NO162857B - Analogifremgangsmaate for fremstilling av terapeutisk aktive amidin-derivater av 2-substituert 4-fenylimidazol. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive amidin-derivater av 2-substituert 4-fenylimidazol. Download PDFInfo
- Publication number
- NO162857B NO162857B NO842921A NO842921A NO162857B NO 162857 B NO162857 B NO 162857B NO 842921 A NO842921 A NO 842921A NO 842921 A NO842921 A NO 842921A NO 162857 B NO162857 B NO 162857B
- Authority
- NO
- Norway
- Prior art keywords
- group
- phenyl
- imidazol
- formamidine
- alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title claims description 6
- -1 2-SUBSTITUTED 4-PHENYLIMIDAZOLE Chemical class 0.000 title abstract description 18
- 150000001409 amidines Chemical class 0.000 title abstract description 4
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 4
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000007858 starting material Substances 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- FXJAOWANXXJWGJ-UHFFFAOYSA-N n-[4-(2-methyl-1h-imidazol-5-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical compound C1=CC(NC=NC(C)C)=CC=C1C1=CN=C(C)N1 FXJAOWANXXJWGJ-UHFFFAOYSA-N 0.000 claims description 3
- XBJNQSVTKIWYEC-UHFFFAOYSA-N n-[4-(2-oxo-1,3-dihydroimidazol-4-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical compound C1=CC(N=CNC(C)C)=CC=C1C1=CNC(O)=N1 XBJNQSVTKIWYEC-UHFFFAOYSA-N 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 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
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 1
- FZISBOZIFIPJTI-UHFFFAOYSA-N n'-tert-butyl-n-[4-(2-methyl-1h-imidazol-5-yl)phenyl]methanimidamide Chemical compound N1C(C)=NC=C1C1=CC=C(NC=NC(C)(C)C)C=C1 FZISBOZIFIPJTI-UHFFFAOYSA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 125000000304 alkynyl group Chemical group 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 abstract 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 125000004442 acylamino group Chemical group 0.000 abstract 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 1
- 125000004414 alkyl thio group Chemical group 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- CAQZTSCRGMRSHX-ODZAUARKSA-N (z)-but-2-enedioic acid;ethanol Chemical compound CCO.OC(=O)\C=C/C(O)=O CAQZTSCRGMRSHX-ODZAUARKSA-N 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- GTJARIVVVORARS-ODZAUARKSA-N (z)-but-2-enedioic acid;propan-2-one Chemical compound CC(C)=O.OC(=O)\C=C/C(O)=O GTJARIVVVORARS-ODZAUARKSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229960001340 histamine Drugs 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- QMXJGQJISYVTAH-UHFFFAOYSA-N 4-(2-methyl-1h-imidazol-5-yl)aniline Chemical compound N1C(C)=NC(C=2C=CC(N)=CC=2)=C1 QMXJGQJISYVTAH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000002057 chronotropic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- CAQZTSCRGMRSHX-TYYBGVCCSA-N (e)-but-2-enedioic acid;ethanol Chemical compound CCO.OC(=O)\C=C\C(O)=O CAQZTSCRGMRSHX-TYYBGVCCSA-N 0.000 description 2
- YCCMWLIBASVZGU-UHFFFAOYSA-N 2-amino-5-(2-methyl-1h-imidazol-5-yl)benzonitrile Chemical compound N1C(C)=NC(C=2C=C(C(N)=CC=2)C#N)=C1 YCCMWLIBASVZGU-UHFFFAOYSA-N 0.000 description 2
- MHYNVIKBHRUCNV-UHFFFAOYSA-N 2-bromo-4-(2-methyl-1h-imidazol-5-yl)aniline Chemical compound N1C(C)=NC(C=2C=C(Br)C(N)=CC=2)=C1 MHYNVIKBHRUCNV-UHFFFAOYSA-N 0.000 description 2
- FXXUXMDXBBUECF-UHFFFAOYSA-N 2-methylsulfanyl-5-(4-nitrophenyl)-1h-imidazole Chemical compound N1C(SC)=NC(C=2C=CC(=CC=2)[N+]([O-])=O)=C1 FXXUXMDXBBUECF-UHFFFAOYSA-N 0.000 description 2
- TXQMNSSQLHWDLB-UHFFFAOYSA-N 4-(4-nitrophenyl)-1,3-dihydroimidazol-2-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=CNC(=O)N1 TXQMNSSQLHWDLB-UHFFFAOYSA-N 0.000 description 2
- VTJUTVFOBSHNSS-UHFFFAOYSA-N 4-(4-nitrophenyl)-1,3-dihydroimidazole-2-thione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=CNC(=S)N1 VTJUTVFOBSHNSS-UHFFFAOYSA-N 0.000 description 2
- BJZNYQMDYLRHPF-UHFFFAOYSA-N 5-(4-nitrophenyl)-1h-imidazol-2-amine Chemical compound N1C(N)=NC(C=2C=CC(=CC=2)[N+]([O-])=O)=C1 BJZNYQMDYLRHPF-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- KSZVHVUMUSIKTC-UHFFFAOYSA-N acetic acid;propan-2-one Chemical compound CC(C)=O.CC(O)=O KSZVHVUMUSIKTC-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000027125 histamine-induced gastric acid secretion Effects 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 125000006501 nitrophenyl group Chemical group 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- 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 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
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- LCDPQGHLYRJZDL-UHFFFAOYSA-N n-cyano-n'-[4-(2-propan-2-yl-1h-imidazol-5-yl)phenyl]methanimidamide Chemical compound N1C(C(C)C)=NC(C=2C=CC(=CC=2)N=CNC#N)=C1 LCDPQGHLYRJZDL-UHFFFAOYSA-N 0.000 description 1
- AOBFSFVQNBTZGP-UHFFFAOYSA-N n-cyano-n'-[4-(2-sulfamoyl-1h-imidazol-5-yl)phenyl]methanimidamide Chemical compound N1C(S(=O)(=O)N)=NC(C=2C=CC(=CC=2)N=CNC#N)=C1 AOBFSFVQNBTZGP-UHFFFAOYSA-N 0.000 description 1
- BZFQCLCUKVQZSO-UHFFFAOYSA-N n-cyano-n'-[4-(2-sulfanylidene-1,3-dihydroimidazol-4-yl)phenyl]methanimidamide Chemical compound N1C(S)=NC(C=2C=CC(=CC=2)N=CNC#N)=C1 BZFQCLCUKVQZSO-UHFFFAOYSA-N 0.000 description 1
- SDLAKRCBYGZJRW-UHFFFAOYSA-N n-tert-butylformamide Chemical compound CC(C)(C)NC=O SDLAKRCBYGZJRW-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005316 response function Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
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- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
Nye farmakologisk aktive amidin-derivater av 2-substituert-4-fenylimidazol med formelen. hvor R betyr alkyl, hydroksy, C^^-alkoksy, merkapto, C__alkyltio, halogen, C^_.j-alky lsulf inyl eller alkyl-sulfonyl, sulfamoyl, en aminogruppe som kan være substituert med én eller to alkylgrupper med 1 til 3 karbonatomer, acylamino eller fenyl; R-og Rbetyr hydrogen eller alkyl; Rbetyr alkyl inneholdende eventuelt ett heteroatom såsom et oksygen-, svovel- eller nitrogen-atom, alkenyl, alkynyl, cyano, aryl eller aralkyl som eventuelt er substituert, cykloalkyl eller cyklo-alifatisk alkyl, en substituert eller usubstituert. heterocyklylalkyl- eller heterocyklisk gruppe; Rbetyr hydrogen, C--alkyl eller alkoksy, halogen, cyano eller karbamoyl, tautomere former derav og syreaddisjonssalter derav.De nye forbindelser er F^-reseptor-blokkerende midler som hemmer mavesyresekresjonen og er nyttige anti-ulcer-midler.Fremstilling av forbindelsene er beskrevet.
Description
Denne oppfinnelse angår fremgangsmåte for fremstilling av nye amidin-derivater av 2-substituert-4-fenylimidazol som er H2" reseptor-blokkerende midler og kan anvendes som mavesyresekresjons-inhibitorer og antiulcer-midler.
Ifølge oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av amidin-derivater av 2-substituert-4-fenylimidazol med den generelle formel I
hvor R betyr en lineær eller forgrenet C^- C^-alkylgruppe, en hydroksygruppe, en 0^-03-alkoksygruppe, en merkaptogruppe, en C1-C3-alkyltiogruppe, et halogenatom, en C1-C3-alkylsulfinyl-gruppe, en sulfamoylgruppe, en aminogruppe som kan være substituert med en alkylgruppe med 1-3 karbonatomer, en ^^4-alkanoylgruppe eller en fenylgruppe;
R^ og R2, som kan være like eller forskjellige, betyr et hydrogenatom eller en C1-C4alkylgruppe;
R3 betyr en lineær eller forgrenet C^-Csalkylgruppe, hydroksy-C^-Cgalkyl-, Cj^-Cgalkoksy-C^^-Cgalkyl-, Cj^-Cgalkyltio-
C^-Cgalkyl- eller cyano-C^-Cg-alkyl-gruppe, en C3-5alkenylgruppe, en C3_4alkynylgruppe, en cyanogruppe, en fenylgruppe, en halogen-fenylgruppe, en benzylgruppe, en C3-6-cykloalkylgruppe, en C3-6-cykloalkyl-C1-C2-alkylgruppe, en furfurylgruppe eller en pyridylgruppe; og
R4 betyr et hydrogenatom, en C1-C3alkyl- eller C1-C3alkoksy-gruppe, et halogenatom, en cyano- eller karbamoylgruppe,
tautomere former derav og syreaddisjonssalter derav.
For farmasøytisk anvendelse vil de nevnte syreaddisjonssalter være fysiologisk forlikelige syreaddisjonssalter. Uttrykket "syreaddisjonssalter" omfatter salter med uorganiske eller organiske syrer. Egnede fysiologisk forlikelige syreaddisjonssalter omfatter f.eks. salter dannet med eddiksyre, maleinsyre, fumarsyre, sitron-syre, saltsyre, vinsyre, bromhydrogensyre, salpetersyre eller svovelsyre.
Det skal forstås at av praktiske grunner vil forbindelsene her omtales som baser eller som de tilsvarende salter.
Det skal understrekes at selv om i formel (I) dobbelt-bindingen i amidin-radikalet og imidazolyl-ringen er angitt i en spesiell stilling, er andre forskjellige tautomere former mulige. Forbindelsene hvor R betyr en hydroksy- eller merkapto-gruppe, kan dessuten være i de tilsvarende imidazolinon- eller imidazolintion-former. Når forbindelsene er angitt her, omfattes også de tautomere former.
I den ovenstående formel (I) kan amidin-radikalet være i orto-, meta- eller para-stilling i benzenringen i forhold til imidazolyl-gruppen, og R4 kan være i en hvilken som helst stilling i benzenringen.
Forbindelsene med formel (I) kan i henhold til oppfinnelsen fremstilles ved de følgende fremgangsmåter:
Fremgangsmåte A. Omsetning av en forbindelse med den generelle formel II (hvor R, R^ og R^ er som ovenfor angitt) med et reaktivt derivat av et karboksamid med formel III
e
hvor R2 og R^ er som ovenfor angitt, X betyr anionet av en uorganisk syre såsom hydroklorid eller fluorborat, og A betyr en benzoyloksygruppe, klor eller en etoksygruppe. Eventuelt kan forbindelsen med formel III bringes til å reagere også
som en base. Omsetningen utføres vanligvis ved en temperatur fra 0 til 100°C, fortrinnsvis fra 20 til, 60°C.
Omsetningen utføres fordelaktig i nærvær av et inert organisk oppløsningsmiddel. Egnede oppløsningsmidler omfatter f.eks. en alkohol med 1 til 3 karbonatomer såsom metanol eller etanol, halo-generte hydrokarboner såsom diklormetan, dioksan eller aceton.
Forbindelsene med formel III som anvendes som utgangsmateriale ved denne fremgangsmåte, kan oppnås ved konvensjonelle metoder ved omsetning av et karboksamid med formelen IV
hvor R2 og R3 er som ovenfor angitt, med benzoylklorid, trietylokso-nium-fluorborat, etylklorformiat, fosforoksyklorid eller fosfor-pentaklorid. Fremgangsmåte B. Omsetning av en N,N'-disubstituert amidin-forbindelse med formel V hvor R, R^, R^ og R4 er som ovenfor angitt, B betyr en egnet utgående gruppe såsom en cyano-, acetyl-, karbetoksy- eller karbamylgruppe, med et amin med formel (VI)
hvor R^ er som ovenfor angitt.
Omsetningen utføres hensiktsmessig i nærvær av vann eller av et inert organisk oppløsningsmiddel som f.eks. en alkohol såsom metanol eller etanol, formamid, dioksan eller acetonitril. Denne omsetning kan f.eks. utføres ved en temperatur fra 10 til 50°C, fortrinnsvis ved romtemperatur.
Forbindelsene med formel (V) som anvendes som utgangsmateriale ved ovenstående fremgangsmåte, oppnås ved fremgangsmåter som er i og for seg kjente i litteraturen, f.eks. ved omsetning av en forbindelse med formel II med et N-substituert etylimidat med formel VII
hvor R^ og B er som ovenfor angitt, eller eventuelt, når i forbindelsen med formel (V) B betyr en cyanogruppe, kan omsetningen også utføres i et enkelt trinn ved omsetning av en forbindelse med formel II med cyanamid i nærvær av en forbindelse med formel VIII
hvor R er som ovenfor angitt, og Y betyr en lavere alkylgruppe såsom metyl eller etyl.
Omsetningen utføres generelt i nærvær av et egnet inert organisk oppløsningsmiddel som f.eks. en lavere alkohol, etere, etylacetat, acetonitril eller dioksan, eller uten oppløsnings-middel ved en temperatur fra 20 til 80°C. Forbindelsen med formel (VII) kan fremstilles ved vanlige metoder.
Forbindelsene med den generelle formel (I) som fremstilles ved fremgangsmåtene A og B, kan eventuelt omdannes med uorganiske eller organiske syrer til de tilsvarende fysiologisk forlikelige syreaddisjonssalter, f.eks. ved vanlige metoder såsom ved omsetning av forbindelsene som baser med en oppløsning av den ønskede syre i et egnet oppløsningsmiddel. Særlig foretrukne syrer omfatter f.eks. saltsyre, svovelsyre, maleinsyre og fumarsyre. Forbindelsen med den generelle formel (I) og deres fysiologisk forlikelige syreaddisjonssalter er H2-reseptor-blokkerende midler som hemmer mavesyresekresjon.
Representative eksempler på de foretrukne forbindelser som fremstilles ifølge oppfinnelsen, på grunn av deres bedre aktivitet som anti-sekretoriske antiulcer-midler og for behandling av for-styrrelser i mave-tarmkanalen, er: N-etyl-N1 -[4-(2-metyl-imidazol-4-yl)fenyl]-formamidin (forb. 2) N-isopropyl-N'-[4-(2-metyl-imidazol-4-yl)fenyl]-formamidin (forb. 3) N-allyl-N'-[4-(2-metyl-imidazol-4-yl)fenyl]-formamidin (forb. 4) N-t.-butyl-N * -[4-(2-metyl-imidazol-4-yl)fenyl]-formamidin (forb. 39) N-isopropyl-N'-[4-(2-hydroksy-imidazol-4-yl)fenyl]-formamidin (forb. ;28) ;Den antagonistiske aktivitet av forbindelsene fremstilt ifølge oppfinnelsen på histamin H2-reseptorer påvises enten "in vitro" eller "in vivo" ved deres hemning av de H^-avhengige bio-logiske virkninger, som omfatter henholdsvis histamin-fremkalt positiv kronotropisk virkning og histamin-forårsaket mavesyresekresjon. ;Hemningen av den positive kronotrope virkning er undersøkt ;i isolerte marsvin-forkammere suspendert i et organbad (50 ml) inneholdende oksygenert (02 : 95% - C02 : 5%) Krebs-Henseleit-oppløsning (pH 7,4) holdt ved 32°C. Det myokardiale preparat, belastet med 1 g isometrisk spenning, får stabilisere seg i 60 min., og myokardiale sammentrekninger nedtegnes gjennom en isometrisk arm forbundet med en deformasjonsmåler, og den øyeblikkelige hastighet overvåkes med et kardiotakometer og en varmepenn-skriver. ;Efter to kontroll-reaksjoner på histamin (10 ^ g/ml "*") settes prøveforbindelsene til badet i den ønskede sluttkonsentrasjon og holdes der i 30 minutter før forkammerene. igjen utsettes for histamin. Den kronotropiske reaksjon som oppnås i nærvær av antagonisten, sammenlignes derefter med kontroll-reaksjonen på histamin, og prosentvis reduksjon av histamin r^-fremkalt reaksjon beregnes. Gjennomsnittlig effektiv konsentrasjon (EC^q) for r^-antagonistene beregnes også ved standard metode ifølge Dr. Waud, Analysis of dose-response curves, i "Methods in Pharmacology", vol. 3 Smooth muscle, Ed. Daniel E.E. Paton, M., Plenum Press.
New York (1975); Ash og Schild, Br. J. Pharmacol. Chemother. 27, 427-439, 1966. Den følgende tabell viser de oppnådde resultater:
Prøveforbindelsenes evne til å hemme histamin-forårsaket mavesyresekresjon er undersøkt efter intravenøs og intraduodenal administrering i mave-perfuserte rotter, ifølge Gosh og Schild (Br. J. Pharmacol. Chemother..13, 54, 1958).
Klargjøring av dyrene i generell anestesi (uretan, 1 g.kg ^ i.p.) og konstant temperatur, oppnås ved å innføre og binde på plass polyetylenrør (PE 50) i spiserøret og i det pylorisk-antrale område. Efter at maven er vasket for å fjerne matrester, ble kontinuerlig perfusjon av maven startet med saltvann, 0,5 ml/min. ^
(37°c), drevet med en Jobling peristaltisk pumpe. 30 minutter efter igangsettelse av perfusjonen, oppsamles mave-perfusatet i 30 minutters prøver og titreres efter syreinnhold, uttrykt som yekv NaOH 1 N. Når kontrollsyre-produksjon blir konstant, igangsettes
intravenøs perfusjon av histamin (1 mg.kg ^"t ^) og opprettholdes under forsøksperioden. Efter at syresekresjonen har nådd et jevnt høyt nivå, injiseres økende doser av prøveforbindelsene intravenøst for å oppnå dose-reaksjons-funksjoner. ED5Q ble derefter beregnet ved standardmetode.
Resultatene er angitt i den følgende tabell:
Farmasøytiske preparater kan som aktiv bestanddel inneholde minst én forbindelse med formel (I) eller et fysiologisk forlikelig syreaddisjonssalt derav sammen med et farmasøytisk bæremiddel eller hjelpestoff. For farmasøytisk administrering kan forbindelsene med den generelle formel (I) og deres fyiologisk forlikelige syreaddisjonssalter innarbeides i vanlige farmasøytiske preparater i enten fast eller flytende form. Preparatene kan f.eks. tilberedes i en form som er egnet for oral eller parenteral administrering. Foretrukne former omfatter f.eks. kapsler, tabletter, belagte tabletter, ampuller eller preparatglass inneholdende saltet i lyofilisert form.
Den aktive bestanddel kan_innarbeides i hjelpestoffer eller bæremidler som vanligvis anvendes i farmasøytiske preparater, som f.eks. talk, gummi arabicum, laktose, gelatin, magnesiumstearat, maisstivelse, vandige eller ikke-vandige bæremidler, polyvinyl-pyrrolidon og mannitol.
Preparatene tilberedes hensiktsmessig som enhetsdoser, idet hver enhetsdose tilpasses slik at den tilfører en bestemt dose av den aktive bestanddel. Hver enhetsdose kan hensiktsmessig inneholde fra 10 til 500 mg og fortrinnsvis fra 20 til 150 mg.
De følgende eksempler illustrerer noen av de nye forbindelser.
Eksempel 1
2- me. tyl- 4- ( 4- nitro- fenyl)' - lH- imidazol
En blanding av 4-nitro-fenacylbromid (100 g), acetamid (300 g) og vann (15 g) ble omrørt ved 140°C i 8 timer og derefter hellet i vann (1500 ml) . Oppløsningen ble filtrert og gjort alkalisk med 10% natriumhydroksyd. "Det utskilte faste stoff ble frafiltrert, vasket med vann og tørket for å gi 48,1 g av tittelforbindelsen. Smp. 216-219°C.
Ved å følge den ovenfor angitte fremgangsmåte, under anvendelse av det passende fenacylbromid og det passende amid som utgangsmaterialer, ble de følgende nitrofenyl-imidazol-derivater fremstilt:
Eksempel 2
2- metyl- 4-( 4- amino- fenyl)- lH- imidazol
2-metyl-4-(4-nitro-fenyl)-lH-imidazol (28 g) oppløst i metanol (210 ml) ble hydrogenert i nærvær av Pd/C 10% (1,35 g) ved atmosfærisk trykk og ved romtemperatur. Da den beregnede mengde hydrogen var opptatt, ble katalysatoren frafiltrert, og oppløs-ningen ble inndampet til tørrhet for å gi 23,2 g av tittelforbindelsen som et svampaktig, fast stoff. Ved å følge den ovenfor beskrevne fremgangsmåte, under anvendelse av det passende nitrofenyl-derivat, ble de følgende aminofenyl-derivater fremstilt:
Eksempel 3
2- metyltio- 4-( 4- nitrofenyl)- lH- imidazol
Til en oppløsning av natrium (2,3 g) i etanol (190 ml) ble satt porsjonsvis 2-merkapto-4-(4-nitrofenyl)-lH-imidazol (21,1 g). Etter 15 minutters omrøring ble en oppløsning av jodmetan (14,2 g) i etanol (50 ml) tilsatt dråpevis. Efter ytterligere 2 timers omrøring ved romtemperatur ble oppløsningen inndampet til tørrhet. Det gjenværende, faste stoff ble behandlet med vann, filtrert og tørket for å gi 18,1 g av tittelforbindelsen. Smp. 200-202°C.
2- metoksy- 4-( 4- nitrofenyl)- lH- imidazol (Smp. 295-300°C) ble fremstilt på samme måte ved å starte med 2-hydroksy-4-(4-nitrofenyl )-lH-imidazol.
Eksempel 4
2- metyltio- 4-( 4- aminofenyl)- lH- imidazol
Konsentrert saltsyre (60 ml) ble satt dråpevis til en omrørt suspensjon av 2-metyltio-4-(nitrofenyl)-lH-imidazol (5,88 g), granulert tinn (8,9 g) i vann (25 ml). Efter ytterligere 3 timers omrøring ved 100°C ble blandingen avkjølt til romtemperatur og filtrert. Det faste stoff ble oppløst i vann, oppløsningen ble filtrert og inndampet til tørrhet. Det gjenværende, faste stoff ble vasket med etanol, filtrert og behandlet med en etanolisk oppløsning av natriumetoksyd for å gi den fri base (3 g), smp. 85-86°C. Ved å følge den ovenfor beskrevne fremgangsmåte ble andre nitrofenyl-derivater redusert for å danne de følgende aminer:
Eksempel 5
2- klor- 4-( 4- nitrofenyl)- lH- imidazol
En blanding av 2-hydroksy-4-(4-nitrofenyl)-lH-imidazol (15 g) og fosforoksyklorid (750 ml) ble tilbakeløpsbehandlet under om-røring i 24 timer. Oppløsningen ble inndampet til tørrhet, residuet ble bragt til pH 6,5 med en H2P04~/HP04 -buffer og ekstrahert med metylenklorid. Efter tørking ble den organiske oppløsning inndampet, og det rå produkt ble kromatografert på silikagel for å gi 6,7 g av tittelforbindelsen. Smp. 136-138°C.
Eksempel 6
2- metylsulfinyl- 4- ( 4- nitrofenyl)- lH- imidazol
Hydrogenperoksyd (36%, 100 ml) ble i løpet av 2 timer under omrøring satt til en varm! (60°C) oppløsning av 2-metyltio-4-(4-nitrofenyl)-lH-imidazol (19,6 g) i metanol (500 ml). Efter ytterligere 24 timers oppvarmning ved 60°C ble blandingen avkjølt til romtemperatur, filtrert, og det faste stoff ble tørket for å gi 16,1 g av tittelforbindelsen. Smp. 220-222°C.
Eksempel 7
2- sulfamoyl- 4-( 4- nitrofenyl)- lH- imidazol
Klor ble innført gjennom et kapillar-rør med moderat hastighet i 40 minutter inn i en omrørt, is-avkjølt blanding av 2-merkapto-4-(4-nitrofenyl)-lH-imidazol (10 g) i N saltsyre (100 ml). Det utskilte sulfonylklorid ble filtrert, vasket med kaldt vann og satt til et overskudd av flytende ammoniakk. Efter avdampning av overskudd av ammoniakk ble residuet tatt opp i litt fortynnet ammonium-hydroksyd og filtrert med trekull. Oppløsningen ble avkjølt og gjort svakt sur, det utskilte, faste stoff ble filtrert og om-krystallisert fra vann for å gi 3,4 g av tittelforbindelsen.
Smp. 227-229°C.
Eksempel 8
2- amino- 4-( 4- nitrofenyl)- lH- imidazol
En blanding av a-amino-4-nitro-acetofenon-hydroklorid (70 g), cyanamid (40,7 g), vann (2100 ml) og konsentrert eddiksyre (70 ml) ble bragt til pH 4,5 med 30% natriumhydroksyd og oppvarmet til 100°C i 45 minutter. Den varme oppløsning ble filtrert og avkjølt. Det utskilte, faste stoff ble filtrert, vasket med vann og tørket for å gi 25 g av tittelforbindelsen. Smp. 235-240°C (som hydroklorid).
Eksempel 9
2- acetamido- 4-( 4- nitrof enyl)- lH- imidazol
En blanding av 2-amino-4-(4-nitrofenyl)-lH-imidazol (17,3 g)
i eddiksyreanhydrid (100 ml) ble oppvarmet ved 100°C i 1 time. Oppløsningen ble inndampet til tørrhet, og residuet ble behandlet med eter, filtrert og tørket for å gi 18,9 g av tittelforbindelsen. Smp. 242-244°C.
Eksempel 10
2- etylamino- 4-( 4- aminofenyl)- lH- imidazol
En suspensjon av 2-acetamido-4-(4-aminofenyl)-lH-imidazol
(16 g) i vannfri tetrahydrofuran (160 ml) ble satt dråpevis til en omrørt suspensjon av litiumaluminiumhydrid (12 g) i vannfri tetrahydrofuran (240 ml). Blandingen ble oppvarmet ved 60°C i 4 timer. Efter avkjøling og behandling med vann ble oppløsningsmidlet av-dampet, og residuet ble oppløst i 10% saltsyre. Oppløsningen ble gjort alkalisk med 30% natriumhydroksyd, og basen ble ekstrahert med etylacetat. Den organiske fase ble inndampet til tørrhet for å gi 8,2 g av tittelforbindelsen. Smp. 89-91°C.
Eksempel 11
2- metyl- 4-( 3- brom- 4- aminofenyl)- lH- imidazol
En blanding av 2-metyl-4-(3-brom-4-acetamido-fenyl)-lH-imidazol (15 g), konsentrert saltsyre (10 ml) og vann (30 ml) ble tilbakeløpsbehandlet i 45 min. Oppløsningen ble avkjølt til romtemperatur og gjort alkalisk med 10% natriumhydroksyd. Basen ble filtrert, vasket med vann og tørket for å gi 10 g av tittelforbindelsen. Smp. 34-36°C.
Eksempel 12
2- metyl- 4- ( 3- cyano- 4- aminofenyl)- lH- imidazol
En blanding av 2-metyl-4-(3-brom-4-aminofenyl)-lH-imidazol
(5,12 g), kobber(I)cyanid (2 g) og kinolin (15 ml) ble tilbake-løpsbehandlet i 4 timer. Efter avkjøling og dekomponering med en syreoppløsning av jern(III)klorid, ble blandingen ekstrahert med etylacetat. Det organiske oppløsningsmiddel ble tørket og inndampet til tørrhet, og residuet ble behandlet med vann, filtrert og tørket for å gi 2,1 g av tittelforbindelsen. Smp. 89-91°C.
Eksempel 13
2- metyl- 4-( 3- karbamoyl- 4- aminofenyl)- lH- imidazol
En blanding av 2-metyl-4-(3-cyano-4-aminofenyl)-lH-imidazol (6,2 g) og "Amberlite" IRA 400 (OH) (12 g) i vann (150 ml) ble tilbakeløpsbehandlet i 5 timer. Efter avkjøling og filtrering ble oppløsningen inndampet til tørrhet for å gi 4,1 g av tittelforbindelsen. Smp. 137-139°C.
Eksempel 14
2- metyl- 4-( 3- metyl- 4- nitrofenyl)- lH- imidazol
2-metyl-4-(3-metylfenyl)-lH-imidazol som nitratsalt (15 g)
ble satt porsjonsvis til 9'6% svovelsyre (40 ml) ved romtemperatur. Oppløsningen ble oppvarmet, ved 90°C i 1 time, avkjølt, fortynnet med vann (200 ml) og nøytralisert med vandig natriumkarbonat.
Det utskilte, faste stoff ble filtrert, og oppløsningen ble gjort sterkt alkalisk med 10% natriumhydroksyd. Den utfelte base ble filtrert og tørket for å gi 5 g av tittelforbindelsen som var tilstrekkelig ren til å kunne anvendes i neste trinn. Smp. 158-160°C. Det følgende mellomprodukt ble fremstilt på lignende måte:
2- metyl- 4-( 3- metoksy- 4- nitrofenyl)- lH- imidazol
Smp. 191-192°C.
Eksempel 15
fc- cyano- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
En oppløsning av 2-metyl-4-(4-aminofenyl)-lH-imidazol (15 g) og etyl-N-cyanoformimidat (9,35 g) i etanol (150 ml) ble omrørt ved romtemperatur natten over. Det krystallinske produkt ble oppsamlet ved filtrering, vasket med kald etanol og tørket for å gi 15,2 g av tittelforbindelsen. Smp. 175-176°C (dekomp.). Ved å følge den ovenfor beskrevne fremgangsmåte, under anvendelse av de passende utgangsmaterialer, ble de følgende N-cyanoamidiner fremstilt:
N- cyano- N'-[ 3-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
Smp. 225-230°C (dekomp.).
N- cyano- N'-[ 4-( 2- etyl- imidazol- 4- yl) fenyl]- formamidin
Smp. 227-229°C (dekomp.).
N- cyano- N'-[ 4-( 2- isopropyl- imidazol- 4- yl) fenyl]- formamidin
Smp. 221-223°C (dekomp.).
N- cyano- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- acetamidin
Smp. 152-153°C (dekomp.).
N- cyano- N'-[ 4-( 2, 5- dimetyl- imidazol- 4- yl) fenyl]- formamidin
Smp. 145-148°C (dekomp.).
N- cyano- N'-[ 4-( 2- merkapto- imidazol- 4- yl) fenyl]- formamidin
Smp. 270°C (dekomp.).
N- cyano- N'-[ 4-( 2- metylmerkapto- imidazol- 4- yl) fenyl]- formamidin Smp. 232-235°C (dekomp.).
N- cyano- N'-[ 4-( 2- hydroksy- imidazol- 4- yl) fenyl]- formamidin
Smp. 255-258°C (dekomp.).
N- cyano- N'-[ 4-( 2- metoksy- imidazol- 4- yl) fenyl]- formamidin
Smp. 270°C (dekomp.).
N- cyano- N'-[ 4-( 2- sulfamoyl- imidazol- 4- yl) fenyl]- formamidin
Smp. 241-242°C (dekomp.).
N- cyano- N'-[ 4-( 2- acetamido- imidazol- 4- yl) fenyl]- formamidin
Smp. 228-230°C (dekomp.).
N- cyano- N'-[ 4-( 2- etylamino- imidazol- 4- yl) fenyl]- formamidin
Smp. 215-216°C (dekomp.).
N- cyano- N'-[ 2- brom- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin Smp. 247-248°C (dekomp.).
N- cyano- N'-[ 2- cyano- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin Smp. 239-241°C (dekomp.).
N- cyano- N'-[ 2- karbamoyl- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin Smp. 250-252°C (dekomp.).
N- cyano- N'-[ 4-( 2- amino- imidazol- 4- yl) fenyl]- formamidin
Smp. 220-222°C (dekomp.).
N- cyano- N'-[ 2- metyl- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin Smp. 234-236°C (dekomp.).
N- cyano- N'-[ 2- metoksy- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin Smp. 263-266°C (dekomp.).
N- cyano- N'-[ 4-( 2- fenyl- imidazol- 4- yl) fenyl]- formamidin
Smp. >280°C.
N- cyano- N'-[ 4-( 2- metylsulfinyl- imidazol- 4- yl) fenyl]- formamidin Smp. 222-224°C (dekomp.).
Eksempel 16
N- metyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin ( forbind. 1)
N-cyano-N1 -[4-(2-metyl-imidazol-4-yl)fenyl]-formamidin
(2,25 g) ble innført i én porsjon i en oppløsning av 33% vandig metylamin (22,5 ml). Efter noen få minutter ble det utskilte, faste stoff filtrert, vasket med vann og tørket for å gi 1,2 g av tittelforbindelsen. Maleatsalt (etanol). Smp. 173-174°C (dekomp.).
Analyse
C20<H>22<N>4°8 Funnet % C 54,07 H 4,79 N 12,31
Beregnet % C 53,81 H 4,97 N 12,55
De følgende forbindelser ble fremstilt på lignende måte ved å starte med de tidligere beskrevne N-cyanoamidin-derivater: N- etyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin ( forbind. 2) Maleatsalt (etanol) Smp.166-168°C (dekomp.)
Analyse
<C>21<H>24<N>4°8 Funnet % C 54,49 H 5,21 N 12,38
Beregnet % C 54,78 H 5,25 N 12,17
N- isopropyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin ( forb. 3) Maleatsalt (etanol) Smp. 192-193°C (dekomp.)
Analyse
C22<H>26<N>4°8 Funnet % C 55,84 H 5,59 N 11,63
Beregnet % C 55,69 H 5,52 N 11,81
N- allyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin ( forb. 4) Maleatsalt (etanol) Smp. 170-171°C (dekomp.)
Analyse
<C>22<H>24<N>4°8 Funnet % C 56,17 H 5,00 N 12,08
Beregnet % C 55,93 H 5,12 N 11,86
N-pro pargyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin ( forb. 5) Maleatsalt (etanol) Smp. 160-162 (dekomp.)
Analyse
<C>22<H>22N4°8 Funnet % C 56,23 H 4,70 N 12,05
Beregnet % C 56,17 H 4,71 N 11,91
N- n- heksyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin ( forb. 6) Maleatsalt (aceton) Smp. 127-130 (dekomp.)
Analyse
C,5H32<N>4<0>g Funnet % C 57,87 H 6,24 N 10,62
Beregnet % C 58,13 H 6,24 N 10,85
N-( 2- metoksyetyl)- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 7)
Maleatsalt (aceton) Smp. 161-163°C (dekomp.)
Analyse
<C>22H26<N>4°9 Funnet % C 54,13 H 5,29 N 11,28
Beregnet % C 53,87 H 5,34 N 11,42
N-( 3- hydroksypropyl)- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 8)
Maleatsalt (aceton) Smp. 166-169°C (dekomp.)
Analyse
<C>22<H>26<N>4°9 Funnet % C 53,57 H 5,21 N 11,59
Beregnet % C 53,87 H 5,34 N 11,42
N-( 2- metyltioetyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 9)
Maleatsalt (etanol) Smp. 170-172°C (dekomp.)
Analyse
<C>22<H>26<N>4°8<S> Funnet % C 51,99 H 5,27 N 11,30
Beregnet % C 52,17 H 5,18 N 11,06
N-( 2- cyanoetyl)- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 10)
Maleatsalt (etanol) Smp. 162-164°C (dekomp.)
Analyse
<C>22<H>23<N>5°8 Funnet % C 54,29 H 4,71 N 14,35
Beregnet % C 54,43 H 4,78 N 14,43
N- cyklopropylmetyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 11)
Fumaratsalt (etanol) Smp. 154-157°C (dekomp.)
Analyse
C23<H>26N4°8 Funnet % C 56,60 H 5,30 N 11,53
Beregnet % C 56,78 H 5,39 N 11,52
N- cykloheksyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 12)
Fumaratsalt (etanol) Smp. 164-166°C (dekomp.)
Analyse
<C>25H30N4°8 Funnet % C 58,07 H 5,95 N 11,00
Beregnet % C 58,36 H 5,88 N 10,89
N- benzyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 13)
Hydrokloridsalt (etanol) Smp. 225-227°C (dekomp.)
Analyse
C18H20C12N4 Funnet % C 59,39 H 5,65 N 15,63
Beregnet % C 59,51 H 5,55 N 15,42
N- furfuryl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 14)
Hydrokloridsalt (etanol) Smp. 235-237°C (dekomp.)
Analyse
C.cH1oCloN.0 Funnet % C 54,67 H 5,27 N 15,68 io lo z 4
Beregnet % C 54,40 H 5,14 N 15,86
N- etyl- N'-[ 4-( 2- etyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 15)
Maleatsalt (etanol) Smp. 165-167°C (dekomp.)
Analyse
<C>22<H>26<N>4°8 Funnet % C 55,78 H 5,51 N 11,59
Beregnet % C 55,69 H 5,52 N 11,81
N- isopropyl- N'-[ 4-( 2- etyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 16)
Maleatsalt (etanol) Smp. 180-181 (dekomp).
Analyse
C23H28N4°8 Funnet % C 56,95 H 5,79 N 11,30
Beregnet % C 56,55 H 5,78 N 11,47
N- ety. l- N '- [ 4- ( 2- isopropyl- imidazol- 4- yl) fenyl] - formamidin
(forbindelse 17)
Maleatsalt (etanol) Smp. 174-175°C (dekomp.)
Analyse
<C>23<H>28<N>4°8 Funnet % C 56,73 H 5,87 N 11,60
Beregnet % C 56,55 H 5,78 N 11,47
N- isopropyl- N'-[ 4-( 2- isopropyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 18)
Maleatsalt (etanol) Smp. 168-170°C (dekomp.)
Analyse
<C>24<H>30<N>4°8 Funnet % C 57,02 H 6,10 N 11,28
Beregnet % C 57,36 H 6,02 N 11,15
N- isopropyl- N'-[ 4-( 2- fenyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 19)
Maleatsalt (etanol) Smp. 208-210°C (dekomp.)
Analyse
C23<H>24<N>4°4 Funnet % C 66,01 H 5,95 N 13,20
Beregnet % C 65,70 H 5,75 N 13,33
N- isopropyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- acetamidin
(forbindelse 20)
Maleatsalt (etanol) Smp. 106-108°C (dekomp.)
Analyse
C23<H>28N4°8 Funnet % C 56,67 H 5,76 N 11,55
Beregnet % C 56,55 H 5,78 N 11,47
N- etyl- N'-[ 4-( 2, 5- dimetyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 21)
Maleatsalt (aceton) Smp. 165-167°C (dekomp.)
Analyse
<C>22<H>26N4°8 Funnet % C 55,41 H 5,70 N 12,01
Beregnet % C 55,69 H 5,52 N 11,81
N- isopropyl- N'-[ 4-( 2, 5- dimetyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 22)
Maleatsalt (aceton) Smp. 157-159°C (dekomp.)
Analy=e
C23H28N4°8 Funnet % C 56,38 H 5,82 N 11,59
Beregnet % C 56,55 H 5,78 N 11,47
N- etyl- N'-[ 3-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 23)
Maleatsalt (aceton) Smp. 171-173°C (dekomp.)
Analyse
C21H24<N>4°8 Funnet % C 54,61 H 5,19 N 11,98
Beregnet % C 54,78 H 5,25 N 12,17
N- isopropyl- N'-[ 3-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 24)
Maleatsalt (aceton) Smp. 168-171°C (dekomp.)
Analyse
<C>22<H>26<N>4°8 Funnet % C 55,44 H 5,48 N 11,69
Beregnet % C 55,69 H 5,52 N 11,81
N- isopropyl- N'-[ 4-( 2- merkapto- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 25)
Maleatsalt (aceton) Smp. 202°C (dekomp.)
Analyse
C,-H.-N.O.S Funnet % C 54,38 H 5,33 N 14,70 17 20 4 4 ' Beregnet % C 54,24 H 5,35 N 14,88
N- etyl- N'-[ 4-( 2- metylmerkapto- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 26)
Maleatsalt (etanol) Smp. 158-160°C (dekomp.)
Analyse
C21<H>24N4°8<S> Funnet % C 51,31 H 5,00 N 11,28
Beregnet % C 51,22 H 4,91 N 11,38
N- isopropyl- N'-[ 4-( 2- metylmerkapto- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 27)
Maleatsalt (aceton) Smp. 150-152°C (dekomp.)
Analyse
C22<H>26<N>4°8<S> Funnet % C 51,93 H 5,20 N 11,25
Beregnet % C 52,17 H 5,18 N 11,06
N- isopropyl- N'-[ 4-( 2- hydroksy- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 28)
Maleatsalt (aceton) Smp. 211-213°C (dekomp.)
Analyse
<C>17<H>20<N>4°5 Funnet % C 56,47 H 5,69 N 15,58
Beregnet % C 56,66 H 5,59 N 15,55
N- isopropyl- N'-[ 4-( 2- metylsulfinyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 29)
Base (vann) Smp. 200-201°C (dekomp.)
Analyse
C14H18N4° S Funnet % C 57,82 H 6,23 N 19,15
Beregnet % C 57,92 H 6,25 N 19,30
N- isopropyl- N'-[ 4-( 2- sulfamoyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 30)
Maleatsalt (aceton) Smp. 243-246°C (dekomp.)
Analyse
C17H2l<N>5°6<S> Funnet % C 47,97 H 5,07 N 16,63
Beregnet % C 48,22 H 5,00 N 16,54
N- isopropyl- N'-[ 4-( 2- amino- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 31)
Maleatsalt (etanol) Smp. 212-215°C (dekomp.)
Analyse
C21<H>25N5°8 Funnet % C 52,80 H 5,23 N 14,81
Beregnet % C 53,05 H 5,30 N 14,73
N- isopropyl- N'-[ 4-( 2- acetamido- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 32)
Maleatsalt (etanol) Smp. 196-198°C (dekomp.)
Analyse
C23<H>27<N>5°9 Funnet % C 53,40 H 5,22 N 13,44
Beregnet % C 53,38 H 5,26 N 13,53
N- isopropyl- N'-[ 4-( 2- etylamino- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 33)
Maleatsalt (etanol) Smp. 225-227°C (dekomp.)
Analyse
<C>23H29<N>5°8 Funnet % C 54,50 H 5,73 N 14,09
Beregnet % C 54,86 H 5,81 N 13,91
N- n- propyl- N'-[ 2- brom- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 34)
Maleatsalt (aceton) Smp. 186-188°C (dekomp.)
Analyse
C22H25<B>rN4°8 Funnet % C 47,66 H 4,60 N 10,01
Beregnet % C 47,75 H 4,55 N .10,12
N- isopropyl- N'-[ 2- cyano- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 35)
Maleatsalt (etanol) Smp. 178-180°C (dekomp.)
Analyse
C23H25<N>5°8 Funnet % C 55,12 H 4,99 N 13,88
Beregnet % C 55,30 H 5,05 N 14,02
N- etyl- N'-[ 2- karbamoyl- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamindin
(forbindelse 36)
Maleatsalt (aceton) Smp. 233-235°C (dekomp.)
Analyse
C22H25N5°9 Funnet % C 52,63 H 5,09 N 14,10
Beregnet % C 52,4 8 H 5,01 N 13,91
N- allyl- N'-[ 2- metyl- 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 37)
Maleatsalt (aceton) Smp. 170-172°C (dekomp.)
Analyse
C00H_,N.00 Funnet % C 57,00 H 5,45 N 11,38
23 26 4 8
Beregnet % C 56,78 H 5,39 N 11,52
N- n- propyl- N'-[ 2- metoksy- 4-( 2- metyl- imiadazol- 4- yl) fenyl]- formamidin
(forbindelse 38)
- Maleatsalt (aceton) Smp. 201-203°C (dekomp.)
Analy<p>e
<C>22<H>28N4°9 Funnet % C 54,44 H 5,59 N 10,97
Beregnet % C 54,75 H 5,59 N 11,11
Eksempel 17
N- tert.- butyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 39)
Til en oppløsning av N-tert.-butyl-formamid (5,06 g) i diklormetan (30 ml) ble ved 0°C langsomt tilsatt en oppløsning av trietyloksoniumfluorborat (9,56 g) i diklormetan (50 ml). Efter 6 timers omrøring ved romtemperatur ble 2-metyl-4-(4-aminofenyl)-lH-imidazol i etanol (20 ml) tilsatt dråpevis. Blandingen ble omrørt natten over og derefter inndampet til tørrhet. Fluorborat-saltet av den ønskede forbindelse ble oppløst i vann, og oppløs-ningen ble gjort alkalisk ved 10% natriumhydroksyd. Det utskilte produkt ble filtrert, vasket med vann og tørket for å gi 2,1 g av tittel-formamidinet.
Sulfatsalt (metanol) Smp. 276-278°C (dekomp.)
Analyse
<C>15<H>22<N>4°4<S> Funnet % C 50,79 H 6,31 N 15,77
Beregnet % C 50,84 H 6,26 N 15,81
Eksempel 18
N- fenyl- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 40)
2-metyl-4-(4-aminofenyl)-lH-imidazol (5 g) ble satt til en oppløsning av etyl-N-fenyl-formimidat (5 g) i aceton (25 ml). Efter 3 timers omrøring ved romtemperatur ble det utskilte, faste stoff filtrert og tørket. Forbindelsen ble behandlet med iseddik i aceton: acetatsaltet som ble utfelt, ble filtrert og tørket for å gi 4,6 g av tittelforbindelsen.
Acetatsalt (aceton) Smp. 147-150°C (dekomp.)
Analyse
<C>21H24N4°4 Funnet % C 63,77 H 6,13 N 14,27
Beregnet % C 63,62 H 6,10 N 14,13
De følgende forbindelser ble fremstilt på lignende måte ved å starte med de passende etyl-formimidater: N-( 4- klorfenyl)- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 41)
Acetatsalt (aceton) Smp. 112-115°C (dekomp.)
Analyse
C21H23CIN4°4 Funnet % C 58,29 H 5,60 N 13,12
Beregnet % C 58,54 H 5,38 N 13,00
N-( 2- pyridyl)- N'-[ 4-( 2- metyl- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 42)
Base (aceton) Smp. 59-61°C (dekomp.)
Analyse
<C>16<H>15N5 Funnet % C 68,99 H 5,30 N 25,36
Beregnet % C 69,29 H 5,45 N 25,26
N- isopropyl- N'-[ 4-( 2- klor- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 43)
Base (aceton) Smp. 85-87°C (dekomp.)
Analyse
C12<H>13CIN4 Funnet % C 57,89 H 5,33 N 22,41
Beregnet % C 57,95 H 5,27 N 22,53
N- isopropyl- N'-[ 4-( 2- metoksy- imidazol- 4- yl) fenyl]- formamidin
(forbindelse 44)
Maleatsalt (metanol) Smp. 236°C (dekomp.)
Analyse
<C>22H26<N>4°9 Funnet % C 54,02 H 5,46 N 11,53
Beregnet % C 53,87 H 5,34 N 11,42
Claims (6)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med den generelle formel I
hvor R betyr en lineær eller forgrenet C1-C4-alkylgruppe, en hydroksygruppe, en C^-^-a1koksygruppe, en merkaptogruppe, en Cj-C^-alkyltiogruppe, et halogenatom, en C1-C3-alkylsulfinyl-gruppe, en sulfamoylgruppe, en aminogruppe som kan være substituert med en alkylgruppe med 1-3 karbonatomer, en C^- C^-alkanoylgruppe eller en fenylgruppe; R^ og R2, som kan være like eller forskjellige, betyr et hydrogenatom eller en C1-C4alkylgruppe;
R3 betyr en lineær eller forgrenet C^-Cgalkylgruppe, hydroksy-C1-C6alkyl-, C1-C6alkoksy-C1-C6alkyl-, C^-Cgalkyltio-C^-Cgalkyl- eller cyano-Cj-Cs-alkyl-gruppe, en C3-5alkenylgruppe, en C3_4alkynylgruppe, en cyanogruppe, en fenylgruppe, en halogen-fenylgruppe, en benzylgruppe, en C3-s-cykloalkylgruppe, en C3-5-cykloalkyl-C1-C2-alkylgruppe, en furfurylgruppe eller en pyridylgruppe; og
R4 betyr et hydrogenatom, en C1-C3alkyl- eller C1-C3alkoksy-gruppe, et halogenatom, en cyano- eller karbamoylgruppe, tautomere former derav og syreaddisjonssalter derav, særlig fysiologisk forlikelige syreaddisjonssalter, så som salter dannet med saltsyre, svovelsyre, maleinsyre eller fumarsyre, karakterisert ved at a) en forbindelse med formel II
hvor R, Ri og R4 er som ovenfor angitt, omsettes med en forbindelse med formel III
hvor R2 og R3 er som ovenfor angitt, X betyr anionet av en uorganisk syre, og A betyr en benzoyloksygruppe, klor eller en etoksygruppe, eller b) en forbindelse med formel V
hvor R, Rj, R2 og R4 er som ovenfor angitt,
B betyr en egnet utgående gruppe, omsettes med et amin med formel VI
hvor R3 er som ovenfor angitt, og
eventuelt omdannes den fremstilte forbindelse til et syreaddisjonssalt derav.
2. Fremgangsmåte ifølge krav 1 for fremstilling av N-etyl-N</->[4-(2-metyl-imidazol-4-yl)fenyl]formamidin, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.
3. Fremgangsmåte ifølge krav 1 for fremstillling av N-isopropyl-N'-[4-(2-metyl-imidazol-4-yl)fenyl]formamidin, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.
4. Fremgangsmåte ifølge krav 1 for fremstilling av N-allyl-N'-[4-(2-metyl-imidazol-4-yl)fenyl]formamidin, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.
5. Fremgangsmåte ifølge krav 1 for fremstilling av N-tert.-butyl-N'-[4-(2-metyl-imidazol-4-yl)fenyl]formamidin, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.
6. Fremgangsmåte ifølge krav 1 for fremstilling av N-isopropyl-N'-[4-(2-hydroksy-imidazol-4-yl)fenyl]formamidin, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT8322110A IT1206498B (it) | 1983-07-18 | 1983-07-18 | Derivati amidinici del4-fenilmidazolo 2-sostituto processi per la loro preparazione e loro uso farmaceutico. |
Publications (3)
Publication Number | Publication Date |
---|---|
NO842921L NO842921L (no) | 1985-01-21 |
NO162857B true NO162857B (no) | 1989-11-20 |
NO162857C NO162857C (no) | 1990-02-28 |
Family
ID=11191639
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO842921A NO162857C (no) | 1983-07-18 | 1984-07-17 | Analogifremgangsmaate for fremstilling av terapeutisk aktive amidin-derivater av 2-substituert 4-fenylimidazol. |
Country Status (28)
Country | Link |
---|---|
US (1) | US4649150A (no) |
EP (1) | EP0131973B1 (no) |
JP (1) | JPS6038367A (no) |
KR (1) | KR910000661B1 (no) |
AT (1) | ATE45149T1 (no) |
AU (1) | AU565292B2 (no) |
CA (1) | CA1257274A (no) |
CS (1) | CS244141B2 (no) |
DD (1) | DD232696A5 (no) |
DE (1) | DE3479212D1 (no) |
DK (1) | DK350084A (no) |
ES (2) | ES8601910A1 (no) |
FI (1) | FI842432A (no) |
GB (1) | GB2149395B (no) |
GR (1) | GR79981B (no) |
HK (1) | HK74287A (no) |
HU (1) | HU193292B (no) |
IL (1) | IL72417A (no) |
IT (1) | IT1206498B (no) |
NO (1) | NO162857C (no) |
NZ (1) | NZ208920A (no) |
PH (1) | PH21566A (no) |
PL (2) | PL143732B1 (no) |
PT (1) | PT78935B (no) |
SG (1) | SG48687G (no) |
SU (2) | SU1322979A3 (no) |
YU (2) | YU43367B (no) |
ZA (1) | ZA845490B (no) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4888348A (en) * | 1986-09-04 | 1989-12-19 | Ciba-Geigy Corporation | Substituted thioureas, isothioureas and carbodiimides |
WO1999001128A1 (en) | 1997-07-03 | 1999-01-14 | Neurogen Corporation | Certain diarylimidazole derivatives; a new class of npy specific ligands |
US6887870B1 (en) | 1999-10-12 | 2005-05-03 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
NZ519272A (en) | 1999-12-16 | 2004-02-27 | Schering Corp | Substituted imidazole neuropeptide Y Y5 receptor antagonists |
FR2917087B1 (fr) | 2007-06-05 | 2012-09-21 | Galderma Res & Dev | Nouveaux 4-phenyl-imidazole-2-thiones comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique. |
US20230349922A1 (en) | 2020-08-11 | 2023-11-02 | Université De Strasbourg | H2 Blockers Targeting Liver Macrophages for the Prevention and Treatment of Liver Disease and Cancer |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1209431B (it) * | 1980-11-28 | 1989-07-16 | Angeli Inst Spa | Imidazolilfenil amidine, processi per la loro preparazione e loro impiego farmaceutico, ed intermedi di preparazione. |
-
1983
- 1983-07-18 IT IT8322110A patent/IT1206498B/it active
-
1984
- 1984-05-08 AT AT84200659T patent/ATE45149T1/de not_active IP Right Cessation
- 1984-05-08 DE DE8484200659T patent/DE3479212D1/de not_active Expired
- 1984-05-08 EP EP84200659A patent/EP0131973B1/en not_active Expired
- 1984-05-16 US US06/610,958 patent/US4649150A/en not_active Expired - Fee Related
- 1984-06-15 FI FI842432A patent/FI842432A/fi not_active Application Discontinuation
- 1984-07-02 YU YU1154/84A patent/YU43367B/xx unknown
- 1984-07-09 JP JP59142099A patent/JPS6038367A/ja active Pending
- 1984-07-11 PH PH30966A patent/PH21566A/en unknown
- 1984-07-16 PL PL1984254625A patent/PL143732B1/pl unknown
- 1984-07-16 IL IL72417A patent/IL72417A/xx unknown
- 1984-07-16 PL PL1984248779A patent/PL143303B1/pl unknown
- 1984-07-16 KR KR1019840004177A patent/KR910000661B1/ko active IP Right Grant
- 1984-07-16 DD DD84265319A patent/DD232696A5/de unknown
- 1984-07-17 HU HU842781A patent/HU193292B/hu not_active IP Right Cessation
- 1984-07-17 GR GR75327A patent/GR79981B/el unknown
- 1984-07-17 GB GB08418149A patent/GB2149395B/en not_active Expired
- 1984-07-17 SU SU843770847A patent/SU1322979A3/ru active
- 1984-07-17 CA CA000459030A patent/CA1257274A/en not_active Expired
- 1984-07-17 DK DK350084A patent/DK350084A/da not_active Application Discontinuation
- 1984-07-17 ES ES534376A patent/ES8601910A1/es not_active Expired
- 1984-07-17 NO NO842921A patent/NO162857C/no unknown
- 1984-07-17 NZ NZ208920A patent/NZ208920A/en unknown
- 1984-07-17 ZA ZA845490A patent/ZA845490B/xx unknown
- 1984-07-17 ES ES534375A patent/ES8505962A1/es not_active Expired
- 1984-07-18 CS CS845542A patent/CS244141B2/cs unknown
- 1984-07-18 PT PT78935A patent/PT78935B/pt unknown
- 1984-07-18 AU AU30800/84A patent/AU565292B2/en not_active Ceased
-
1985
- 1985-01-29 SU SU853844125A patent/SU1313345A3/ru active
-
1986
- 1986-06-26 YU YU1126/86A patent/YU43701B/xx unknown
-
1987
- 1987-06-03 SG SG486/87A patent/SG48687G/en unknown
- 1987-10-15 HK HK742/87A patent/HK74287A/xx unknown
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