIJK-UHFFFAOYSA-N 1,6-diisocyanohexane Chemical compound [C-]#[N+]CCCCCC[N+]#[C-] WJCPMQQLTJQIJK-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
- 241000196324 Embryophyta Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- UFRXPQAXDSQBDB-UHFFFAOYSA-N [2-methoxy-4-[3-(2,4,4-trimethylpentan-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC)=CC(C2=C(N3C=CC=NC3=N2)NC(C)(C)CC(C)(C)C)=C1 UFRXPQAXDSQBDB-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 3
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 3
- FSBLVBBRXSCOKU-UHFFFAOYSA-N n-butyl isocyanide Chemical compound CCCC[N+]#[C-] FSBLVBBRXSCOKU-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- DNJLFZHMJDSJFN-UHFFFAOYSA-N 2-isocyano-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1[N+]#[C-] DNJLFZHMJDSJFN-UHFFFAOYSA-N 0.000 description 2
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 2
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- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QSACPWSIIRFHHR-UHFFFAOYSA-N dimethylphenyl isocyanide Natural products CC1=CC=CC(C)=C1C#N QSACPWSIIRFHHR-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 108700039855 mouse a Proteins 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 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 description 1
- YDHQSLJHCXALKX-UHFFFAOYSA-N n-(diethoxyphosphorylmethyl)-2-phenylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NCP(=O)(OCC)OCC)=C1C1=CC=CC=C1 YDHQSLJHCXALKX-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000002731 stomach secretion inhibitor Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000000699 topical effect Effects 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
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
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Description
Den foreliggende oppfinnelsen vedrører substituerte bicykliske imidazo-3-yl-aminer, legemidler inneholdende disse forbindelser, anvendelse av aminene for fremstilling av legemidler samt en fremgangsmåte for fremstilling av aminene.
For enkelte forbindelser fra klassen av imidazo-3-yl-aminer kjennes interessante farmakologiske egenskaper. Således blir bestemte imidazo[l,2-a]pyridiner beskrevet som blodtrykkssenkende virkestoffer (GB-B-1.135.893), som antalmintika og antimykotika (J. Med. Chem. 1972, 15, 982-985) og som antisekretoriske virkestoffer for behandling av betennelsessykdommer (EP-A-0 068 378). En virkning av enkelte imidazopyridiner mot betennelsessykdommer spesielt i magen beskrives også i EP-A-0 266 890 og J. Med. Chem. 1987, 30, 2031-2046. Videre for enkelte representanter fra klassen av imidazo-3-yl-aminer beskrevne farmakologiske virkninger er antibakterielle egenskaper (Chem. Pharm. Bull. 1992,40,1170), antivirale egenskaper (J. Med. Chem. 1998,41, 5108-5112) så vel som virkningen som benzodiazepin-reseptorantagonist (J. Heterocyclic Chem. 1998, 35,1205-1217).
I lys av disse interessante virkninger ble det i fortiden syntetisert forskjellige representanter fra klassen av substituerte imidazo-3-yl-aminer. Spesielt ble det forsøkt å øke antallet av tilgjengelige substituerte imidazo-3-yl-aminer ved kombinatoriske syntesefremgangsmåter. Således beskriver C. Blackburn et al. i Tetrahedron Lett. 1998, 39, 5469-5472 en trekomponent-fastfasesyntese for fremstilling av imidazo-3-yl-aminer og i Tetrahedron Lett. 1998, 39, 3635-3638 en trekomponent-kondensasjon til parallellsyntese av imidazo-3-yl-aminer. Lignende på den sistnevnte reaksjonen er den i K. Groebke et al. i Synlett 1998,661-663 publiserte syntesen. En flerkomponent-reaksjon for den kombinatoriske syntesen av imidazo-3-yl-aminer, med hvilken også enkelte imidazo-5-aminer ble fremstilt beskrives også av H. Bienayme og K. Bouzid i Angew. Chem. 1998,110 (16), 2349-2352.
Den ifølge den kjente teknikke mulige variasjonsbredde på substituentene på amino-nitrogen og på 2-posisjonen til imidazolringen var dog begrenset.
Til grunn for den foreliggende oppfinnelsen lå derfor oppgaven å tilveiebringe bicykliske imidazo-3-yl-aminer og legemidler inneholdende disse.
Gjenstand for oppfinnelsen er derfor bicykliske imidazo-3-yl-aminer av den generelle formel I,
hvor
X og Y betyr CH eller N med det forbehold at X og Y ikke samtidig kan bety N,
R<1> betyr tert-butyl, (CH2)nCN med n = 4, 5 eller 6, eventuelt med CH3 substituert fenyl, C4-C8-cykloalkyl, CH2CH2R (R = 4-morfolino), 1,1,3,3,-tetrametylbutyl eller CH2R<a>, hvor Ra står for hydrogen, OH, Ci-C8-alkyl (forgrenet eller uforgrenet), fenyl, CO(OR')
(med R' = uforgrenet Ci-C4-alkyl eller forgrenet Ci-C5-alkyl), PO(OR')2 (med R' = uforgrenet d-C4-alkyl eller forgrenet Ci-C5-alkyl) eller Si^R^<2>) (hvor Rx, Ry og R<z >respektivt uavhengig av hverandre betyr Ci-Cg-alkyl (forgrenet eller uforgrenet), C4-C8-cykloalkyl eller fenyl),
R<2> betyr hydrogen, COR<b>, hvor R<b> står Ci-C4-alkyl (forgrenet eller uforgrenet) eller C3-C8-cykloalkyl, eller R<2> betyr for CH2CH2CO(OR<c>) (hvor R<c> står for C,-C4-alkyl (forgrenet eller uforgrenet), adamantyl, fenyl, 1-naftyl eller 2-naftyl eller 2-pyridyl, 3-pyridyl, 4-pyridyl, tiazolyl eller furoyl, eller R<2> betyr for CH2fenyl, CH2CH2R<d>, hvor Rd står for fenyl, eller R<2> betyr CONHR", hvor R<c> står for Ci-Cg-alkyl (forgrenet eller uforgrenet), C3-Cg-cykloalkyl eller fenyl,
R<3> betyr metyl, etyl, terf-butyl, C3-Cs-cykloalkyl, fenyl eventuelt substituert en gang i 3-, 5- eller 6-posisjon med CH3, OH, OCH3, Cl, NC(0)CH3, Br, F, fenoksy, 4-C1-fenoksy eller CF3 eller eventuelt substituert flere ganger i 4-posisjon og ytterligere i 2-og/eller 3- og/eller 5- og/eller 6-posisjon med CH3, OH, OCH3, Cl, NC(0)CH3, Br, F, fenoksy, 4-Cl-fenoksy eller CF3; - eller R<3> betyr fenoksy, naftyl, pyrrol, pyridyl, furan, tiofen, antracen, fenantren eller kinolin,
med det forbehold at R<3> ikke betyr n-propyl, cykloheksyl, usubstituert fenyl eller på 3-posisjonen med en karboksylsyreamidgruppe monosubstituert fenyl, når R<1> betyr tert-butyl, n-propyl, n-butyl, 1,1,3,3-tetrametylbutyl, cykloheksyl, CH2CH2R (R = 4-morfolino), monosubstituert fenyl, 2,6, -dimetylfenyl eller benzyl og R<2> samtidig betyr
hydrogen eller -CO(metyl), og at R<2> ikke betyr hydrogen når R<1> samtidig betyr benzyl og R<3> betyr metyl eller når R<1> samtidig betyr CH2C(0) tert-butyl og R<3> betyr usubstituert fenyl;
i form av deres baser eller farmasøytiske akseptable salter.
Foretrukket ifølge oppfinnelsen er slike forbindelser i hvilke R<2> betyr hydrogen, R<1> er valgt fra gruppen (CH2)nCN med n = 4, 5 eller 6, cykloheksyl, CH2CO (Ometyl), 2,6-dimetylfenyl, 1,1,3,3-tetrametylbutyl, terf-butyl eller n-butyl og R3 er valgt fra gruppen 2- pyridyl, 3-pyridyl, 2-furanyl, 2-pyrroyl, metyl, terf-butyl, 3-hydroksyfenyl, 3,4-dimetoksyfenyl, 2,3-diklorfenyl, 2,4-diklorfenyl, 2-metoksyfenyl, 2,3-dimetoksyfenyl, 3- bromfenyl, 4-brom-2-fluorfenyl, 5-brom-2-fluorfenyl, 3-brom-4-fluorfenyl, 3-klorfenyl, 3,4-diklorfenyl, 3-fluorfenyl, 3-metylfenyl, 3-fenoksyfenyl, 3-(4-klorfenoksy)fenyl, 2-klor-4-fluorfenyl, 2-klor-6-fluorfenyl, 2,4-dimetylfenyl, 2,5-dimetylfenyl, 2-bromfenyl, 2-fluorfenyl eller 2-(trifluormetyl)fenyl.
Spesielt foretrukket er ifølge oppfinnelsen bicykliske imidazo-3-yl-aminer valgt fra gruppen
(6-isocyano-heksyl)-(2-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-(6-isocyanoheksyl)-amin,
(2-cykloheksyl-imidazo[l,2-a]pyrazin-3-yl)-(6-isocyanoheksyl)-amin,
(2,6-dimetyl-fenyl)-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
(2-furan-2-yl-imidazo[l,2-a]pyrazin-3-ylamino)eddiksyremetylester,
(2-cykloheksyl-imidazo[l,2-a]pyrimidin-3-ylamino)eddiksyremetylester,
(2-metyl-imidazo[ 1,2-a]pyrazin-3-ylamino)eddiksyremetylester,
(2-pyridin-4-yl-imidazo[ 1,2-a]pyrazin-3-yl) 1,1,3,3-tetrametyl-butyl)-amin,
(2-metyl-imidazo[l ,2-a]pyrazin-3-yl)l ,1,3,3-tetrametyl-butyl)-amin,
3-(3-tert-butylamino-imidazo[ 1,2-a]pyridin-2-yl)fenol,
butyl-[2-(2,3-diklor-fenyl)-imidazo[ 1,2-a]p<y>razin-3-<y>l)-amin,
[(2-fenyl-imidazo [ 1,2-a]pyridin-3 -ylamino)-metyl] -fosforsyre,
te^butyl-(2-efrNbutyl-imidazo[l,2-a]pyridin-3-yl)-amin,
butyl-(2-o-tolyl-imidazo[l,2-a]pyrimidin-3-yl)-amin,
(2,6-dimetyl-fenyl)-[2-(2-metoksy-fenyl)-imidazo[l,2-a]pyrazin-3-yl)-arnin,
butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin,
te^butyl-(2-pyirdin-3-yl-imidazo[l,2-a]pyrimidin-3-yl)-arnin,
tert-butyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
[2-(lH-pyrrol-2-yl)-imidazo[ 1,2-a]pyrimidin-3-yl)-(l, 1,3,3-tetrametyl-butyl-amin),
cykloheksyl-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
tert-butyl-(2-pyridin-3-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
fer/-butyl-(2-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
ter^but<y>l-(2-tiofen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
cykloheksyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
N-cykloheksyl-N-[2-(5-metyl-furan-2-yl-imidazo[l,2-a]pyridin-3-yl)-acetamid,
ter^butyl-[2-(5-metylsulfanyl-tiofeii-2-^^
[2-(3 -brom-tiofen-2-yl-imidazo [ 1,2-a]pyridin-3 -y l)-cykloheksyl-amin,
eddiksyre-2-metoksy-4- [3 -(1,1,3,3-tetrametylbutylamino)-imidazo [ 1,2-a]pyrimidin-2-yl]-fenylester,
[2-(2-klor-4-fluor-fenyl)-imidazo[l,2-a]pyrimidin-3-yl]-(l,l,3,3-tetrametyft (2-antracen-9-yl-imidazo[ 1,2-a]pyrazin-3-yl]-teAtf-butyl-amin,
te^butyl-(2-natfalin-l-yl-imidazo[l,2-a]pyridin-3-yl]-arnin,
N-cykloheksyl-N-[2-(4,5-dimetyl-furan-2-yl)-imidazo[l,2-a]pyrimidin-3-yl]-ace^ eller
(1,1,3,3-terxametylbutyl)-[2-(3,4,5-rrimetoksyfenyl)-imidazo[ 1,2-a]pyridin-3-yl]-amin.
For så vidt at de bicykliske imidazo-3-yl-aminene ifølge oppfinnelsen innholder optisk aktive karbonatomer, er også enantiomerene av disse forbindelser og deres blandinger gjenstand for den foreliggende oppfinnelsen.
Gjenstand for oppfinnelsen er videre et legemiddel inneholdende som virkestoff minst et bicyklisk imidazo-3-yl-amin av den generelle formel I i hvilket R , R , R , X og Y har den ovenfor angitte betydning, i form av basen eller et farmasøytisk akseptabelt salt, fortrinnsvis av bromhydrogensyre, svovelsyre, metansulfonsyre, maursyre, eddiksyre, oksalsyre, ravsyre, vinsyre, mandelsyre, furmarsyre, melkesyre, sitronsyre, glutaminsyre og/eller asparaginsyre eller spesielt av saltsyre.
Overraskende ble herved funnet at forbindelsene ifølge oppfinnelsen ikke kun er potensielle virkestoffer for de innenfor den kjente teknikk nevnte indikasjonene men også viser analgetisk virkning.
Spesielt foretrukket inneholder legemidlene ifølge oppfinnelsen som virkestoff minst et bicykliske imidazo-3-yl-amin valgt fra gruppen
(6-isocyano-heksyl)-(2-pyirdin-2-yl-imidazo[l,2-aipyridin-3-yl)-amin,
(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-(6-isocyanoheksyl)-amin,
(2-cykloheksyl-imidazo[l,2-a]pyrazin-3-yl)-(6-isocyanoheksyl)-amin,
(2,6-dimetyl-fenyl)-(2-furan-2-yl-imidazo[ 1,2-a]p<y>irdin-3-<y>l)-amin,
(2-furan-2-yl-imidazo[ 1,2-a]pyrazin-3-ylamino)eddiksyremetylester,
(2-cykloheksyl-imidazo[l,2-a]pyrimidin-3-ylamino)eddiksyremetylester,
(2-metyl-imidazo[ 1,2-a]pyrazin-3-ylamino)eddiksyremetylester,
(2-pyridin-4-yl-imidazo [ 1,2-a]pyrazin-3 -yl) 1,1,3,3 -tetrametyl-butyl)-amin,
(2-metyl-imidazo[ 1,2-a]pyrazin-3-yl) 1,1,3,3-tetrametyl-butyl)-amin,
3-(3-tert-butylamino-imidazo[l,2-a]pyridin-2-yl)fenol,
butyl-[2-(2,3-diklor-fenyl)-imidazo[ 1,2-a]pyrazin-3-yl)-amin,
[(2-fenyl-imidazo[ 1,2-a]pyridin-3-ylamino)-metyl]-fosforsyre,
/e^butyl-(2-etr^butyl-imidazo[l,2-a]pyridin-3-yl)-amin,
butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin,
(2,6-dimetyl-fenyl)-[2-(2-metoksy-fenyl)-imidazo[l,2-a]pyrazin-3-yl)-amin,
butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin,
rert-butyl-(2-pyridin-3-yl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin,
ter?-butyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
[2-( 1 H-pyrrol-2-yl)-imidazo[ 1,2-a]pyrimidin-3 -yl)-( 1,1,3,3 -tetrametyl-butyl-amin),
cykloheksyl-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
fe^butyl-(2-pyirdin-3-yl-imidazo[l,2-a]pyridin-3-yl)-amin,
/er/-butyl-(2-pyridin-2-yl-imidazo[ 1,2-a]p<y>ridin-3-<y>l)-amin,
te^-butyl-(2-tiofen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
cykloheksyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
N-cykloheksyl-N-[2-(5-metyl-mran-2-yl-imidazo[l,2-a]pyridin-3-yl)-acetamid,
terf-butyl- [2-(5 -metylsulfanyl-tiofen-2-yl-imidazo[ 1,2-a]pyrimidin-3 -yl)-amin,
[2-(3-brom-tiofen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-cykloheksyl-arnin,
eddiksyre-2-metoksy-4-[3-(l,l,3,3-tetrametylbutylamino)-imidazo[l,2-a]pyrimidin yl]-fenylester,
[2-(2-klor-4-fluor-fenyl)-imidazo[l,2-a]pyirmidin-3-yl]-(l,l,3,3-tetrametylbutyl)-am (2-antracen-9-yl-imidazo[ 1,2-a]pyrazin-3-yl]-etrr-butyl-amin,
te^butyl-(2-naftalin-l-yl-imidazo[l,2-a]pyridin-3-yl]-amin,
N-cykloheksyl-N- [2-(4,5 -dimetyl-furan-2-yl)-imidazo[ 1,2-a]pyrimidin-3 -yl] -acetamid, eller
(1,1,3,3 -tetrametylbutyl)- [2-(3,4,5 -trimetoksyfenyl)-imidazo[ 1,2-a]pyridin-3-yl] -amin.
eller de farmasøytisk akseptable saltene av disse forbindelsene.
Videre omfatter foreliggende oppfinnelse anvendelsen av minst et bicyklisk imidazo-3-yl-amin ifølge oppfinnelsen sammen med et eller flere hjelpestoffer for fremstilling av et legemiddel for bekjempelse av smerte.
Foreliggende oppfinnelse omfatter også en fremgangsmåte for bicykliske imidazo-3-yl-aminer ifølge oppfinnelsen ved trekomponentreaksjon av amidin, aldehyd og isonitril, kjennetegnet ved at syntensen av forbindelsene foregår i diklormetan som løsemiddel og i nærvær av perklorsyre, hvor utgangsforbindelsene tilsettes
etterhverandre i rekkefølgen amidin, aldehyd og isonitril og de dannede produktene eventuelt etterfølgende omsettes med en forbindelse R<2>Hal eller et isocyanat R^CO.
For fremstilling av tilsvarende legemidler anvendes ved siden av minst et virkestoff ifølge oppfinnelsen et eller flere hjelpestoffer, fortrinnsvis bæremateriale, fyllstoffer, løsemidler, fortynningsmidler, fargestoffer og/eller bindemidler. Valget av hjelpestoffer så vel som den anvendte mengde av disse avhenger av om legemidlet skal administreres oralt, intravenøst, interperitonelt, intradermalt, intramuskulært, intranasalt, bukalt eller lokalt. For oral administrering er preparater i form av tabletter, drageer, kapsler, granulater, dråper, safter og siruper egnet, for den parenterale, topiske og innhalative administrering er oppløsninger, suspensjoner, lett rekonstruerbare tørr tilberedninger så vel som spray egnet. Virkestoffer ifølge oppfinnelsen i et depot, i oppløst form eller i et plaster, eventuelt under anvendelsen av hudpenetreringsfremmende midler er egnede perkutane administreringspreparater. Oral eller perkutan anvendbare preparatformer kan frigi virkestoffene ifølge oppfinnelsene forsinket.
Virkestoffmengden som skal administreres til pasientene varierer avhengig av vekten til pasienten, administreirngsmåten, indikasjonen og sværhetsgraden av sykdommen.
Syntensen av forbindelsene ifølge oppfinnelsen foregår på den måte at man omsetter amidiner med den generelle formelen II, spesielt 2-aminopyridin, 2-aminopyrazin og 2-amionpyrimidinderivater som tilbys kommersielt fra bedrifter som eksempelvis Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma eller TCI-Jp, med forskjellige ketoner eller fortrinnsvis aldehyder III og isonitriler IV i nærvær av 20% perklorsyre ifølge en trekomponentreaksjon. R<1> til R<3>, X og Y har herved de ovenfor for forbindelser av formel I angitte betydning.
For et problemfritt forløp av reaksjonen er det herved vesentlig at utgangsforbindelsene tilsettes etter hverandre i rekkefølgen amidin II, aldehyd III og isonitril IV. Fortrinnsvis blir reaksjonen gjennomført i diklormetan ved en temperatur på fortrinnsvis 0°C til 40°C, spesielt ved en temperatur fra 10°C til 20°C.
For fremstilling av forbindelsene ifølge oppfinnelsen i hvilke R<2> ikke betyr hydrogen, blir de i den foregående beskrevne reaksjon dannede forbindelser Ia som fortrinnsvis først oppløses i THF, alt etter ønsket sluttprodukt omsatt med en forbindelse R<2>Hal, hvor Hal står for brom, jod eller spesielt klor, eksempelvis et eventuelt substituert alkyl-, aryl- eller syreklorid eller et eventuelt substituert isocyanat R^CO i nærvær av en morfolin-harpiks (for eksempel polystyren-morfolin fra firmaet Argonaut) i diklormetan i løpet av 2 til 24 timer ved temperaturer mellom 10°C og 40°C ifølge det følgende reaksjonsskjema:
Overskuddet av reagenser blir etterfølgende fjernet fra reaksjonsblandingen ved filtrering over et sjikt med polymerbundet tris(2-aminoetyl)amin (Fremstiller: Novabiochem) eller 3-(3-merkaptofenyl)propanamidornetylpolystyren og filtratet oppkonsentrert fortrinnsvis i en vakuumsentrifuge. Hele fremgangsmåten lar seg uten videre også gjennomføre i et automatisert synteseanlegg.
Forbindelsene av formel I lar seg på for så vidt kjent måte overføre i deres salter med fysiologisk godtagbare syre, fortrinnsvis bromhydrogensyre, svovelsyre, metansulfonsyre, maursyre, eddiksyre, oksalsyre, ravsyre, vinsyre, mandelsyre, fumarsyre, melkesyre, sitronsyre, glutaminsyre og/eller asparaginsyre. Fortrinnsvis blir saltdannelsen gjennomført i et løsemiddel fortrinnsvis dietyleter, diisopropyleter, eddiksyrealkylester, aceton eller 2-butanon eller en blanding av disse løsemidler. For fremstilling av hydrokloridet egner seg alternativt også trimetylsilan i vandig oppløsning.
Eksempler:
De følgende eksemplene skal forklare oppfinnelsen.
Generell fremgangsmåte 1 (automatisk syntese)
Syntesen foregikk på et automatisk anlegg til firmaet Zymark ifølge følgende generell syntesefremgangsmåte: Et lite rundbunnet rør av glass (diameter 16 mm, lengde 125 mm) med gjenge ble manuelt utstyrt med en omrører og på Capper-stasjonen lukket med et skruelokk med septum. Røret ble av robot 1 anbrakt på den 15°C tempererte reaktorblokk. Robot 2 tilpipitterte etterhverandre følgende reagenser:
1. ) 1 ml av en 0,1 M amidinoppløsning + 20% HCIO4 i diklormetan
2. ) 0,5 ml av en 0,3 M aldehydoppløsning i diklormetan
3. ) 0,575 ml av en 0,2 M isonitriloppløsning i diklormetan.
Reaksjonsblandingen ble omrørt ved 15°C i en av røreblokkene i 660 minutter. Deretter ble reaksjonsoppløsningen filtrert ved filtreringsstasjonen. Røret ble herved spylet to ganger med hver gang 1 ml diklormetan og 200 ul vann.
Stativet med rør ble etterfølgende manuelt anbrakt på opparbeidningsanlegget. Der ble reaksjonsblandingen på en vortex omsatt med 3 ml av en 10% NaCl-oppløsning og 1,5 ml diklormetan. I spinn-reaktoren ble det blandet grundig i 10 minutter og ved langsom reduksjon av dreiebevegelsen ble det dannet en tydelig fasegrense. Denne fasegrensen ble detektert optisk og den organiske fasen pipittert av. I det neste trinn ble reaksjonsblandingen igjen omsatt med 1,5 ml diklormetan. Oppløsningen ble rystet, sentrifugert og den organiske fasen pipittert av. De samlede organiske fasene ble tørket over 2,4 g MgS04 (granulert). Løsemidlet ble fjernet i en vakuumsentrifuge.
Generell fremgangsmåte 2 (manuell syntese)
(Ekvivalent betyr molekvivalent basert på det anvendte isonitril):
I en egnet reaktorbeholder ble først 1,15 ekvivalenter av det heterocykliske amin suspendert hhv. oppløsti diklormetan (2 ml pr. mmol anvendt isonitril). Hertil ble det etterhverandre tilsatt 1,5 ekvivalenter aldehyd, en ekvivalent isonitril og etterfølgende vandig perklorsyre (20 m%, 0,098 ml pr. mmol anvendt isonitril) og satsen omrørt i 20 timer ved romtemperatur. Til opparbeidning ble mettet natriumkloridoppløsning (ca. 5 ml pr. mmol anvendt isonitril) og diklormetan (ca. 4 ml pr. mmol anvendt isonitril) tilsatt, fasen adskilt og den organiske fasen ekstrahert enda to ganger med diklormetan (hver gang ca. 2 ml pr. mmol anvendt isonitril). De samlede organiske fasene ble vasket etterhverandre med bufferoppløsning (pH 10; ca. 2 ml pr. mmol anvendt isonitril) og mettet natriumkloirdoppløsning (ca. 2 ml pr. mmol anvendt isonitril), tørket over natriumsulfat, filtrert og inndampet på rotasjonsinndamper i vakuum og befriet for løsemiddelrester ved oljepumpevakuum.
De anvendte kjemikaliene og løsemidlene ble oppnådd kommersielt. Hver substans ble analysert med ESI-MS og/eller NMR.
Generell fremgangsmåte 3 (omsetning med acetylklorid)
Det etter den generelle fremgangsmåten 1 oppnådde produkt ble oppløst i diklormetan, omsatt med 4 molekvivalenter acetylklorid og omrørt i 4 timer ved 18°C. Overskuddet av acetylklorid og løsemidlet ble fjernet i vakuum ved 40-60°C. Hver substans ble analysert med ESI-MS.
Eksempel 1
(6-isocyano-heksyl)-(2-pyirdin-2-yl)-imidazo [ 1,2-a]pyridin-3 -yl)-amin
(1)
Forbindelse 1 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,6-diisocyanheksan-opp løsning (0,2M, DCM), 0,500 ml pyridin-2-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 321,43;
funnet masse M-H = 320,4 (ESI-MS)
Eksempel 2
(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-(6-isocyanoheksyl)-amin
(2)
Forbindelse 2 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,6-diisocyanheksan-oppløsning (0,2M, DCM), 0,500 ml furfural-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 310,40;
funnet masse M-H = 309,4 (ESI-MS)
Eksempel 3
(2-cykloheksyl-imidazo[ 1,2-a]pyrazin-3-yl)-(6-isocyanoheksyl)-amin
(3)
Forbindelse 3 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,6-diisocyanheksan-oppløsning (0,2M, DCM), 0,500 ml cykloheksankarbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 327,48;
funnet masse M-H = 326,5 (ESI-MS)
Eksempel 4
(2,6-dimetyl-fenyl)-(2-furan-2-yl-imidazo[l,2-a]pyridin-3-yl)-amin
(4)
Forbindelse 4 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 2,6-dimetylfenylisonitril-oppløsning (0,2M, DCM), 0,500 ml furfural-oppløsning (0.3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 303,37;
funnet masse M-H = 304,4 (ESI-MS)
Eksempel 5
(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-eddiksyremetylester
(5)
Forbindelse 5 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml aminopyrazin-oppløsning (0,1M, DCM), 0,575 ml isocyanoeddiksyremetylester-oppløsning (0,2M, DCM), 0,500 ml furfural-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 272,27;
funnet masse M-H = 273,4 (ESI-MS)
Eksempel 6
(2-cykloheksyl-imidazo[l,2-a]pyirmidin-3-yl)-eddiksyremetylester
(6)
Forbindelse 6 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyrimidin-oppløsning (0,1M, DCM), 0,575 ml isocyanoeddiksyremetylester-oppløsning (0,2M, DCM), 0,500 ml cykloheksylkarbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 288,35;
funnet masse M-H = 289,4 (ESI-MS)
Eksempel 7
(2-metyl-imidazo[ 1,2-a]pyrazin-3-ylamino)-eddiksyremetylester
(7)
Forbindelse 7 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml aminopyrazin-oppløsning (0,1M, DCM), 0,575 ml isocyanoeddiksyremetylester-oppløsning (0,2M, DCM), 0,500 ml acetaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 220,23;
funnet masse M-H = 221,3 (ESI-MS)
Eksempel 8
(2-pyridin-4-yl-imidazo[l,2-a]pyrazin-3-yl)-(l,l,3,3-tetrametyl-butyl)-amin
(8)
Forbindelse 8 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml aminopyrazin-oppløsning (0,1M, DCM), 0,575 ml 1,1,3,3-tetrametylbutylisocyanid (0,2M, DCM), 0,500 ml pyridin-4-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 323,44;
funnet masse M-H = 324,4 (ESI-MS)
Eksempel 9
(2-metyl-imidazo[ 1,2-a]pyrazin-3-yl)-(l, 1,3,3-tetrametyl-butyl)-amin
(9)
Forbindelse 9 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml aminopyrazin-oppløsning (0,1M, DCM), 0,575 ml 1,1,3,3-tetrametylbutylisocyanid
(0,2M, DCM), 0,500 ml acetaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 260,39;
funnet masse M-H = 261,4 (ESI-MS)
Eksempel 10
3-(3-tert-butylamino-imidazo[ 1,2-a]pyridin-2-yl)-fenol
(10)
Forbindelse 10 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml terf.-butylisonitril-oppløsning (0,2M, DCM), 0,500 ml 3-hydroksybenzaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 281,36;
funnet masse M-H = 282,3 (ESI-MS)
Eksempel 11
Butyl-[2-(2,3-diklor-fenyl)-imidazo[ 1,2-a]pyrazin-3-yl)-amin
(11)
Forbindelse 11 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml aminopyrazin-oppløsning (0,1M, DCM), 0,575 ml n-butylisonitril-oppløsning (0,2M, DCM), 0,500 ml 2,3-diklorbenzaldehydpyridin-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 335,24;
funnet masse M-H = 335,4 (ESI-MS)
Eksempel 12
[(2-fenyl-imidazo[ 1,2-a]pyirdin-3-ylamino)-metyl]-fosfonsyredietylester
(12)
Forbindelse 12 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin-dietylisocyanometylfosfat, benzaldehyd og perklorsyre (W = 20%). Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 13
rert-butyl-(2-fe/"f-butyl-imidazo[l,2-a]pyirdin-3-yl)-amin
(13)
Forbindelse 13 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin, tert.-butylisonitril, pivaldehyd og perklorsyre. Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 14
Butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin
(14)
Forbindelse 14 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml n-butylisonitril-oppløsning (0,2M, DCM), 0,500 ml 2-metylbenzaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 280,38;
funnet masse M-H = 281,3 (ESI-MS)
Eksempel 15
(2,6-dimetyl-fenyl)-[2-(2-metoksy-fenyl)-imidazo[l,2-a]pyrazin-3-yl)
(15)
Forbindelse 15 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml aminopyrazin-oppløsning (0,1M, DCM), 0,575 ml 2,6-dimetylfenylisocyanid-oppløsning (0,2M, DCM), 0,500 ml 2-metoksybenzaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 344,42;
funnet masse M-H = 345,4 (ESI-MS)
Eksempel 16
Butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin
(16)
Forbindelse 16 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml n-butylisonitril-oppløsning (0,2M, DCM), 0,500 ml 2-metylbenzaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 280,38;
funnet masse M-H = 281,3 (ESI-MS)
Eksempel 17
tert-butyl-(2-pyridin-3-yl-imidazo[l,2-a]pyrimidin-3-yl)-amin
(17)
Forbindelse 17 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml terf.-butylisonitril-oppløsning (0,2M, DCM), 0,500 ml pyridin-4-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 267,34;
funnet masse M-H = 268,3 (ESI-MS)
Eksempel 18
ter/-butyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin
(18)
Forbindelse 18 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml ter^butylisonitril-oppløsning (0,2M, DCM), 0,500 ml acetaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 203,29;
funnet masse M-H = 204,3 (ESI-MS)
Eksempel 19
[2-(lH-pyrrol-2-yl)-imidazo[ 1,2-a]pyrimidin-3-yl]-l, 1,3,3-tetrametyl-butyl)-amin
(19)
Forbindelse 19 ble fremstilt ifølge den generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,1,3,3-tetrametylbutyl-isocyanid-oppløsning (0,2M, DCM), 0,500 ml pyrrol-2-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 311,43;
funnet masse M-H = 312,4 (ESI-MS)
Eksempel 20
(cykloheksyl-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin
(20)
Forbindelse 20 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin, cykloheksylisonitril, furfural og perklorsyre. Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 21
fe^butyl-(2-pyirdin-3-yl-imidazo[l,2-a]pyirdin-3-yl)-amin
(21)
Forbindelse 21 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin, tert-butylisonitril, nikotinaldehyd og perklorsyre. Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 22
tert-butyl-(2-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin
(22)
Forbindelse 22 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin, terf-butylisonitril, 2-pyridylkarbaldehyd og perklorsyre. Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 23
terf-butyl-(2-tiofen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin
(23)
Forbindelse 23 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin, terf-butylisontril, tiofen-2-karbaldehyd og perklorsyre. Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 24
(cykloheksyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin
(24)
Forbindelse 24 ble fremstilt ifølge generelle fremgangsmåte 2 ut fra 2-aminopyridin, cykloheksylisonitril, acetaldehyd og perklorsyre. Strukturen ble bekreftet ved NMR-spektroskopi.
Eksempel 25
N-cykloheksyl-N-[2-(5-metyl-mran-2-yl)-imidazo[l,2-a]pyirmidin-3-(25)
Forbindelse 25 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml cykloheksylisocyanid-oppløsning (0,2M, DCM), 0,500 ml 5-metylfurfural-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%) oppnådde produkt med acetylklorid ifølge generell fremgangsmåte 3.
Beregnet masse 337,4;
funnet masse 338,5;
M-acetyl 296,5 (ESI-MS)
Eksempel 26
rer/-butyl-[2-(5-metylsulfanyl-tiofen-2-yl)-imidazo[l,2-a]pyrimidin-3-yl)-amind
(26)
Forbindelse 26 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml tert-butylisonitrilisocyanid-oppløsning (0,2M, DCM), 0,500 ml 5-metylsulfanyl-tiofen-2-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 318,5;
funnet masse 319,2 (ESI-MS)
Eksempel 27
[2-(3 -brom-tiofen-2-yl)-imidazo [ 1,2-a]pyridin-3-yl] -cykloheksyl-amin
(27)
Forbindelse 27 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml cykloheksylisocyanid-oppløsning (0,2M, DCM), 0,500 ml 3-bromtiofen-2-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 376,3;
funnet masse 376,4/378,3 (ESI-MS)
Eksempel 28
Eddiksyre-2-metoksy-4-[3-(l,l,3,3-tetrametylbutylamino)-imidazo[l,2-a]pyrimidin-2-yl]-fenylester
(28)
Forbindelse 28 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,1,3,3-tetrametylbutylisocyanid-oppløsning (0,2M, DCM), 0,500 ml eddiksyre-4-formyl-2-metoksy-fenylester-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 410,5;
funnet masse 411,3 (ESI-MS)
Eksempel 29
[2-(2-klor-4-fluor-fenyl)-imidazo[ 1,2-a]pyrimidin-3-yl]-(l, 1,3,3-tetrametylbutyl)-amin
(29)
Forbindelse 29 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,1,3,3-tetrametylbutylisocyanid-oppløsning (0,2M, DCM), 0,500 ml 2-klor-4-fluorbenzaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 374,9;
funnet masse 375,3 (ESI-MS)
Eksempel 30
(2-antracen-9-yl-imidazo[ 1,2-a]pyrazin-3-yl]-/ert-butyl-amin
(30)
Forbindelse 30 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml tert-butylisocyanid-oppløsning (0,2M, DCM), 0,500 ml antracen-9-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 366,5;
funnet masse 367,3 (ESI-MS)
Eksempel 31
tert-butyl-(2-naftalin-1 -yl)imidazo[ 1,2-a]pyridin-3-yl]-amin
(31)
Forbindelse 31 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml tert-butylisocyanid-oppløsning (0,2M, DCM), 0,500 ml naftalin-1-karbaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 315,4;
funnet masse 316,3 (ESI-MS)
Eksempel 32
N-cykloheksyl-N-[2-(4,5-dimetyl-furan-2-yl)-imidazo[l,2-a]pyrimidin-3-yl]-acetamid
(32)
Forbindelse 32 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml cykloheksylisocyanid-oppløsning (0,2M, DCM), 0,500 ml 4,5-dimetylfurfural-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%) oppnådde produkt med acetylklorid ifølge den generelle fremgangsmåten 3.
Beregnet masse 352,4;
funnet masse 353,4 (ESI-MS)
Eksempel 33
(1,1,3,3-tetrametylbutyl)-[2-(3,4,5-trimetoksyfenyl)-imidazo[ 1,2-a]pyridin-3-yl]-amin
(33)
Forbindelse 28 ble fremstilt ved omsetning av det ifølge generelle fremgangsmåten 1 ut fra 1,0 ml 2-aminopyridin-oppløsning (0,1M, DCM), 0,575 ml 1,1,3,3-tetrametylbutylisocyanid-oppløsning (0,2M, DCM), 0,500 ml 3,4,5-trimetoksybenzaldehyd-oppløsning (0,3M, DCM) og 10 ul perklorsyre (W = 20%).
Beregnet masse 411,5;
funnet masse 412,3 (ESI-MS)
Analgesiprøvning i Writhing-test på mus
Undersøkelsen av analgetisk effektivitet ble gjennomført i fenylkinon-indusert Writing-test på mus (modifisert ifølge I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125,237-240 (1959)). Hertil ble det anvendt mannlige NMRI-mus med vekt på 25-30 g. Grupper av 10 dyr pr. substansdosis mottok 10 minutter etter intravenøs eller subkutan administrering av prøvesubstansen 0,3 ml/mus en 0,02 % vandig oppløsning av fenylkinon (fenylbenzokinon, Fa. Sigma, Deisenhofen; fremstilling av oppløsning under tilsetning av 5% etanol og oppbevaring i vannbad ved 45°C) administrert intraperitonelt. Dyrene ble enkeltvis anbrakt i observasjonsbur. Ved hjelp av en trykknappteller ble antallet av smerteinduserte strekkbevegelser (såkalte Writhing-reaksjoner = gjennomtrykning av kroppen med utstrekning av bakbenene) talt i 5-20 minutter etter fenylkinon-administreringen. Som kontroll ble det ført med dyr som kun fikk fysiologisk kokesaltoppløsning. Substituentene ble testet i standarddoseringer på 10 mg/kg intravenøst eller 21,5 mg/kg subkutant. Den prosentuelle hemming (%-hemming) av Writhing-reaksjonen gjennom en substans ble beregnet etter følgende formel:
De undersøkte forbindelsene ifølge oppfinnelsen viste en analgetisk virkning. Resultatene er sammenfattet i den etterfølgende tabellen.
Claims (7)
1.
Bicykliske imidazo-3-yl-aminer av den generelle formel I,
hvor
X og Y betyr CH eller N med det forbehold at X og Y ikke samtidig kan bety N,
R<1> betyr tert-butyl, (CH2)nCN med n = 4, 5 eller 6, eventuelt med CH3 substituert fenyl, C4-C8-cykloalkyl, CH2CH2R (R = 4-morfolino), 1,1,3,3,-tetrametylbutyl eller CH2R<a>, hvor Ra står for hydrogen, OH, Ci-Cg-alkyl (forgrenet eller uforgrenet), fenyl, CO(OR') (med R' = uforgrenet Ci-C4-alkyl eller forgrenet Ci-C5-alkyl), PO(OR')2 (med R' = uforgrenet Ci-C4-alkyl eller forgrenet Ci-C5-alkyl) eller Si(R<x>R<*>R<z>) (hvor Rx, Ry og R<z >respektivt uavhengig av hverandre betyr Ci-C8-alkyl (forgrenet eller uforgrenet), C4-C8-cykloalkyl eller fenyl),
R<2> betyr hydrogen, COR<b>, hvor R<b> står Ci-C4-alkyl (forgrenet eller uforgrenet) eller C3-C8-cykloalkyl, eller R<2> betyr for CH2CH2CO(OR<c>) (hvor R<c> står for Ci-C4-alkyl (forgrenet eller uforgrenet), adamantyl, fenyl, 1-naftyl eller 2-naftyl eller 2-pyridyl, 3-pyridyl, 4-pyridyl, tiazolyl eller furoyl, eller R<2> betyr for CH2fenyl, CH2CH2R<d>, hvor Rd står for fenyl, eller R<2> betyr CONHR<e>, hvor Re står for Ci-C8-alkyl (forgrenet eller uforgrenet), C3-C8-cykloalkyl eller fenyl,
R<3> betyr metyl, etyl, terf-butyl, C3-C8-cykloalkyl, fenyl eventuelt substituert en gang i 3-, 5- eller 6-posisjon med CH3, OH, OCH3, Cl, NC(0)CH3, Br, F, fenoksy, 4-C1-fenoksy eller CF3 eller eventuelt substituert flere ganger i 4-posisjon og ytterligere i 2-og/eller 3- og/eller 5- og/eller 6-posisjon med CH3, OH, OCH3, Cl, NC(0)CH3, Br, F, fenoksy, 4-Cl-fenoksy eller CF3; - eller R<3> betyr fenoksy, naftyl, pyrrol, pyridyl, furan, tiofen, antracen, fenantren eller kinolin,
med det forbehold at R<3> ikke betyr n-propyl, cykloheksyl, usubstituert fenyl eller på 3-posisjonen med en karboksylsyreamidgruppe monosubstituert fenyl, når R<1> betyr tert-butyl, n-propyl, n-butyl, 1,1,3,3-tetrametylbutyl, cykloheksyl, CH2CH2R (R = 4-morfolino), monosubstituert fenyl, 2,6, -dimetylfenyl eller benzyl og R<2> samtidig betyr hydrogen eller -CO(metyl), og at R *? ikke betyr hydrogen når R 1 samtidig betyr benzyl og R<3> betyr metyl eller når R<1> samtidig betyr CH2C(0) tert-butyl og R<3> betyr usubstituert fenyl;
i form av deres baser eller farmasøytiske akseptable salter.
2.
Bicykliske imidazo-3-yl-aminer ifølge krav 1, karakterisert ved at R<2> betyr hydrogen, R<1> er valgt fra gruppen (CH2)nCN med n = 4, 5 eller 6, cykloheksyl, CH2CO (Ometyl), 2,6-dimetylfenyl, 1,1,3,3-tetrametylbutyl, tert-butyl eller n-butyl og R<3> er valgt fra gruppen 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrroyl, metyl, terf-butyl, 3-hydroksyfenyl, 3,4-dimetoksyfenyl, 2,3-diklorfenyl, 2,4-diklorfenyl, 2-metoksyfenyl, 2,3-dimetoksyfenyl, 3-bromfenyl, 4-brom-2-fluorfenyl, 5-brom-2-fluorfenyl, 3-brom-4-fluorfenyl, 3-klorfenyl, 3,4-diklorfenyl, 3-fluorfenyl, 3-metylfenyl, 3-fenoksyfenyl, 3-(4-klorfenoksy)fenyl, 2-klor-4-fluorfenyl, 2-klor-6-fluorfenyl, 2,4-dimetylfenyl, 2,5-dimetylfenyl, 2-bromfenyl, 2-fluorfenyl eller 2-(trifluormetyl)fenyl.
3.
Bicykliske imidazo-3-yl-aminer ifølge krav 1 eller 2, karakterisert ved at det dreier seg om (6-isocyano-heksyl)-(2-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yi)-amin, (2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-(6-isocyanoheksyl)-amin, (2-cykloheksyl-imidazo [ 1,2-a]pyrazin-3 -yl)-(6-isocyanoheksyl)-amin, (2,6-dimetyl-fenyl)-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin, (2-furan-2-yl-imidazo[ 1,2-a]pyrazin-3-ylamino)eddiksyremetylester,
(2-cykloheksyl-imidazo[l,2-a]pyrimidin-3-ylamino)eddiksyremetylester, (2-metyl-imidazo[ 1,2-a]pyrazin-3-ylamino)eddiksyremetylester, (2-pyridin-4-yl-imidazo[ 1,2-a]pyrazin-3-yl) 1,1,3,3-tetrametyl-butyl)-amin, (2-metyl-imidazo[ 1,2-a]pyrazin-3-yl) 1,1,3,3-tetrametyl-butyl)-amin, 3-(3-tert-butylamino-imidazo[ 1,2-a]pyridin-2-yl)fenol, butyl-[2-(2,3-diklor-fenyl)-imidazo[ 1,2-a]pyrazin-3-yl)-amin, [(2-fenyl-imidazo[ 1,2-a]pyridin-3-ylamino)-metyl]-fosforsyre, /m-butyl-(2-te/-/-butyl-imidazo[ 1,2-a]pyridin-3-yl)-amin, butyl-(2-o-tolyl-irmdazo[l,2-a]pyrimidin-3-yl)-amin, (2,6-dimetyl-fenyl)-[2-(2-metoksy-fenyl)-imidazo[l,2-a]pyrazm-3-yl)-amin, butyl-(2-o-tolyl-imidazo[l,2-a]pyrimidin-3-yl)-amin, tert-butyl-(2-pyridin-3-yl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin, te^but<y>l-(2-met<y>l-irnidazo[l,2-a]pyridin-3-yl)-arnin,
[2-( 1 H-pyrrol-2-yl)-imidazo[ 1,2-a]pyrimidin-3-yl)-(l, 1,3,3-tetrametyl-butyl-amin), cykloheksyl-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin, fm-butyl-(2-pyirdin-3-yl-imidazo[l,2-a]pyridin-3-yl)-amin, ter/-butyl-(2-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin, ter?-butyl-(2-tiofen-2-yl-imidazo[ 1,2-a]p<y>ridin-3-<y>l)-amin, cykloheksyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-arnin,
N-cykloheksyl-N- [2-(5-metyl-furan-2-yl-imidazo [ 1,2-a]pyridin-3 -yl)-acetamid, ^e^butyl-[2-(5-metylsulfanyl-tiofen-2-yl-imidazo[l,2-a]pyirmidin-3-yl)-amin, [2-(3-brom-tiofen-2-yl-irmdazo[l,2-a]pyridin-3-yl)-cykloheksyl-amin, eddiksyre-2-metoksy-4-[3-(l,l,3,3-tetrametylbutylamino)-imidazo[l,2-a]pyrimidin-2^ yl]-fenylester,
[2-(2-klor-4-fluor-fenyl)-imidazo[ 1,2-a]pyrimidin-3-yl]-(l, 1 ,3,3-tetrametylbutyl)-amin, (2-antracen-9-yl-irnidazo[l,2-a]pyrazin-3-yl]-etrt-butyl-amin, te^butyl-(2-natfalin-l-yl-imidazo[l,2-a]pyridin-3-yl]-amin, N-cykloheksyl-N-[2-(4,5 -dimetyl-furan-2-yl)-imidazo [ 1,2-a]pyrimidin-3 -yl] -acetamid, eller (lJ,3,3-tetrametylbutyl)-[2-(3,4,5-trimeto
4.
Legemiddel inneholdende som virkestoff minst et bicyklisk imidazo-3-yl-amin av den generelle formelen I ifølge krav 1, i hvilket R<1>, R<2>, R<3>, X og Y har den i krav 1 angitte betydning, i form av basen eller et farmasøytisk akseptabelt salt.
5.
Legemiddel ifølge krav 4, karakterisert ved at det som virkestoff inneholder minst et bicyklisk imidazo-3-yl-amin valgt fra gruppen (6-isocyano-heksyl)-(2-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-amin, (2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-(6-isocyanoheksyl)-amin, (2-cykloheksyl-imidazo[l,2-a]pyrazin-3-yl)-(6-isocyanoheksyl)-amin, (2,6-dimetyl-fenyl)-(2-furan-2-yl-imidazo[l,2-a]pyridin-3-yl)-amin, (2-furan-2-yl-imidazo[l,2-a]pyraa^ (2-cykloheksyl-imidazo[l,2-a]pyrimidin-3-ylamino)eddiksyremetylester, (2-metyl-imidazo[l ,2-a]pyrazin-3-ylamino)eddiksyremetylester, (2-pyridin-4-yl-imidazo[ 1,2-a]pyrazin-3-yl) 1,1,3,3-tetrametyl-butyl)-amin, (2-metyl-imidazo[ 1,2-a]pyrazin-3-yl) 1,1,3,3-tetrametyl-butyl)-amin, 3-(3-tert-butylarnino-imidazo[ 1,2-a]pyridin-2-yl)fenol, butyl-[2-(2,3-diklor-fenyl)-imidazo[ 1,2-a]pyrazin-3-yl)-amin, [(2-fenyl-imidazo[ 1,2-a]pyridin-3-ylamino)-metyl]-fosforsyre, tert-butyl-(2-ter/-butyl-imidazo[ 1,2-a]pyridin-3-yl)-amin, butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin, (2,6-dimetyl-fenyl)-[2-(2-metoksy-fenyl)-imidazo[l,2-a]pyrazm-3-yl)-arnin, butyl-(2-o-tolyl-imidazo[ 1,2-a]pyrimidin-3-yl)-amin, ter^butyl-(2-pyirdin-3-yl-imidazo[l,2-a]pyrimidin-3-yl)-amin, tert-butyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
[2-( 1 H-pyrrol-2-yl)-imidazo[ 1,2-a]pyrimidin-3-yl)-( 1,1,3,3-tetrametyl-butyl-amin), cykloheksyl-(2-furan-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin, terf-butyl-(2-pyridin-3-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin, ter/-butyl-(2-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin,
tert-butyl-(2-tiofen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-amin, cykloheksyl-(2-metyl-imidazo[ 1,2-a]pyridin-3-yl)-amin, N-cykloheksyl-N-[2-(5-metyl-furan-2-yl-imidazo[l,2-a]pyri(hn-3 te^butyl-[2-(5-metylsulfanyl-tiofen-2-yl-imidazo[l,2-a]pyrimidin-3-yl)-ami^ [2-(3-brom-tiofen-2-yl-imidazo[l,2-a]pyridin-3-yl)-cykloheksyl-arrun, eddiksyre-2-metoksy-4-[3-(l,l,3,3-tetrametylbutylam^ yl]-fenylester,
[2-(2-klor-4-fluor-fenyl)-imidazo[ 1,2-a]pyirmidin-3-yl]-(l, 1,3,3-tetrametylbutyl)-amin, (2-antracen-9-yl-imidazo[ 1,2-a]pyrazin-3-yl]-fer/-butyl-amin, te^butyl-(2-natfalin-l-yl-imidazo[l,2-a]pyridin-3-yl]-amin, N-cykloheksyl-N-[2-(4,5-dimetyl-furan-2-yl)-imi^ eller (1,1,3,3-tetrametylbutyl)-[2-(3,4,5-trimetoksyfenyl)-imidazo[ 1,2-a]pyridin-3-yl]-amin. eller de farmasøytisk akseptable saltene av disse forbindelser.
6.
Anvendelse av minst et bicyklisk imidazo-3-yl-amin ifølge krav 1,2 eller 3 sammen med et eller flere hjelpestoffer for fremstilling av et legemiddel for bekjempelse av smerte.
7.
Fremgangsmåte for fremstilling av bicykliske imidazo-3-yl-aminer ifølge krav 1,2 eller 3 ved trekomponentreaksjon av amidin, aldehyd og isonitril, karakterisert ved at syntensen av forbindelsene foregår i diklormetan som løsemiddel og i nærvær av perklorsyre, hvor utgangsforbindelsene tilsettes etterhverandre i rekkefølgen amidin, aldehyd og isonitril og de dannede produktene eventuelt etterfølgende omsettes med en forbindelse R<2>Hal eller et isocyanat R^CO.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1999148438 DE19948438B4 (de) | 1999-10-08 | 1999-10-08 | Bicyclische Imidazo-3-aminderivate |
| DE19948434A DE19948434A1 (de) | 1999-10-08 | 1999-10-08 | Substanzbibliothek enthaltend bicyclische Imidazo-5-amine und/oder bicyclische Imidazo-3-amine |
| PCT/EP2000/009096 WO2001027111A2 (de) | 1999-10-08 | 2000-09-18 | Bicyclische imidazo-3-yl-aminderivate |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20021565D0 NO20021565D0 (no) | 2002-04-03 |
| NO20021565L NO20021565L (no) | 2002-05-27 |
| NO322754B1 true NO322754B1 (no) | 2006-12-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20021565A NO322754B1 (no) | 1999-10-08 | 2002-04-03 | Bicykliske imidazo-3-yl-aminderivater, legemiddel inneholdende disse, deres anvendelse for fremstilling av et legemiddel samt en fremgangsmate for fremstilling av derivatene. |
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| US (1) | US6638933B2 (no) |
| EP (1) | EP1218382B1 (no) |
| JP (1) | JP2003511451A (no) |
| KR (1) | KR100756592B1 (no) |
| CN (1) | CN1257169C (no) |
| AR (1) | AR025962A1 (no) |
| AT (1) | ATE258554T1 (no) |
| AU (1) | AU779197B2 (no) |
| BR (1) | BR0014818A (no) |
| CA (1) | CA2382919C (no) |
| CO (1) | CO5251378A1 (no) |
| CZ (1) | CZ20021210A3 (no) |
| DE (1) | DE50005155D1 (no) |
| DK (1) | DK1218382T3 (no) |
| ES (1) | ES2213611T3 (no) |
| HK (1) | HK1047747B (no) |
| HU (1) | HUP0203052A3 (no) |
| NO (1) | NO322754B1 (no) |
| NZ (2) | NZ518439A (no) |
| PE (1) | PE20010634A1 (no) |
| PL (1) | PL355206A1 (no) |
| PT (1) | PT1218382E (no) |
| RU (1) | RU2264402C2 (no) |
| SK (1) | SK286788B6 (no) |
| UY (1) | UY26372A1 (no) |
| WO (1) | WO2001027111A2 (no) |
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| US20040077605A1 (en) * | 2001-06-20 | 2004-04-22 | Salvati Mark E. | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
| DE10043845A1 (de) * | 2000-09-06 | 2002-03-14 | Gruenenthal Gmbh | Verfahren zur Messung der Aktivität der NO-Synthase |
| EP1854798A3 (en) | 2000-09-19 | 2007-11-28 | Bristol-Myers Squibb Company | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
| EP1343785A2 (de) * | 2000-12-13 | 2003-09-17 | Basf Aktiengesellschaft | Verwendung von substituierten imidazoazinen, neue imidazoazine, verfahren zu deren herstellung, sowie sie enthaltende mittel |
| US20040087548A1 (en) | 2001-02-27 | 2004-05-06 | Salvati Mark E. | Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
| DE102004021716A1 (de) * | 2004-04-30 | 2005-12-01 | Grünenthal GmbH | Substituierte Imidazo[1,2-a]pyridin-Verbindungen und Arzneimittel enthaltend substituierte Imidazo[1,2-a]pyridin-Verbindungen |
| ES2321315T3 (es) * | 2004-06-09 | 2009-06-04 | Oncalis Ag | Inhibidores de proteina kinasa. |
| US7923041B2 (en) * | 2005-02-03 | 2011-04-12 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
| BRPI0609719B8 (pt) * | 2005-03-23 | 2021-05-25 | Hoffmann La Roche | derivados de acetilenil-pirazol-pirimidina como antagonistas de mgbur2 |
| BRPI0610863A2 (pt) * | 2005-05-20 | 2010-08-03 | Array Biopharma Inc | compostos inibidores de raf e métodos para sua utilização |
| EP1901748B1 (en) * | 2005-06-09 | 2010-09-08 | Oncalis AG | Angiogenesis inhibitors |
| TW200800213A (en) | 2005-09-02 | 2008-01-01 | Abbott Lab | Novel imidazo based heterocycles |
| EP1845098A1 (en) * | 2006-03-29 | 2007-10-17 | Ferrer Internacional, S.A. | Imidazo[1,2-b]pyridazines, their processes of preparation and their use as GABA receptor ligands |
| EA200870592A1 (ru) * | 2006-05-31 | 2009-08-28 | Галапагос Н.В. | Триазолопиразиновые соединения, пригодные для лечения дегенеративных и воспалительных заболеваний |
| US20100173930A1 (en) * | 2006-08-01 | 2010-07-08 | Alex Muci | Certain Chemical Entities, Compositions and Methods |
| US8227603B2 (en) * | 2006-08-01 | 2012-07-24 | Cytokinetics, Inc. | Modulating skeletal muscle |
| PT2583970E (pt) * | 2006-08-02 | 2016-02-08 | Cytokinetics Inc | Certas entidades químicas, composições e métodos compreendendo imidazopirimidinas |
| US8299248B2 (en) | 2006-08-02 | 2012-10-30 | Cytokinetics, Incorporated | Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use |
| EP1974729A1 (en) * | 2007-03-28 | 2008-10-01 | Santhera Pharmaceuticals (Schweiz) AG | Substituted imidazopyridine derivates as melanocortin- 4 receptor antagonists |
| EP2139478A4 (en) * | 2007-03-30 | 2010-05-05 | Cytokinetics Inc | CHEMICAL ENTITIES, COMPOSITIONS AND METHODS |
| GB0708188D0 (en) * | 2007-04-27 | 2007-06-06 | Merck Sharp & Dohme | Therapeutic compounds |
| KR101601994B1 (ko) * | 2008-04-15 | 2016-03-17 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 3-페닐피라졸로[5,1-ｂ]티아졸 화합물 |
| WO2010006251A1 (en) * | 2008-07-10 | 2010-01-14 | Southern Research Institute | 5-quinolinone and imidazopyridine compounds and use thereof |
| WO2010032195A1 (en) * | 2008-09-16 | 2010-03-25 | Csir | Imidazopyridines and imidazopyrimidines as hiv-i reverse transcriptase inhibitors |
| SG10202007719TA (en) | 2008-12-05 | 2020-09-29 | Takeda Vaccines Inc | Compositions, methods and uses for inducing viral growth |
| AR078521A1 (es) * | 2009-10-08 | 2011-11-16 | Eisai R&D Man Co Ltd | Compuesto pirazolotiazol |
| EA201791043A1 (ru) | 2011-07-13 | 2017-09-29 | Сайтокинетикс, Инк. | Комбинированная терапия бокового амиотрофического склероза |
| RU2015118985A (ru) | 2012-11-14 | 2017-01-10 | Ф. Хоффманн-Ля Рош Аг | Производные имидазопиридина |
| MY170260A (en) * | 2013-03-14 | 2019-07-13 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
| WO2017160922A1 (en) | 2016-03-16 | 2017-09-21 | Kalyra Pharmaceuticals, Inc. | Analgesic compounds |
| WO2018200988A1 (en) * | 2017-04-28 | 2018-11-01 | Dana-Farber Cancer Institute, Inc. | Inhibitors of trim33 and methods of use |
| US11530209B2 (en) | 2017-10-04 | 2022-12-20 | Dana-Farber Cancer Institute, Inc. | Small molecule inhibition of transcription factor SALL4 and uses thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068378B1 (en) | 1981-06-26 | 1986-03-05 | Schering Corporation | Novel imidazo(1,2-a)pyridines and pyrazines, processes for their preparation and pharmaceutical compositions containing them |
| NZ221996A (en) * | 1986-10-07 | 1989-08-29 | Yamanouchi Pharma Co Ltd | Imidazo-pyridine derivatives and pharmaceutical compositions |
| TW274551B (no) * | 1991-04-16 | 1996-04-21 | Takeda Pharm Industry Co Ltd | |
| DE4327027A1 (de) * | 1993-02-15 | 1994-08-18 | Bayer Ag | Imidazoazine |
| EP0822194A4 (en) * | 1995-04-21 | 1998-04-29 | Shinnippon Pharmaceutical Inc | ANNELLLIED IMIDAZO [1,2-a] PYRIDINE |
| AU2001270297A1 (en) * | 2000-06-30 | 2002-01-14 | Neurogen Corporation | 2-phenylimidazo(1,2-a)pyridine derivatives: a new class of gaba brain receptor ligands |
-
2000
- 2000-09-18 BR BR0014818-0A patent/BR0014818A/pt not_active Application Discontinuation
- 2000-09-18 PT PT00967692T patent/PT1218382E/pt unknown
- 2000-09-18 HU HU0203052A patent/HUP0203052A3/hu unknown
- 2000-09-18 ES ES00967692T patent/ES2213611T3/es not_active Expired - Lifetime
- 2000-09-18 PL PL00355206A patent/PL355206A1/xx not_active IP Right Cessation
- 2000-09-18 DE DE50005155T patent/DE50005155D1/de not_active Expired - Lifetime
- 2000-09-18 NZ NZ518439A patent/NZ518439A/en unknown
- 2000-09-18 SK SK436-2002A patent/SK286788B6/sk not_active IP Right Cessation
- 2000-09-18 WO PCT/EP2000/009096 patent/WO2001027111A2/de active IP Right Grant
- 2000-09-18 EP EP00967692A patent/EP1218382B1/de not_active Expired - Lifetime
- 2000-09-18 CA CA002382919A patent/CA2382919C/en not_active Expired - Fee Related
- 2000-09-18 KR KR1020027004516A patent/KR100756592B1/ko not_active IP Right Cessation
- 2000-09-18 AT AT00967692T patent/ATE258554T1/de active
- 2000-09-18 AU AU77771/00A patent/AU779197B2/en not_active Ceased
- 2000-09-18 RU RU2002110102/04A patent/RU2264402C2/ru not_active IP Right Cessation
- 2000-09-18 NZ NZ518390A patent/NZ518390A/en unknown
- 2000-09-18 CN CNB008159866A patent/CN1257169C/zh not_active Expired - Fee Related
- 2000-09-18 CZ CZ20021210A patent/CZ20021210A3/cs unknown
- 2000-09-18 DK DK00967692T patent/DK1218382T3/da active
- 2000-09-18 JP JP2001530329A patent/JP2003511451A/ja not_active Withdrawn
- 2000-10-05 CO CO00075814A patent/CO5251378A1/es not_active Application Discontinuation
- 2000-10-05 UY UY26372A patent/UY26372A1/es not_active Application Discontinuation
- 2000-10-05 AR ARP000105254A patent/AR025962A1/es unknown
- 2000-10-06 PE PE2000001064A patent/PE20010634A1/es not_active Application Discontinuation
-
2002
- 2002-04-03 NO NO20021565A patent/NO322754B1/no not_active IP Right Cessation
- 2002-04-08 US US10/117,333 patent/US6638933B2/en not_active Expired - Fee Related
- 2002-12-28 HK HK02109382.5A patent/HK1047747B/zh not_active IP Right Cessation
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