NO873432L - Fremgangsmaate for fremstilling av imidazolforbindelser. - Google Patents
Fremgangsmaate for fremstilling av imidazolforbindelser.Info
- Publication number
- NO873432L NO873432L NO873432A NO873432A NO873432L NO 873432 L NO873432 L NO 873432L NO 873432 A NO873432 A NO 873432A NO 873432 A NO873432 A NO 873432A NO 873432 L NO873432 L NO 873432L
- Authority
- NO
- Norway
- Prior art keywords
- pyridyl
- methyl
- nujol
- melting point
- imidazole
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 35
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title description 50
- 238000002360 preparation method Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 81
- -1 nitro, amino, substituted amino, hydroxy Chemical group 0.000 claims description 75
- 150000003839 salts Chemical class 0.000 claims description 62
- 125000003545 alkoxy group Chemical group 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000004442 acylamino group Chemical group 0.000 claims description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 238000003379 elimination reaction Methods 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 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 3
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- 238000002844 melting Methods 0.000 description 281
- 230000008018 melting Effects 0.000 description 281
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 78
- 238000001819 mass spectrum Methods 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 68
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 150000002460 imidazoles Chemical class 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 238000001816 cooling Methods 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 235000011054 acetic acid Nutrition 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 238000006722 reduction reaction Methods 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- LDLJPVOBMJSVFC-UHFFFAOYSA-N 2-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)aniline Chemical compound CC=1N=C(C=2C(=CC=CC=2)N)NC=1C1=CC=CN=C1 LDLJPVOBMJSVFC-UHFFFAOYSA-N 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000010531 catalytic reduction reaction Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 230000002411 adverse Effects 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- SZWIBPZNNPKBKB-UHFFFAOYSA-N 3-[2-(2-methoxy-4-methylsulfanylphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC(SC)=CC=C1C1=NC(C=2C=NC=CC=2)=C(C)N1 SZWIBPZNNPKBKB-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- GZMDJFGGSUILDA-UHFFFAOYSA-N n-[2-chloro-5-methoxy-4-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)phenyl]acetamide Chemical compound COC1=CC(NC(C)=O)=C(Cl)C=C1C1=NC(C=2C=NC=CC=2)=C(C)N1 GZMDJFGGSUILDA-UHFFFAOYSA-N 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
- VXYIFBJCMQUFME-UHFFFAOYSA-N 1-hydroxyimino-1-pyridin-3-ylpropan-2-one Chemical compound CC(=O)C(=NO)C1=CC=CN=C1 VXYIFBJCMQUFME-UHFFFAOYSA-N 0.000 description 4
- JTMQPIWQTLVTLP-UHFFFAOYSA-N 2-chloro-4-methoxy-5-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)aniline Chemical compound COC1=CC(Cl)=C(N)C=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 JTMQPIWQTLVTLP-UHFFFAOYSA-N 0.000 description 4
- IEXWFKFVMYTVKZ-UHFFFAOYSA-N 2-chloro-5-methoxy-n-methyl-4-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)aniline Chemical compound C1=C(Cl)C(NC)=CC(OC)=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 IEXWFKFVMYTVKZ-UHFFFAOYSA-N 0.000 description 4
- AVNRKEGUSALBSN-UHFFFAOYSA-N 3-[2-(2,4-dimethoxyphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC(OC)=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 AVNRKEGUSALBSN-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- VDLSGWABQRFJOZ-UHFFFAOYSA-N n-[2-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 VDLSGWABQRFJOZ-UHFFFAOYSA-N 0.000 description 4
- UQPXJHUMNXDDGA-UHFFFAOYSA-N n-[3-methoxy-4-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)phenyl]acetamide Chemical compound COC1=CC(NC(C)=O)=CC=C1C1=NC(C=2C=NC=CC=2)=C(C)N1 UQPXJHUMNXDDGA-UHFFFAOYSA-N 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- OEXRZZMPNACKSP-UHFFFAOYSA-N 1-methyl-3-[2-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)phenyl]thiourea Chemical compound CNC(=S)NC1=CC=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 OEXRZZMPNACKSP-UHFFFAOYSA-N 0.000 description 3
- IFTYKUALNOLUPZ-UHFFFAOYSA-N 1-methyl-3-[2-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)phenyl]urea Chemical compound CNC(=O)NC1=CC=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 IFTYKUALNOLUPZ-UHFFFAOYSA-N 0.000 description 3
- BXLCAZBQEADHJQ-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)-5-ethyl-1h-imidazol-4-yl]pyridine Chemical compound CCC=1NC(C=2C=C(OC)C(OC)=CC=2)=NC=1C1=CC=CC=N1 BXLCAZBQEADHJQ-UHFFFAOYSA-N 0.000 description 3
- GIBXUWRWLXXVEJ-UHFFFAOYSA-N 3-[2-(2,4-dimethoxyphenyl)-5-ethyl-1h-imidazol-4-yl]pyridine Chemical compound CCC=1N=C(C=2C(=CC(OC)=CC=2)OC)NC=1C1=CC=CN=C1 GIBXUWRWLXXVEJ-UHFFFAOYSA-N 0.000 description 3
- KORRLLBRODMOKX-UHFFFAOYSA-N 3-[2-(2-fluorophenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound CC=1N=C(C=2C(=CC=CC=2)F)NC=1C1=CC=CN=C1 KORRLLBRODMOKX-UHFFFAOYSA-N 0.000 description 3
- LZZKPPHJWYRXKH-UHFFFAOYSA-N 3-[2-(2-methoxy-4-methylsulfinylphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 LZZKPPHJWYRXKH-UHFFFAOYSA-N 0.000 description 3
- CHFSSUXKCICDPZ-UHFFFAOYSA-N 3-[2-(2-methoxy-4-methylsulfonylphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC(S(C)(=O)=O)=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 CHFSSUXKCICDPZ-UHFFFAOYSA-N 0.000 description 3
- LAXFXVCOZXSTQL-UHFFFAOYSA-N 3-[2-(2-methoxy-4-phenylmethoxyphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound C=1C=C(C=2NC(=C(C)N=2)C=2C=NC=CC=2)C(OC)=CC=1OCC1=CC=CC=C1 LAXFXVCOZXSTQL-UHFFFAOYSA-N 0.000 description 3
- QVNXLVKVZJSJMC-UHFFFAOYSA-N 3-[2-(2-methoxyphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC=CC=C1C1=NC(C=2C=NC=CC=2)=C(C)N1 QVNXLVKVZJSJMC-UHFFFAOYSA-N 0.000 description 3
- QRPGPBXSILZFFP-UHFFFAOYSA-N 3-[2-(4-chloro-2-methoxy-5-nitrophenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC(Cl)=C([N+]([O-])=O)C=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 QRPGPBXSILZFFP-UHFFFAOYSA-N 0.000 description 3
- VORQOUQLEKZGIZ-UHFFFAOYSA-N 3-[2-(4-chloro-2-methoxyphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound COC1=CC(Cl)=CC=C1C1=NC(C=2C=NC=CC=2)=C(C)N1 VORQOUQLEKZGIZ-UHFFFAOYSA-N 0.000 description 3
- YJNFQAGBTGGRDN-UHFFFAOYSA-N 3-[2-(5-bromo-2,4-dimethoxyphenyl)-5-methyl-1h-imidazol-4-yl]pyridine Chemical compound C1=C(Br)C(OC)=CC(OC)=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 YJNFQAGBTGGRDN-UHFFFAOYSA-N 0.000 description 3
- NQYSBVGHSRVVJW-UHFFFAOYSA-N 3-[5-methyl-2-(2-nitrophenyl)-1h-imidazol-4-yl]pyridine Chemical compound CC=1N=C(C=2C(=CC=CC=2)[N+]([O-])=O)NC=1C1=CC=CN=C1 NQYSBVGHSRVVJW-UHFFFAOYSA-N 0.000 description 3
- AZGSDCUHMZSAGB-UHFFFAOYSA-N 3-methoxy-4-(5-methyl-4-pyridin-3-yl-1H-imidazol-2-yl)phenol Chemical compound COC1=CC(O)=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 AZGSDCUHMZSAGB-UHFFFAOYSA-N 0.000 description 3
- PBFMYDIMFVZMLC-UHFFFAOYSA-N 3-methoxy-4-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)aniline Chemical compound COC1=CC(N)=CC=C1C1=NC(C=2C=NC=CC=2)=C(C)N1 PBFMYDIMFVZMLC-UHFFFAOYSA-N 0.000 description 3
- IIDYLOIANVDZJH-UHFFFAOYSA-N 4-[2-(2,4-dimethoxyphenyl)-5-ethyl-1h-imidazol-4-yl]pyridine Chemical compound CCC=1NC(C=2C(=CC(OC)=CC=2)OC)=NC=1C1=CC=NC=C1 IIDYLOIANVDZJH-UHFFFAOYSA-N 0.000 description 3
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- 239000000872 buffer Substances 0.000 description 1
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 229940062993 ferrous oxalate Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 125000006635 hexyloxycarbonylamino group Chemical group 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- OWZIYWAUNZMLRT-UHFFFAOYSA-L iron(2+);oxalate Chemical compound [Fe+2].[O-]C(=O)C([O-])=O OWZIYWAUNZMLRT-UHFFFAOYSA-L 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- ZDRRWYKWNKGSPK-UHFFFAOYSA-N n,3-dimethyl-4-(5-methyl-4-pyridin-3-yl-1h-imidazol-2-yl)aniline Chemical compound CC1=CC(NC)=CC=C1C1=NC(C)=C(C=2C=NC=CC=2)N1 ZDRRWYKWNKGSPK-UHFFFAOYSA-N 0.000 description 1
- YFTSXEONXVOMIY-UHFFFAOYSA-N n-(2-chloro-4-formyl-5-methoxyphenyl)acetamide Chemical compound COC1=CC(NC(C)=O)=C(Cl)C=C1C=O YFTSXEONXVOMIY-UHFFFAOYSA-N 0.000 description 1
- XGNDNYNNDNJPKV-UHFFFAOYSA-N n-[2-chloro-4-(1-hydroxy-4-methyl-5-pyridin-3-ylimidazol-2-yl)-5-methoxyphenyl]-n-methylacetamide Chemical compound COC1=CC(N(C)C(C)=O)=C(Cl)C=C1C(N1O)=NC(C)=C1C1=CC=CN=C1 XGNDNYNNDNJPKV-UHFFFAOYSA-N 0.000 description 1
- HZCGSQHHWYQFSQ-UHFFFAOYSA-N n-[2-chloro-4-(1-hydroxy-4-methyl-5-pyridin-3-ylimidazol-2-yl)-5-methoxyphenyl]acetamide Chemical compound COC1=CC(NC(C)=O)=C(Cl)C=C1C(N1O)=NC(C)=C1C1=CC=CN=C1 HZCGSQHHWYQFSQ-UHFFFAOYSA-N 0.000 description 1
- UXWBXXCPBJIPBB-UHFFFAOYSA-N n-[2-chloro-4-(1-hydroxy-4-methyl-5-pyridin-3-ylimidazol-2-yl)phenyl]acetamide Chemical compound C1=C(Cl)C(NC(=O)C)=CC=C1C(N1O)=NC(C)=C1C1=CC=CN=C1 UXWBXXCPBJIPBB-UHFFFAOYSA-N 0.000 description 1
- YEDFDODUJUPVEZ-UHFFFAOYSA-N n-[4-(1-hydroxy-4-methyl-5-pyridin-3-ylimidazol-2-yl)phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C(N1O)=NC(C)=C1C1=CC=CN=C1 YEDFDODUJUPVEZ-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000006634 pentyloxycarbonylamino group Chemical group 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 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
- 230000009466 transformation Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- WORJEOGGNQDSOE-ASTXPPQBSA-N trichloro(deuterio)methane;trideuterio(deuteriooxy)methane Chemical compound [2H]C(Cl)(Cl)Cl.[2H]OC([2H])([2H])[2H] WORJEOGGNQDSOE-ASTXPPQBSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Resins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Den foreliggende oppfinnelse angår fremstilling av hittil ukjente imidazolforbindelser og farmasøytisk godtagbare salter derav.
Oppfinnelsen angår særlig fremstilling av hittil ukjente imidazolforbindelser og farmasøytisk godtagbare salter derav,
som har farmakologisk virkning.
Et av formålene med oppfinnelsen er å fremstille hittil ukjente og nyttige imidazolforbindelser og farmasøytisk godtagbare salter derav, som har kardiotonisk virkning og evne til å redusere hjertefrekvensen, antiblodplatevirkning og/eller antiinflammatorisk virkning.
Et farmasøytisk preparat kan som aktivt stoff inneholde nevnte imidazolforbindelser eller farmasøytisk godtagbare salter derav.
Hjertelidelser, trombose og inflammasjon hos mennesker eller dyr kan behandles ved administrering av nevnte imidazolforbindelser eller farmasøytisk godtagbare salter derav.
Noen imidazolforbindelser med substituert eller usubstituert fenyl ved 2-stillingen i imidazolringen er kjent og beskrevet i US 3.707.475, US 4.440,774, etc.
Forbindelsene fremstilt ifølge foreliggende oppfinnelse er hittil ukjente og karakteriseres ved at de har følgende generelle formel I:
hvor
R1 er pyridyl,
R<2>er hydrogen, lavere alkyl eller hydroksy(lavere)alkyl, R<3>er hydrogen, hydroksy eller lavere alkyl, og
R<4>er aryl, som eventuelt er substituert med én eller flere substituenter valgt fra gruppen bestående av lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, nitro, amino, substituert amino, hydroksy, lavere alkoksy, lavere alkynyloksy, substituert eller usubstituert ar(lavere)alkoksy, halogen, halogen(lavere)alkyl, karboksy og forestret karboksy.
Forbindelsen med formel I eller et salt derav kan fremstilles som vist i følgende reaksjonsskjemaer.
hvor
R<3>aer lavere alkyl,
R<4>aer aryl substituert med acylamino og lavere alkoksy, med acylamino, lavere alkoksy og halogen, eller med N-acyl-N-lavere alkylamino, lavere alkoksy og halogen,
R<4>ber aryl substituert med amino og lavere alkoksy, med
amino, lavere alkoksy og halogen, eller med lavere
alkylamino, lavere alkoksy og halogen,
R<4>cer aryl substituert med amino, med amino og lavere alkyl,
med amino og lavere alkoksy, med amino og halogen, med amino, lavere alkoksy og nitro, eller med amino, lavere
alkoksy og halogen,
R4 ei er aryl substituert med acylamino, med acylamino og lavere alkyl, med acylamino og lavere alkoksy, med acylamino og halogen, med acylamino, lavere alkoksy og nitro, eller med
acylamiano, lavere alkoksy og halogen,
R<4>eer aryl substituert med lavere alkyltio og lavere alkoksy, R4 f er aryl substituert med lavere alkylsulfinyl og lavere
alkoksy, eller med lavere alkylsulfonyl og lavere alkoksy, R<4>g er aryl substituert med nitro, med nitro og lavere alkoksy,
eller med nitro, lavere alkoksy og halogen,
R<4>her aryl substituert med amino, med amino og lavere alkoksy,
eller med amino, lavere alkoksy og halogen,
R<4>i er aryl substituert med ar(lavere)alkoksy og lavere alkoksy, R<4>j er aryl substituert med hydroksy og lavere alkoksy,
R5 er halogen,
R<6>og R<7>er hver lavere alkoksy eller substituert amino,
R8 og R<9>er hver lavere alkoksy,
én av X<1>og X<2>er 0, og den annen er en gruppe med formlen:
=N-R3 , hvor R<3>har den ovenfor angitte betydning, og
R1, R2 , R3 og R<4>hver har den ovenfor angitte betydning.
Hensiktsmessige eksempler på de forskjellige definisjoner
i beskrivelsen, og som ligger innenfor oppfinnelsens ramme, er detaljert angitt i det følgende.
Uttrykkket "lavere" angir en gruppe med 1-6 karbonatomer, hvis ikke annet er angitt.
En egnet "lavere alkyl" og lavere alkyldel i uttrykket "hydroksy(lavere)alkyl" kan være lineær eller forgrenet, så som metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, heksyl eller lignende, hvorav den foretrukne er Ci-4-alkyl, og den mest foretrukne er metyl eller etyl.
En egnet "aryl" kan være fenyl, naftyl, lavere alkyl-substituert fenyl (f.eks. tolyl, mesityl, kumenyl, etc.) eller lignende, hvorav den foretrukne er fenyl eller tolyl.
Arylgruppen R<4>kan være substituert med lavere alkyltio (f.eks. metyltio, etyltio, propyltio, isopropyltio, butyltio, isobutyltio, tert.butyltio, pentyltio, heksyltio, etc.), lavere alkylsulfinyl (f.eks. metylsulfinyl, etylsulfinyl, propyl-sulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, tert.butylsulfinyl, pentylsulfinyl, heksylsulfinyl, etc), lavere alkylsulfonyl (f.eks. metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutyl-sulf onyl, tert.butylsulfonyl, pentylsulfonyl, heksylsulfonyl, etc.), nitro, amino, substituert amino så som mono- eller di(lavere)alkylamino (f.eks. metylamino, etylamino, propylamino, dimetylamino, dietylamino, metyletylamino, etc.), acylamino [f.eks. lavere alkanoylamino (f.eks. formylamino, acetylamino, propionylamino, heksanoylamino, pivaloylamino, etc), substituert eller usubstituert aroylamino (f.eks. benzoylamino, 3-nitro-benzoylamino, 4-klorbenzoylamino, etc.), lavere alkoksykarbonylamino (f.eks. metoksykarbonylamino, etoksykarbonylamino, tert.butoksykarbonylamino, tert.pentyloksykarbonylamino, heksyloksykarbonylamino, etc.), ar(lavere)alkoksykarbonylamino (f.eks. benzyloksykarbonylamino, etc.), lavere alkansulfonylamino (f.eks. mesylamino, etansulfonylamino, etc.), arensulfonylamino (f.eks. benzensulfonylamino, tosylamino, etc.), ureido, tioureido, lavere alkylureido (f.eks. metylureido, etylureido, propylureido, isopropylureido, etc.), lavere alkyltioureido (f.eks. metyltioureido, etyltioureido, propyltioureido, isopropyltioureido, etc), aroyltioureido (f.eks. benzoyltioureido, etc.), etc.], N-acyl-N-lavere alkylamino [f.eks. N-lavere alkanoyl-N-lavere alkylamino (f.eks. N-acetyl-N-metylamino, etc), etc] eller lignende, hydroksy, lavere alkoksy (f.eks. metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, tert.butoksy, pentyloksy, heksyloksy, etc), lavere alkynyloksy (f.eks. etynyloksy, propynyloksy, butynyloksy, etc), substituert eller usubstituert ar(lavere)alkoksy (f.eks. benzyloksy, fenetyloksy, benzhydryloksy, 4-klorbenzyloksy, etc), halogen (f.eks. fluor, klor, brom og jod), halogen-(lavere)alkyl (f.eks. klormetyl, kloretyl, trifluormetyl,
etc), karboksy eller forestret karboksy [f.eks. lavere alkoksykarbonyl (f.eks. metoksykarbonyl, etoksykarbonyl, tert.butoksykarbonyl, tert.pentyloksykarbonyl, heksyloksy-karbonyl, etc), etc), hvor antallet av substituent (er) er 1-3, og flere substituenter kan være like eller forskjellige.
Egnede substituenter på arylgruppen R<4>a-R<4>j kan være de samme som nevnt for substituentene på arylgruppen R4 .
Egnet "halogen" R5 , "lavere alkoksy" og "substituert
amino" R<6>og R<7>og "lavere alkoksy" R<8>og R<9>kan være de samme som nevnt for substituentene på arylgruppen R4 .
Egnede farmasøytisk godtagbare salter av de omhandlede forbindelser I kan være konvensjonelle ikke-toksiske salter og omfatter organiske syreaddisjonssalter (f.eks. formiat, acetat, trifluoracetat, maleat, tartrat, metansulfonat, benzensulfonat, toluensulfonat, etc.), uorganiske syreaddisjonssalter (f.eks. hydroklorid, hydrobromid, sulfat, fosfat, etc), salter med en sur aminosyre (f.eks. asparaginsyresalt, glutaminsyresalt,
etc.) og lignende.
Med hensyn til salter av forbindelsene la-Iq i fremgangsmåtevariantene 1-10 skal det bemerkes at disse forbindelser ligger innenfor rammene av forbindelsen I, og følgelig er egnede eksempler på salter av disse forbindelser de samme som nevnt for forbindelsen I ifølge oppfinnelsen.
Fremgangsmåtevariantene for fremstilling av forbindelsene I er forklart i detaljer nedenfor.
Fremgangsmåtevariant 1
Forbindelsen I eller et salt derav kan fremstilles ved at en forbindelse II eller et salt derav omsettes med en forbindelse III eller et salt derav i nærvær av ammoniakk eller et middel som frigjør ammoniakk.
Egnede salter av forbindelsen II kan være de samme som nevnt for forbindelsen I og dessuten et basesalt så som et alkalimetallsalt (f.eks. litiumsalt, natriumsalt, kaliumsalt, etc.) eller lignende.
Egnede salter av forbindelsen III kan være de samme som nevnt for forbindelsen I.
Reaksjonen utføres vanligvis i et konvensjonelt opp-løsningsmiddel så som vann, alkohol (f.eks. metanol, etanol, propanol, etc), eddiksyre, dioksan, tetrahydrofuran, metylenklorid, kloroform, acetonitril, N,N-dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløsnings-middel, som ikke har noen uheldig innflytelse på reaksjonen, eller en blanding derav.
Egnede midler som frigjør ammoniakk, kan være ammonium-lavere alkanoat (f. eks. ammoniumf ormiat, amrnoniumacetat, ammoniumpropionat, ammoniumbutyrat, etc.), ammoniumkarbonat, ammoniumhydrogenkarbonat, ammoniumkarbamat eller lignende.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved omgivelsestemperatur eller under temperaturbetingelser varier ende fra avkjøling til oppvarmning.
Fremgangsmåtevariant 2
Forbinde! san Ib eller et salt derav kan fremstilles ved
at en forbindelse T> dier et salt derav reduseres.
Reduksjonen kan ui: f ørts på konvensjonell r. å u, nemlig ved kjemisk reduksjon e" ': i.-r katalytisk reduksjon.
Egnede reduks j onsm idi er som kan anvendes til kjemisk reduksjon, kan være en metallhydridfocbi :idels<- så som en aiuriiniurrihydriof orbindeise (f 1: 1 l upi a 1 Muiniuinhydrid , nat ri unial uroiniumhydr id , aluminiumhydrid, li t lumtrimetoksy-alumin:; uinhydrid, litiumtr i tert. butoksya" ur.:; niumnydrid, etc.) ,
en borhydridforbindelse (f.eks. natriumborhydrid, litiumborhydrid, na triumcyanoborhydrid, tetrametylammoniumborhydrid, etc.), boran, diboran, et aluminiumhalogenid (f.eks.aluminium-klorid, etc.), et fosfortrihalogenid (f.eks. fosfortriklorid, fosfortribromid, etc.), en tri(lavere)alkylfosfitt (f.eks. trietylfosfitt, etc.), ferrooksalat, en kombinasjon av metall (f.eks. tinn, sink, jern, etc.) eller en metallforbindelse (f.eks. kromklorid, kromacetat, etc.) og en organisk eller uorganisk syre (f.eks. maursyre, eddiksyre, propionsyre,
trifluoreddiksyre, p-toluensulfonsyre, saltsyre, bromhydrogensyre, etc.) eller lignende.
Egnede katalysatorer som kan anvendes ved katalytisk reduksjon, kan være konvensjonelle så som en platinakatalysator (f.eks. platinaplate, platinasvamp, platinasort, kolloidalt platina, platinaoksyd, platinatråd, etc), en palladium-katalysator (f.eks. palladiumsvamp, palladiumsort, palladium-oksyd, palladium på trekull, kolloidalt palladium, palladium på bariumsulfat, palladium på bariumkarbonat, etc.), en nikkel-katalysator (f.eks. redusert nikkel, nikkeloksyd, Raney-nikkel, etc.), en koboltkatalysator (f.eks. redusert kobolt, Raney-kobolt, etc), en jernkatalysator (f.eks. redusert jern, Raney-jern, etc), en kobberkatalysator (f.eks. redusert kobber, Ullman-kobber, etc.) eller lignende.
Reaksjonen utføres vanligvis i et oppløsningsmiddel så som vann, alkohol (f.eks. metanol, etanol, propanol, etc.), eddiksyre, dietyleter, dioksan, tetrahydrofuran, metylenklorid, kloroform, N,N-dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløsningsmiddel som ikke har noen uheldig innflytelse på reaksjonen, eller en blanding derav.
Reaksjonen utføres fortrinnsvis under noe mildere be-tingelser så som under temperaturbetingelser varierende fra avkjøling til oppvarmning.
Under denne reaksjonsbetingelse kan det R<2>i betydningen hydroksy(lavere)alkyl oppnås fra den tilsvarende lavere alkylforbindelse, og det således oppnådde produkt ligger likeledes innenfor rammene av denne fremgangsmåte.
Fremgangsmåtevariant 3
Forbindelsen Ic eller et salt derav kan fremstilles ved at en forbindelse Ib eller et salt derav underkastes en lavere alkyleringsreaksjon.
Egnede lavere alkyleringsmidler som kan anvendes ved denne reaksjon, kan være lavere alkylhalogenid (f.eks. metyljodid, etyljodid, propyljodid, butyljodid, butylklorid, pentylklorid, etc.), 2-lavere-alkyltio-2-imidazolin (f.eks. 2-metyltio-2-imidazolin, etc.) lavere alkylsulfonat (f.eks. metylbenzen- sulfonat, etylmesylat, etc), di-(lavere)alkylsulfat (f.eks. dimetylsulfat, dietylsulfat, etc) eller lignende.
Reaksjonen utføres vanligvis i nærvær av en base så som et alkalimetall (f.eks. natrium, kalium, etc), et jordalkalimetall (f.eks. magnesium, kalsium, etc), hydridet eller hydroksydet derav, et alkalimetallalkoksyd (f.eks. natriummetoksyd, natriumetoksyd, kaliumtert.butoksyd, etc), en trialkylamin (f.eks. trimetylamin, trietylamin, etc), pikolin, 1,5-diaza-bicyklo(4.3.0)non-5-en, l,4-diazabicyklo(2.2.2)-oktan, 1,8-diaza-bicyklo(5.4.0)undec-7-en eller lignende.
Reaksjonen utføres vanligvis i et konvensjonelt opp-løsningsmiddel så som vann, alkohol (f.eks. metanol, etanol, propanol, etc.), tetrahydrofuran, dioksan, etylacetat, metylenklorid, N,N-dimetylformamid, dimetylsulfoksyd, dietyleter eller et hvilket som helst annet organisk oppløsningsmiddel som ikke har noen uheldig innflytelse på reaksjonen. Hvis det ovennevnte lavere alkyleringsmiddel er i væskeform, kan det likeledes anvendes som oppløsningsmiddel.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved omgivelsestemperatur eller under temperaturbetingelser varierende fra avkjøling til oppvarmning.
Fremqanqsmåtevariant 4
Forbindelsen le eller et salt derav kan fremstilles ved at en forbindelse Id eller et salt derav underkastes en reaksjon for eliminering av acylgruppen.
Reaksjonen utføres i overensstemmelse med en konvensjonell metode så som hydrolyse, reduksjon eller lignende.
Hydrolysen kan fortrinnsvis utføres i nærvær av en base eller en syre, herunder Lewis-syre. En egnet base kan være et alkalimetall (f.eks. natrium, kalium, etc), et jordalkalimetall (f.eks. magnesium, kalsium, etc), hydroksydet eller karbonatet eller hydrogenkarbonatet derav, et alkalimetall-alkanoat (f.eks. natriumacetat, etc.) eller lignende. En egnet syre kan omfatte en organisk syre (f. eks. maursyre, eddiksyre, propionsyre, trikloreddiksyre, trifluoreddiksyre, etc.) og en uorganisk syre (f.eks. saltsyre, bromhydrogensyre, svovelsyre, etc). Eliminering under anvendelse av en Lewis-syre så som trihalogeneddiksyre (f.eks. trikloreddiksyre, trifluoreddiksyre, etc.) eller lignende utføres fortrinnsvis i nærvær av kationopptagelsesmidler (f.eks. anisol, fenol, etc).
Reaksjonen utføres vanligvis i et oppløsningsmiddel så som vann, alkohol (f.eks. metanol, etanol, etc), metylenklorid, tetrahydrofuran, en blanding derav eller et hvilket som helst annet oppløsningsmiddel som ikke har noen uheldig innflytelse på reaksjonen. En flytende base eller syre kan også anvendes som oppløsningsmiddel. Reaksjonstemperaturen er ikke kritisk,
og reaksjonen utføres vanligvis under temperaturbetingelser varierende fra avkjøling til oppvarmning.
Den reduksjonsmetode som kan anvendes for eliminerings-reaksjonen, kan omfatte kjemisk reduksjon og katalytisk reduksjon.
Egnede reduksjonsmidler som kan anvendes ved kjemisk reduksjon, kan være en kombinasjon av metall (f.eks. tinn, sink, jern, etc.) eller en metallforbindelse (f.eks. kromklorid, kromacetat, etc.) og en organisk eller uorganisk syre (f.eks. maursyre, eddiksyre, propionsyre, trifluoreddiksyre, p-toluensulfonsyre, saltsyre, bromhydrogensyre, etc.),
Egnede katalysatorer som kan anvendes ved katalytisk reduksjon, kan være de samme som nevnt under Fremgangsmåtevariant 2.
Reduksjonen utføres vanligvis i et konvensjonelt opp-løsningsmiddel, som ikke har noen uheldig innflytelse på reaksjonen, så som vann, metanol, etanol, propanol, N,N-dimetyl-formamid eller en blanding derav. Dessuten kan de ovennevnte syrer, som kan anvendes ved kjemisk reduksjon, hvis de er i flytende form, likeledes anvendes som oppløsningsmiddel. Videre kan et egnet oppløsningsmiddel som kan anvendes ved katalytisk reduksjon, være de ovennevnte oppløsningsmidler og andre konvensjonelle oppløsningsmidler så som dietyleter, dioksan, tetrahydrofuran, etc. eller en blanding derav. Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under temperaturbetingelser varierende fra avkjøling til oppvarmning.
Fremqangsmåtevariant 5
Forbindelsen lg eller et salt derav kan fremstilles ved at en forbindelse If eller et salt derav omsmttes med et acyleringsmiddel.
Egnede acyleringsmidler kan være de tilsvarende syre-forbindelser, som har formelen: R<10->OH, hvor R<10>er acyl, og reaktive derivater derav, og de tilsvarende isocyanat- eller isotiocyanatforbindelser.
Som slike egnede reaktive derivater kan nevnes syrehalogenider, syreanhydrider, aktive amider og aktive estere. Egnede eksempler er syrehalogenider så som syreklorid og syre-bromid, blandede syreanhydrider med forskjellige syrer (f.eks. substituert fosforsyre så som dialkylfosforsyre, svovelsyre, alifatisk karboksylsyre, aromatisk karboksylsyre, etc), symmetriske syreanhydrider, aktive amider med forskjellige imidazoler, og aktive estere så som cyanometylester, metoksy-metylester, p-nitrofenylester, 2,4-dinitrofenylester, penta-klorfenylester, fenylazofenylester, karboksymetyltioester og N-hydroksysuccinimidester. Slike reaktive derivater kan velges avhengig av den type acylgruppe som skal innføres.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsnings-middel så som alkohol (f.eks. metanol, etanol, etc.), metylenklorid, kloroform, benzen, toluen, pyridin, dietyleter, dioksan, tetrahydrofuran, aceton, acetonitril, etylacetat, eddiksyre, N,N-dimetylformamid eller et hvilket som helst annet organisk oppløsningsmiddel, som ikke har noen uheldig innflytelse på reaksjonen. Hvis acyleringsmidlet er i flytende form, kan det likeledes anvendes som oppløsningsmiddel. Hvis karboksyl-syreforbindelsene anvendes som acyleringsmiddel i fri syreform eller i saltform, foretrekkes det å utføre reaksjonen i nærvær av et konvensjonelt kondenseringsmiddel så som N,N'-dicyklo-heksylkarbodiimid eller lignende.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen kan utføres ved omgivelsestemperatur eller under temperaturbetingelser varierende fra oppvarmning til avkjøling.
Reaksjonen utføres fortrinnsvis i nærvær av en uorganisk base, f.eks. et alkalimetallhydroksyd så som natriumhydroksyd eller kaliumhydroksyd, eller et alkalimetallkarbonat eller -hydrogenkarbonat så som natriumkarbonat, kaliumkarbonat, natriumhydrogenkarbonat eller kaliumhydrogenkarbonat, eller i nærvær av en organisk base, f.eks. et tertiært amin så som trietylamin, pyridin eller N,N-dimetylanilin.
Fremgangsmåtevariant 6
Forbindelsen li eller et salt derav kan fremstilles ved at en forbindelse Ih eller et salt derav oksyderes.
Denne oksydasjonsreaksjon kan utføres ved en konvensjonell metode, som anvendes til transformasjon av -S- til -SO- eller -SO2-, f.eks. ved å anvende et oksydasjonsmiddel så som m-klorperbenzoesyre, perbenzoesyre, pereddiksyre, ozon, hydrogen-peroksyd, perjodsyre, kaliumpermanganat eller lignende.
Reaksjonen utføres vanligvis i et oppløsningsmiddel så som vann, aceton, dioksan, acetonitril, eddiksyre, kloroform, etylenklorid, etylacetat eller et hvilket som helst annet oppløsningsmiddel som ikke har noen uheldig innflytelse på reaksjonen.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres fortrinnsvis under avkjøling eller ved omgivelsestemperatur .
Fremgangsmåtevariant. 7
Forbindelsen Ik eller et salt derav kan fremstilles ved at en forbindelse Ij eller et salt derav reduseres.
Reduksjonen kan utføres på konvensjonell måte, nemlig ved kjemisk reduksjon eller katalytisk reduksjon.
Egnede reduksjonsmidler som kan anvendes ved kjemisk reduksjon, kan være en kombinasjon av metall (f.eks. tinn, sink, jern, etc.) og ammoniumklorid eller en base (f.eks. ammoniakk, natriumhydroksyd, etc.) en kombinasjon av ovennevnte metall eller metallforbindelse (f. eks. kromklorid, kromacetat, etc,) og en organisk eller uorganisk syre (f.eks. maursyre, eddiksyre, propionsyre, trifiuoreddiksyre, p-toluensyre, saltsyre, bromhydrogensyre, etc.), et alkalimetallborhydrid (f.eks. litiumborhydrid, natriumborhydrid, kal iumborhydrid, etc.), et alkalimetalicyanoborhydrid (f.eks. natriumcyanoborhydrid, etc.) eller et aikalimetallaiuminiumhydrid (f. eks. litiumaluminium-hydrid, etc.) eller lignende.
Egnede katalysatorer som kan anvendes ved katalytisk reduksjon, kan være de samme som nevnt under Fremgangsmåtevariant 2.
Reaksjonen ved denne fremgangsmåtevariant utføres vanligvis i et oppløsningsmiddel så som vann, alkohol (f.eks. metanol, etanol, propanol, etc), eddiksyre, dietyleter, dioksan, tetrahydrofuran, etc. eller en blanding derav.
Reaksjonen utføres vanligvis under temperaturbetingelser varierende fra oppvarmning til avkjøling.
Fremgangsmåtevariant 8
Forbindelsen eller et salt derav kan fremstilles ved at en forbindelse II eller et salt derav reduseres.
Reaksjonen kan utføres på i det vesentlige samme måte som den i Fremgangsmåtevariant 7 beskrevne, og reaksjonsmåten og reaksjonsbetingelsene for denne reaksjon kan derfor være de samme som anført for Fremgangsmåtevariant 7.
Fremgangsmåtevariant 9
Forbindelsen Io eller et salt derav kan fremstilles ved at en forbindelse In eller et salt derav halogeneres.
Halogeneringen utføres i nærvær av et halogeneringsmiddel.
Egnede halogeneringsmidler til denne reaksjon kan være halogen (f.eks. klor, brom, jod, etc,), sulfurylhalogenid (f.eks. sulfurylklorid, sulfurylbromid, etc.), N-halogen-succinimid (f.eks. N-klorsuccinimid, N-bromsuccinimid, etc.), pyridiniumhydrohalogenidperhalogenid (f.eks. pyridiniumhydrobromidperbromid, pyridiniumhydrokloridperklorid, etc.), kvaternært ammoniumperhalogenid (f.eks. fenyltrimetylammonium-perbromid, etc.), co - trihalogenacetof enon (f.eks. co-tribromaceto-fenon, etc.), seleniumoksyklorid og lignende. Disse halogeneringsmidler kan velges i overensstemmelse med den type utgangsforbindelse In som skal anvendes.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsnings-middel så som kloroform, metylenklorid, karbontetraklorid, N,N-dimetylformamid, eddiksyre, en blanding av hydrogenhalog- enid (f.eks. hydrogenbromid, hydrogenklorid, etc.) og eddiksyre eller lignende.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved omgivelsestemperatur eller under temperaturbetingelser varierende fra avkjøling til oppvarmning.
Fremgangsmåtevariant 10
Forbindelsen Iq eller et salt derav kan fremstilles ved at en forbindelse lp eller et salt derav reduseres.
Reaksjonen kan utføres ved en katalytisk reduksjonsmetode.
Den katalytiske reduksjon kan utføres på i det vesentlige samme måte som den i Fremgangsmåtevariant 7 beskrevne, og reaksjonsmåten og reaksjonsbetingelsene for denne reaksjon kan derfor være de samme som de under Fremgangsmåtevariant 7 anførte.
De forbindelser som oppnås ved ovennevnte fremgangsmåter, isoleres og renses ved en konvensjonell metode så som pulveriser-ing, omkrystallisasjon, kolonnekromatografi, gjenutfeining eller lignende.
De hittil ukjente imidazolforbindelser I og farmasøytisk godtagbare salter derav har kardiotonisk virkning og evne til å redusere hjertefrekvensen, antiblodplatevirkning og/eller anti-inflammatorisk virkning og er nyttige til terapeutisk behandling av hjertelidelser så som hjerteinsufficiens, trombose og inflammasjon.
Til terapeutiske formål kan forbindelsen I fremstilt ifølge oppfinnelsen eller et farmasøytisk godtagbart salt derav anvendes i form av et farmasøytisk preparat inneholdende en av forbindelsene som aktivt stoff i blanding med en farmasøytisk godtagbar bærer så som en organisk eller uorganisk fast eller flytende eksipiens, som er egnet for oral, parenteral eller utvortes administrering. De farmasøytiske preparater kan være kapsler, tabletter, drageer, granuler, oppløsninger, suspensjoner, emulsjoner eller lignende. Om ønsket kan preparatene inneholde hjelpestoffer, stabiliseringsmidler, fuktemidler eller emulgeringsmidler, buffere og andre almindelig anvendte tilsetningsstoffer.
Idet dosen av forbindelsen I varierer avhengig av pasientens alder og tilstand, kan en gjennomsnittlig enkeltdose på ca. 0,1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg og 1000 mg av forbindelsen I være virksom til behandling av ovennevnte lidelser. Vanligvis kan det administreres mengder på mellom 0,1 mg/kg legemsvekt og ca. 1.000 mg/kg legemsvekt daglig.
For å illustrere nytten av forbindelsene I fremstilt ifølge oppfinnelsen er de farmakologiske testdata for noen representa-tive forbindelser blant forbindelsene I vist i det følgende.
Testforbindelser
2-(2,4-Dimetoksyfenyl)-5-metyl-4-<3-pyridyl)imidazol
(herefter benevnt Forbindelse a)
2-(2,4-Dimetoksyfenyl)-4-etyl-5-(3-pyridy1)imidazol
(herefter benevnt Forbindelse b)
2-(2-Metoksy-4-metyltiofenyl)-5-mety1-4-(3-pyridyl)imidazol
(herefter benevnt Forbindelse c)
2-(3,4-Dimetoksyfenyl)-5-etyl-4-(2-pyridy1)imidazol
(herefter benevnt Forbindelse d)
2-(2,4-Dimetoksyfenyl)-5-metyl-4-(4-pyridyl)imidazol
(herefter benevnt Forbindelse e)
2-(2,4-Dimetoksyfenyl)-5-etyl-4-(4-pyridyl)imidazol
(herefter benevnt Forbindelse f)
2-(4-Acetamido-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)-imidazol (herefter benevnt Forbindelse g)
2-(2-Metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol
(herefter benevnt Forbindelse h)
2-(2-Fluorfenyl)-4-mety1-5-(3-pyridyl)imidazol
(herefter benevnt Forbindelse i)
2-(2-Acetamidofenyl)-4-mety1-5-(3-pyridyl)imidazol
(herefter benevnt Forbindelse J)
2-(4-Klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol
(herefter benevnt Forbindelse k)
Kardiotonisk virkning
Test 1
Testmetode
Bastardhunder av vilkårlig kjønn ble bedøvet med natrium-pentobarbital, 35 mg/kg i.p. Dyrene fikk lov til å puste spontant. Den venstre carotidarterie ble isolert, og et kateter (USCI, #8F) fylt med heparinisert saltvann ble innført og ført inn i den venstre ventrikkel. Kateteret ble forbundet til en trykktransducer (Nihonkohden, MPU-0,5A) for å måle det venstre ventrikkeltrykk, hvorav dp/dt maks ble funnet ved analog-beregning. For å måle det systemiske blodtrykk ble den venstre femoralarterie forsynt med kanyle. Blodtrykkspulsen ble anvendt til å stimulere en hjertefrekvensmåler.
Et annet kateter ble anbragt i vena cava gjennom den høyre femoral-vene for injisering av medikamenter. Det systemiske blodtrykk, det venstre ventrikkeltrykk, dp/dt maks og hjertefrekvensen ble notert simultant på en polygram (Nihonkohden, RJG-4008).
Testforbindelse ble oppløst i destillert vann (0,2 ml/kg) eller dimetylsulfoksyd (0,04 ml/kg) og injisert i femoralvenen. Parametrene efter dosering ble sammenlignet med parametrene i perioden før dosering.
Testresultatene ble vist uttrykt i prosent av dp/dt maks-endringer (dp/dt M.C.) beregnet efter følgende formel:
dp/dtM.C.(%)=(dp/dt maks efter doserina, x 1Q<Q>
dp/dt maks før dosering
Test 2
Testmetode
Hannmarsvin av Hartley-stammen med en vekt på 530-600 g ble avlivet ved blødning, og hjertet ble tatt ut. En atriestrimmel ble fjernet og suspendert i et organbad inneholdende 50 ml Tyrode's oppløsning, som ble holdt på 30°C og ble luftet med en gassblanding av 95% O2og 5% CO2. Atriet ble forbundet til en belastningsmåler med en startbelastning på 0,4-0,6 g. Efter at konstant motilitet var oppnådd, ble medikamentet satt til badoppløsningen, og virkningen på sammentrekningskraften og hjertefrekvensen ble observert i 30 min. Virkningen ble uttrykt som prosentverdier før og efter dosering.
Antiblodplatevirkning
Test 3
Testmetode
Sprague-Dawley-hannrott er med en vekt på ca. 250 g ble anvendt efter faste natten over. En time efter oral administrering av testforbindelse eller bærermedium for testforbindelse (kontroll) ble blod oppsamlet i et glass inneholdende 0,1 volum 3,8%'s natriumcitrat. Til de 0,45 ml blod ble det satt 0,05 ml kollagen (sluttkonsentrasjon 5,0 pg/ml), og derefter ble det inkubert i 5 min. ved 37°C under rystning.
Reaksjonen ble stanset ved tilsetning av 1 ml 10 mM fosfatbufret saltvann (pH-verdi 7,4) inneholdende 11,5 mM EDTA og 1% formalin. Reaksjonsblandingen ble sentrifugert ved 70xg i 5 min., og blodplatetelling av den øvre fase ble utført med en Technicon Auto Analizer.
Blodplateaggregasjon ble beregnet efter følgende formel:
A: Blodplatetelling efter tilsetning av kollagenbærer B: Blodplatetelling efter tilsetning av kollagen
Testforbindelsens inhibering ble beregnet efter følgende formel:
C: Blodplateaggregasjon (%) for kontroll
D: Blodplateaggregasjon (%) for testforbindelse
Test 4
Testmetode
Det ble samlet blod fra carotidarterien hos kaniner i plastbeholdere inneholdende 0,1 volum 3,8%'s natriumcitrat. Blodplaterikt plasma (PRP) ble fremstilt ved sentrifugering ved 150 g i 15 min. Blodplateaggregasjon ble undersøkt ved anvendelse av den turbidimetriske metode med et aggregometer (NKK HEMATRACER 1). Til de 225 pl PRP ble satt 25 pl test-forbindelseoppløsning, som derefter ble omrørt ved 1000 opm i 2 min. ved 37°C. Til oppløsningen ble satt 5 ul 9,ll-azo-PGH2(sluttkonsentrasjon 1,0 uM) som aggregeringsfremkaller.
Anti- inflammatorisk virkning
Test 5
Testmetode
Det ble anvendt Sprague-Dawley-hannrotter med en vekt på ca. 180 g i grupper på fem. Poteødem ble fremkalt ved subplantar injeksjon av 1%'s carrageenin (0,1 ml/rotte) i den høyre bakpote (carrageeninpoteødem). Testforbindelsen ble suspendert i metylcellulose og administrert oralt 60 minutter før flogogenet. Potevolumet ble målt med et pletysmometer (Ugo Basil Co., Ltd.) ved vannfortrengning ved å nedsenke poten til den laterale malleolus. Forskjellen i pote-volum før og 3 timer efter flogogenet ble angitt som ødemvolum.
Tallene ble analysert statistisk ved Student<*>s t-test.
Følgende fremstillinger og eksempler er anført for å illustrere foreliggende oppfinnelse i detaljer.
Fremstilling 1
Til en oppløsning av isoamylnitritt (2,6 ml) og natriummetoksyd (28% i metanol, 3,4 ml) i metanol (40 ml) ble dråpevis satt en oppløsning av 4-propionylpyridin (2,0 g) i metanol (10 ml) under isavkjøling. Reaksjonsblandingen ble omrørt ved omgivelsestemperatur i 3 timer og derefter nøytralisert med IN saltsyre. Efter avdampning for å fjerne metanol ble den organiske fase ekstrahert med etylacetat. Ekstrakten ble vasket med saltvann, tørret over natriumsulfat, inndampet og utgnidd med diisopropyleter, hvilket ga 4-(2-hydroksyimino-propionyl)pyridin (0,95 g).
smeltepunkt : 150-151°C
IR (Nujol) : 1670, 1605 cm"<1>
NMR (CDCI3, 5) : 2,15 (3H, s), 7,65 og 8,60 (4H, AB type, J=7HZ)
Følgende forbindelser (fremstilling 2-4) ble erholdt på lignende måte som den i fremstilling 1 beskrevne.
Fremstilling 2
4-(2-Hydroksyiminobutyry1)pyridin
smeltepunkt : 146-149°C
IR (Nujol) : 3250, 1680, 1590 cm"<1>
Fremstilling 3
1-Hydroksyimino-l-(3-pyridyl)-2-butanon
smeltepunkt : 172-174°C
IR (Nujol) : 1690, 1600, 1585 cm"<1>
NMR (DMSO-de, 5) 1,10 (3H, t, J=7Hz), 2,98 (2H, q, J=7Hz), 7,45 (1H, dd, J=8Hz, J=8Hz), 7,70 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,45-8,70 (2H,m)
Fremstilling 4
2-(2-Hydroksyiminobutyryl)pyridin
smeltepunkt : 134-135°C
IR (Nujol) : 1670, 1580, 1490 er1
NMR (CDCI3, 5) : 1,16 (3H, t, J=7Hz), 2,78 (2H, q, J=7Hz), 7,2-7,5 (1H, m), 7,7-8,1 (1H, m), 7,90 (1H, d, J=2Hz),
8,63 (1H, dd, J=5,5Hz, 2Hz)
Eksempel 1
Til en suspensjon av 4-(2-hydroksyiminopropionyl)pyridin (2,0 g) i en blanding av dioksan (40 ml) og etanol ble satt konsentrert ammoniakkvann (58 ml) og 2,4-dimetoksybenzaldehyd (2,02 g), og blandingen ble omrørt ved omgivelsestemperatur i én uke. Efter inndampning ble blandingen utgnidd med kloroform, hvilket ga 1-hydroksy-2-{2,4-dimetoksyfenyl)-5-metyl-4-(4-pyrid-yDimidazol (3,01 g) .
smeltepunkt : 240-241°C
IR (Nujol) : 1605 cm"<1>
NMR (DMSO-de, 6) : 2,38 (3H, s), 3,77 (3H, s), 3,83 (3H, s), 6,5-6,9 (2H, m), 7,31 (1H, d, J=8Hz), 7,67 (2H, d, J=6Hz), 8,55 (2H, d, J=6Hz)
Eksempel 2
Til en suspensjon av 1-hydroksyimino-l-(3-pyridyl)aceton (1,5 g) i en blanding av dioksan (30 ml) og etanol (8 ml) ble satt konsentrert ammoniakkvann (40 ml) og 2-metoksybenzaldehyd (1,24 g), og blandingen ble omrørt ved omgivelsestemperatur i 8 dager. Efter inndampning ble blandingen utgnidd med kloroform, hvilket ga l-hydroksy-2-(2-metoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol (1,65 g).
smeltepunkt : 105-120°C
IR (Nujol) : 1605 cm"<1>
NMR (DMSO-de, 5) : 2,22 (3H, s), 3,73 (3H, s), 6,7-7,6 (5H, m), 7,92 (1H, ddd, J=2Hz, 2Hz, 8Hz), 8,47 (1H, dd, J=2Hz, 5Hz), 8,72 (1H, d, J=2Hz)
Eksempel 3
Til en suspensjon av 1-hydroksyimino-l-(3-pyridyl)aceton (1,64 g) i en blanding av dioksan (30 ml), etanol (10 ml) og vann (5 ml) ble satt 3,4-dimetoksybenzaldehyd (1,66 g) og konsentrert ammoniakkvann (0,69 ml). Oppløsningen ble omrørt ved 60°C i 2 timer. Ytterligere ammoniakkvann (0,7 ml) ble tilsatt, og oppløsningen ble omrørt ved 45-50°C i én dag. Blandingen ble inndampet, og residuet ble oppløst i kloroform
og underkastet kolonnekromatografi på silikagel under eluering med en blanding av kloroform og metanol. Fraksjonene ble samlet og inndampet, og residuet ble utgnidd med diisopropyleter, hvilket ga l-hydroksy-2-(3,4-dimetoksyfenyl)-4-metyl-5-(3-pyri-dyDimidazol (1,20 g) .
smeltepunkt : 131-135°C
IR (Nujol) : 1505, 1260, 1230 cm"<1>
NMR (DMSO-de, 5) : 2,26 (3H, s), 3,80 (3H, s), 3,83 (3H, s), 7,04 (1H, d, J=9Hz), 7,3-8,1 (4H, m), 8,56 (1H, dd, J=2Hz, 5Hz), 8,75 (1H, d, J=2Hz)
Eksempel 4
Til en suspensjon av 1-hydroksyimino-l-(3-pyridyl)aceton (3,3 g) i en blanding av dioksan (80 ml), etanol (20 ml) og konsentrert ammoniakkvann (40 ml) ble satt 4-acetamido-5-klor-2-metoksybenzaldehyd (4,54 g), og den resulterende blanding ble omrørt ved omgivelsestemperatur i 3 dager. Reaksjonsblandingen ble inndampet i vakuum, og residuet ble oppløst i en blanding av etylacetat og 5% saltsyre. Den fraskilte vandige fase ble innstilt på en pH-verdi på 8,0 med 20% kaliumkarbonat under omrøring, og bunnfallet ble oppsamlet ved filtrering og tørret, hvilket ga l-hydroksy-2-(4-acetamido-5-klor-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (3,1 g).
smeltepunkt : 178-180°C (dekomponering)
IR (Nujol) : 3450, 3150, 1660, 1600, 1570, 1530, 1505 er<1>NMR (D20 - DC1, 5) : 2,35 (3H, s), 2,60 (3H, s), 4,00 (3H, s), 7,83 (1H, s), 8,07 (1H, s), 8,40 (1H, dd, J=6Hz, 8Hz), 8,95 (1H, dd, J=2Hz, 8Hz), 9,08 (1H, dd, J=2Hz, 6Hz), 9,25
(1H, d, J=2Hz)
massespektrum (m/e) : 372 (M<+>)
Eksempel 5
Til en suspensjon av 1-hydroksyimino-l-(3-pyridyl)aceton (1,0 g) i en blanding av dioksan (20 ml) og etanol (6 ml) ble satt 2-metoksy-4-metylbenzaldehyd (1,01 g) og konsentrert ammoniakkvann (15 ml). Oppløsningen ble omrørt ved omgivelsestemperatur i 8 dager. Efter inndampning ble residuet oppløst i kloroform og kromatografert på silikagel under eluering med en blanding av kloroform og metanol. Fraksjonene ble samlet, inndampet og utgnidd i diisopropyleter, hvilket ga l-hydroksy-2-(2-metoksy-4-metylfenyl)-4-metyl-5-(3-pyridyl)imidazol (1,46 g).
smeltepunkt : 75-80°C
IR (Nujol) : 1615, 1580 cm"<1>
NMR (DMSO-de, 5) :2,24 (3H, s), 2,34 (3H, s), 3,75 (3H, s), 6,74 (1H, d, J=8Hz), 6,88 (1H, s), 7,6-7,2 (2H, m), 7,87 (1H, ddd, J=8Hz, J=2Hz, J=2Hz) , 8,43 (1H, dd, J=5Hz, J=2Hz) , 8,65 (1H, d, J=2Hz), 11,35 (1H, br s) massespektrum : (M/Z) : 295 (M<*>)
Følgende forbindelser (eksempel 6-119) ble erholdt på lignende måte som de i eksempel 1, 2, 3, 4 eller 5 beskrevne.
Eksempel 6
l-Hydroksy-2-(2,4-dimetoksyfenyl)-5-metyl-4-(2-pyridyl)imidazol smeltepunkt : 141-144°C (dekomponering)
IR (Nujol) : 1600, 1570, 1460, 1310, 1280 er1
NMR (CDCI3 , 5) : 2,49 (3H, s) , 3,73 (3H, s), 3,86 (3H, s) , 6,3-6,6 (2H, m), 7,0-7,4 (1H, m), 7,6-7,8 (2H, m), 8,4-8,8
(2H, m)
Massespektrum (m/e) : 311 (M+ )
Eksempel 7
l-Hydroksy-2-(2,4-dimetoksyfenyl)-5-etyl-4-(4-pyridyl)imidazol smeltepunkt : 206-208°C (dekomponering)
IR (Nujol) : 1600, 1570, 1520, 1430 er1
NMR (DMSO-de, 5) : 1,23 (3H, t, J=7Hz), 2,86
(2H, q, J=7Hz), 3,73 (3H, s), 3,83 (3H, s), 6,58 (1H, d, J=8Hz), 6,70 (1H, s), 7,35 (1H, d, J=8Hz), 7,65 (2H, dd, J=2Hz, 5Hz), 8,55 (2H, dd, J=2Hz, 5Hz)
Eksempel 8
l-Hydroksy-2-(3,4-dimetoksyfenyl)-5-metyl-4-(4-pyridyl)imidazol smeltepunkt : 131-136°C
IR (Nujol) : 1610, 1600 er1
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,80 (3H, s),
3,83 (3H, s), 7,05 (1H, d, J=9Hz), 7,6-7,9 (4H, m), 8,23
(2H, br d, J=6Hz)
Eksempel 9
l-Hydroksy-2-(3,4-dimetoksyfenyl)-5-metyl-4-(2-pyridyl)imidazol smeltepunkt : 141-144°C (dekomponering)
IR (Nujol) : 3200, 1603, 1595, 1560, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,62 (3H, s), 3,78 (3H, s),
3,81 (3H, s), 6,99 (1H, d, J=9Hz), 7,0-7,2 (1H, m), 7,5-7,7 (2H, m), 7,75 (1H, dd, J=2Hz, 8Hz), 7,96 (1H, d, J=8Hz), 8,4-8,6 (1H, m), 10,7 (1H, br s)
Eksempel 10
l-Hydroksy-2-(3,4-dimetoksyfenyl)-5-etyl-4-(4-pyridyl)imidazol IR (Nujol) : 3470, 3200, 1600, 1520, 1430 cm"<1>
NMR (DMSO-de, 5) : 1,18 (3H, t, J=7Hz), 2,82
(2H, q, J=7Hz), 3,74 (6H, s), 6,90 (1H, d, J=9Hz), 7,6-7,8 (3H, m), 7,76 (1H, s), 8,51 (2H, dd, J=6Hz, 8Hz)
Eksempel 11
l-Hydroksy-2-(3,4-dimetoksyfenyl)-5-ety1-4-(2-pyridyl)imidazol smeltepunkt : 92-94°C
IR (Nujol) : 1590, 1510, 1490, 1270 cm"<1>
NMR (DMSO-de, 5) : 1,24 (3H, t, J=8Hz), 3,15
(2H, q, J=8Hz), 3,80 (3H, s), 3,83 (3H, s), 7,01 (1H, d, J=9Hz), 7,0-7,2 (1H, m), 7,5-7,7 (2H, m), 7,74 (1H, dd, J=2Hz, 8Hz), 7,98 (1H, d, J=8Hz), 8,48 (1H, m), 11,6 (1H, br s)
Massespektrum (m/e) :325 (M<+>)
Eksempel 12
l-Hydroksy-2-(3,4-dimetoksyfenyl)-4-(2-pyridyl)imidazol smeltepunkt : 71-73°C
IR (Nujol) : 1590, 1500, 1440 cm"<1>
NMR (CDCla, 5) : 3,94 (3H, s), 3,95 (3H, s),
6,92 (1H, d, J=9Hz), 7,0-7,4 (2H, m), 7,5-7,9 (3H, m), 7,66 (1H, s), 8,56 (1H, d, J=5Hz)
Massespektrum (m/e) : 296 (M - 1)
Eksempel 13
l-Hydroksy-5-metyl-2-fenyl-4-(3-pyridyl)imidazol smeltepunkt : 75-85°C
IR (Nujol) : 1600 cm"<1>
NMR (DMSO-de, 5) : 2,43 (3H, s), 7,2-7,5 (4H, m),
7,8-8,1 (3H, m), 8,34 (1H, br d, J=4Hz), 8,81 (1H, br s), 11,7 (1H, br s)
Eksempel 14
l-Hydroksy-2-(2,5-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 115-125°C
IR (Nujol) : 1590 cm"<1>
NMR (DMSO-de, 6) : 2,19 (3H, s), 3,65 (6H, s),
6,8-7,2 (3H, m), 7,30 (1H, dd, J=5Hz, 8Hz), 7,84 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,43 (1H, dd, J=2Hz, 5Hz), 8,66 (1H, d, J=7Hz)
Eksempel 15
l-Hydroksy-2-(2,4-dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazol smeltepunkt : 75-80°C
IR (Nujol) : 1615, 1583 cm"<1>
NMR (DMSO-de, 6) : 1,17 (3H, t, J=7Hz), 2,40-2,55
(2H, m), 3,75 (3H, s), 3,80 (3H, s), 6,57 (1H, dd, J=8Hz, 2Hz), 6,66 (1H, s), 7,30-7,5 (1H, m), 7,67 (1H, dd, J=8Hz, 4Hz), 7,91 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,50 (1H, dd, J=4Hz, 2Hz), 8,67 (1H, d, J=2Hz)
Eksempel 16
l-Hydroksy-2-(3,4-dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazol smeltepunkt : 75-80°C
IR (Nujol) : 1608, 1587, 1512 cm"<1>
NMR (DMSO-de, 5) : 1,17 (3H, t, J=7Hz), 2,40-2,65
(2H, m), 3,75 (3H, s), 3,80 (3H, s), 7,00 (1H, d, J=8Hz), 7,32-7,75 (3H, m), 7,86 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,50 (1H, dd, J=4Hz, 2Hz), 8,63 (1H, d, J=2Hz)
Eksempel 17
l-Hydroksy-2-(2,3-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 110-115°C
IR (Nujol) : 1580 cm"<1>
NMR (DMSO-de, 5) : 2,27 (3H, s), 3,78 (3H, s),
3,86 (3H, s), 7,13 (3H, s), 7,48 (1H, dd, J=8Hz, 4Hz), 7,98 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,52 (1H, dd, J=2Hz, 4Hz), 8,75
(1H, d, J=2Hz)
Eksempel 18
l-Hydroksy-2-(3,4,5-trimetoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 135-138°C
IR (Nujol) : 1590 cm"<1>
NMR (DMSO-de, 5) : 2,24 (3H, s), 3,73 (3H, s),
3,80 (6H, s), 7,40 (2H, s), 7,48 (1H, dd, J=8Hz, 5Hz), 7,95 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,53 (1H, br d, J=5Hz), 8,73
(1H, br s)
Eksempel 19
l-Hydroksy-2-(2,3,4-trimetoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 90-100°C
IR (Nujol) : 1600 cm"<1>
NMR (DMSO-de, 5) : 2,26 (3H, s), 3,79 (6H, s),
3,86 (3H, s), 6,87 (1H, d, J=8Hz), 7,26 (1H, d, J=8Hz), 7,44 (1H, dd, J=8Hz, 4Hz), 7,92 (1H, ddd, J=2Hz, 2Hz, 8Hz), 8,50 (1H, dd, J=2Hz, 4Hz), 8,73 (1H, d, J=2Hz)
Eksempel 20
l-Hydroksy-2-(2-metoksy-4-nitrofenyl)-4-metyl-5-(3-pyridyl) imidazol
NMR (DMSO-de, 5) : 2,31 (3H, s), 3,96 (3H, s),
7,45 (1H, dd, J=8Hz, 4Hz), 7,75-8,08 (4H, m), 8,48 (1H, d, J=4Hz), 8,73 (1H, br s)
Eksempel 21
l-Hydroksy-2-(4-klor-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 130-135°C
IR (Nujol) : 1600, 1575 cm"<1>
NMR (DMSO-de, 5) : 2,19 (3H, s), 3,70 (3H, s), 6,83 (1H, dd, J=2Hz, 8Hz), 7,03 (1H, d, J=2Hz), 7,22 (1H, d, J=8Hz), 7,31 (1H, dd, J=8Hz, 4Hz), 7,82 (1H, ddd, J=8Hz, 2Hz,
2Hz), 8,38 (1H, dd, J=2Hz, 4Hz), 8,61 (1H, d, J=2Hz)
Eksempel 22
l-Hydroksy-2-(4-acetamido-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 170-175°C
IR (Nujol) : 1680, 1610 cm"<1>
NMR (DMSO-de, 5) : 2,05 (3H, s), 2,23 (3H, s),
3,71 (3H, s), 7,6-7,0 (4H, m), 7,86 (1H, br d, J=8Hz), 8,40 (1H, dd, J=4Hz, 2Hz), 8,64 (1H, br s), 9,96 (1H, br s), 11,05 (1H, br s)
Eksempel 23
l-Hydroksy-2-[2-metoksy-4-(metylsulfinyl)fenyl]-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 90-95°C
IR (Nujol) : 1600, 1565 cm"<1>
NMR (DMSO-de, 5) : 2,24 (3H, s), 2,53 (3H, s),
3,81 (3H, s), 6,7-7,0 (2H, m), 7,43 (1H, dd, J=8Hz, 4Hz), 7,62 (1H, d, J=8Hz), 7,92 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,48 (1H, dd, J=2Hz, 4Hz), 8,69 (1H, d, J=2Hz)
Eksempel 24
l-Hydroksy-2-(2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 110-120°C
IR (Nujol) : 1610 er1
NMR (DMSO-de, 5) : 2,16 (3H, s), 3,70 (3H, s) ,
3,77 (3H, s), 6,2-6,5 (2H, m), 7,0-7,4 (1H, m), 7,91 (1H, dd, J=2Hz, 8Hz), 7,98 (1H, d, J=9Hz), 8,43 (1H, dd, J=2Hz, 5Hz), 8,56 (1H, d, J=2Hz)
Eksempel 25
2-(2-Fluorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 76-82°C
IR (Nujol) : 1585, 1630, 1500 er1
NMR (DMSO-de, 5) : 2,30 (3H, s), 7,2-7,85 (5H, m), 8,00 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,60 (1H, dd, J=5Hz, 2Hz), 8,80 (1H, d, J=2Hz)
Eksempel 26
2-(4-Fluorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 101-102°C
NMR (DMSO-de, 5) : 2,23 (3H, s), 7,12-7,56 (3H, m), 7,80-8,30 (3H, m), 8,56 (1H, d, J=5Hz), 8,74 (1H, s)
Eksempel 27
2-(3-Klorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 74-84°C
IR (Nujol) : 1598, 1567 cm"<1>
NMR (DMSO-de, 5) : 2,25 (3H, s), 7,4-7,65 (3H, m), 7,88-8,2 (3H, m), 8,60 (1H, d, J=5Hz), 8,78 (1H, s)
Eksempel 28
2-(2-Klorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 105-112°C
IR (Nujol) : 1600, 1565 cm"<1>
NMR (DMSO-de, 5) : 2,28 (3H, s), 7,3-7,7 (5H, m), 7,95 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,3-8,8 (2H, m)
Eksempel 29
2-(4-Klorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 108-110°C
IR (Nujol) : 1640, 1600, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,32 (3H, s), 7,4-7,75 (3H, m), 7,85-8,3 (3H, m), 8,62 (1H, dd, J=5Hz, 2Hz), 8,78 (1H, d, J=2Hz)
Eksempel 30
2-(3,4-Diklorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 139-145°C
IR (Nujol) : 1635, 1496 cm"<1>
NMR (DMSO-de, 5) : 2,4 (3H, s), 7,56 (1H, dd,
J=8Hz, 5Hz), 7,78 (1H, d, J=8Hz), 7,9-8,2 (2H, m), 8,33 (1H, d, J=2Hz), 8,68 (1H, dd, J=5Hz, 2Hz), 8,8 (1H, d, J=2Hz)
Eksempel 31
1- Hydroksy-2-(2,4-diklorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 104-108°C
IR (Nujol) : 1596, 1552 cr1
NMR (DMSO-de , 5) : 2,32 (3H, s), 7,42-7,89 (4H, m) , 8,07 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,67 (1H, dd, J=5Hz, 2Hz), 8,86 (1H, d, J=2Hz)
Eksempel 32
2- (4-Dimetylamino-2-metoksyfenyl)-1-hydroksy-4-mety1-5-(3-pyridyl)imidazol
smeltepunkt : 96-98°C
IR (Nujol) : 1607, 1611, 1562 cm"<1>
NMR (DMSO-de, 5) : 2,24 (3H, s), 2,96 (6H, s),
3,82 (3H, s), 6,15-6,46 (2H, m), 7,28-7,78 (2H, m), 7,98 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,52 (1H, dd, J=5Hz, 2Hz), 8,77
(1H, d, J=2Hz)
Eksempel 33
1- Hydroksy-2-(3-hydroksy-4-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol
NMR (DMSO-de, 5) : 2,18 (3H, s), 3,75 (3H, s),
6,86 (2H, d, J=8Hz), 7,25-7,52 (2H, m), 7,60 (1H, s), 7,88 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,43 (1H, dd, J=5Hz, 2Hz), 8,66
(1H, d, J=2Hz)
Eksempel 34
2- (5-Klor-2-metoksyfenyl)-1-hydroksy-4-mety1-5-(3-pyridyl)-imidazol
smeltepunkt : 81-83°C
IR (Nujol) : 1673, 1596, 1483 cm"<1>
NMR (DMSO-de, 5) : 2,26 (3H, s), 3,78 (3H, s),
7,08 (1H, d, J=8Hz), 7,25-7,52 (3H, m), 7,91 (1H, d, J=8Hz), 8,47 (1H, d, J=5Hz), 8,69 (1H, s)
Eksempel 35
l-Hydroksy-4-metyl-2-(2-metoksy-5-nitrofenyl)-5-(3-pyridyl)-imidazol
smeltepunkt : 151-155°C
IR (Nujol) : 1611, 1586, 1538, 1515 cm"<1>
NMR (DMSO-de, 5) : 2,30 (3H, s), 3,98 (3H, s),
7,36 (1H, d, J=9Hz), 7,48 (1H, dd, J=8Hz, 5Hz), 8,01 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,34 (1H, dd, J=8Hz, 2Hz), 8,57 (1H, dd, J=5Hz, 2Hz), 8,75 (1H, d, J=2Hz)
Eksempel 36
l-Hydroksy-4-metyl-2-(2-metoksy-3-nitrofenyl)-5-(3-pyridyl)-imidazol
smeltepunkt : 106-111°C
IR (Nujol) : 1536 cm"<1>
NMR (DMSO-de, 5) : 2,30 (3H, s), 3,71 (3H, s), 7,31-8,15 (4H, m), 8,42-8,67 (2H, m), 8,31 (1H, s), 11,72
(1H, brs)
Eksempel 37
2-(5-Klor-2,4-dimetoksyfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 146-149°C
IR (Nujol) : 1610 cm"<1>
NMR (DMSO-de, 5) : 2,25 (3H, s), 3,86 (3H, s),
3,96 (3H, s), 6,86 (1H, s), 7,46 (1H, dd, J=8Hz, J=4Hz), 7,80 (1H, br s), 7,97 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,52 (1H, dd, J=4Hz, J=2Hz), 8,73 (lH,d, J=2Hz) Massespektrum (M/Z) : 345 (M<+>)
Eksempel 38
2-(3-Klor-4,5-dimetoksyfenyl)-1-hydroksy-4-mety1-5-(3-pyridyl)imidazol
smeltepunkt : 123-132°C
IR (Nujol) : 1598, 1565 cm"<1>
NMR (DMSO-de, 5) : 2,20 (3H, s), 3,76 (3H, s),
3,78 (3H, s), 7,25-8,08 (4H, m), 8,45 (1H, d, J=5Hz), 8,69
(1H, s)
Eksempel 39
2-(3-Klor-4-hydroksy-5-metoksyfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 190-195°C
IR (Nujol) : 1573, 1504 cm"<1>
NMR (DMSO-de, 5) : 2,21 (3H, s), 3,82 (3H, s),
7,3-7,7 (3H, m), 7,88 (1H, d, J=8Hz), 8,46 (1H, s), 8,66
(1H, s)
Eksempel 40
l-Hydroksy-2-(4-hydroksy-3-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 152-155°C
IR (Nujol) : 1595, 1511 cm"<1>
NMR (DMSO-de, 5) : 2,21 (3H, s), 3,76 (3H, s),
6,78 (1H, d, J=8Hz), 7,22-7,66 (3H, m),
7,87 (1H, d, J=8Hz), 8,45 (1H, d, J=5Hz), 8,65 (1H, s)
Eksempel 41
1- Hydroksy-4-metyl-2-(2-nitrofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 135-145°C
IR (Nujol) : 1613, 1530 er1
NMR (DMSO-de, 5) : 2,30 (3H, s), 7,52 (1H, dd, J=8Hz, 8Hz), 7,7-8,3 (5H, m), 8,58 (1H, dd, J=8Hz, 2Hz), 8,75 (1H, d, J=2Hz)
Eksempel 42
2- [4-(N-Acetyl-N-metylamino)-5-klor-2-metoksyfenyl]-1-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 222-224°C
IR (Nujol) : 1662, 1600, 1492 er1
NMR (DMSO-de, 5) : 2,31 (3H, s), 2,80 (3H, s),
3,15 (3H, s), 3,59 (3H, s), 7,35-7,62 (2H, m), 7,82-8,2 (2H, m), 8,58 (1H, dd, J=5Hz, 2Hz), 8,77 (1H, d, J=2Hz) Massespektrum (M/Z) : 385 (M<+>)
Eksempel 43
l-Hydroksy-4-metyl-2-(o-tolyl)-5-(3-pyridyl)imidazol smeltepunkt : 90-95°C
IR (Nujol) : 1565 cm'<1>
NMR (DMSO-de, 5) : 2,25 (3H, s), 2,35 (3H, s), 7,25-7,66 (5H, m), 7,95 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,56 (1H, dd, J=5Hz, 2Hz), 8,78 (1H, d, J=2Hz)
Eksempel 44
l-Hydroksy-2-(2-metoksy-4-metylsulfinylfenyl)-5-metyl-4-(4-pyridyl)imidazol
smeltepunkt : 205-208°C
IR (Nujol) : 1600 cm"<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 2,54 (3H, s), 3,81 (3H, s), 6,93 (1H, d, J=8Hz), 7,0 (1H, s), 7,35 (1H, d, J=8Hz), 7,66 (2H, d, J=8Hz), 8,54 (2H, d, J=8Hz)
Eksempel 45
1- Hydroksy-2-(3-metoksy-4-metyltiofenyl)-5-metyl-4-{4-pyridyl)imidazol
smeltepunkt : 252-257°C
IR (Nujol) : 1610 er1
NMR (DMSO-de, 5) : 2,46 (3H, s), 2,52 (3H, s),
3,92 (3H, s), 7,26 (1H, d, J=8Hz), 7,9-7,6 (4H, m), 8,7-8,5 (2H,m)
Eksempel 46
2- (2,6-Dimetoksyfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 236-239°C
IR (Nujol) : 1590 cm"<1>
NMR (DMSO-de, 5) : 2,25 (3H, s), 3,71 (6H, s),
6,73 (2H, d, J=8Hz), 7,6-7,2 (2H, m), 7,96 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,48 (1H, dd, J=5Hz, J=2Hz), 8,75 (1H, d, J=2Hz), 11,1 (1H, br s)
Eksempel 47
l-Hydroksy-2-(3-metoksy-4-metyltiofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 145-150°C
IR (Nujol) : 1630, 1600, 1565 cm"<1>
NMR (DMSO-de, 5) : 2,24 (3H, s), 2,43 (3H, s),
3,86 (3H, s), 7,22 (1H, d, J=8Hz), 7,50 (1H, dd, J=8Hz, J=5Hz), 7,9-7,65 (2H, m), 7,95 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,56 (1H, dd, J=5Hz, J=2Hz), 8,78 (1H, d, J=2Hz)
Eksempel 48
2-(4-Etoksy-2-metoksyfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt: 90-95°C
IR (Nujol) : 1615, 1580 cm"<1>
NMR (DMSO-de, 5) : 1,35 (3H, t, J=7Hz), 2,24 (3H, s), 3,78 (3H, s), 4,10 (2H, q, J=7Hz), 6,57 (1H, dd, J=-8Hz, J=2Hz), 6,64 (1H, d, J=2Hz), 7,7-7,4 (2H, m), 7,98 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,51 (1H, dd, J=4Hz, J=2Hz), 8,76
(1H, d, J=2Hz)
Eksempel 49
2-(4-Benzyloksy-2-metoksyfenyl)-1-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 191-193°C
IR (Nujol) : 1615, 1580 er1
NMR (DMSO-de, 5) : 2,25 (3H, s), 3,78 (3H, s), 5,17 (2H, s), 6,68 (1H, dd, J=2Hz, J=8Hz), 6,77 (1H, d, J=2Hz), 7,7-7,3 (7H, m), 7,98 (1H, ddd, J=2Hz, J=2Hz, J=8Hz), 8,54 (1H, dd, J=2Hz, J=5Hz), 8,77 (1H, d, J=2Hz), 11,4 (1H, br s)
Eksempel 50
l-Hydroksy-4-metyl-5-(3-pyridyl)-2-(2,4,5-trimetoksyfenyl)-imidazol
smeltepunkt : 80-90°C
IR (Nujol) : 1615 cm"<1>
NMR (DMSO-de, 5) : 2,25 (3H, s), 3,64 (3H, s),
3,79 (3H, s), 3,84 (3H, s), 6,78 (1H, s), 7,50 (1H, br s), 7,46 (1H, dd, J=4Hz, J=8Hz), 7,99 (1H, ddd, J=2Hz, J=2Hz, J=8Hz), 8,53 (1H, dd, J=2Hz, J=4Hz), 8,77 (1H, d, J=2Hz), 11,5 (1H, br s)
Massespektrum (M/Z) : 341 (M<+>)
Eksempel 51
l-Hydroksy-4-metyl-5-(3-pyridyl)-2-(2,4,6-trimetoksyfenyl)-imidazol
smeltepunkt : 197-199°C
IR (Nujol) : 1615, 1590 er1
NMR (DMSO-de, 5) : 2,22 (3H, s), 3,66 (6H, s), 3,82 (3H, s), 6,29 (2H, s), 7,45 (1H, dd, J=8Hz, J=5Hz), 7,97 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,50 (1H, dd, J=5Hz, J=2Hz), 8,76 (1H, d, J=2Hz), 11,0 (1H, br s)
Eksempel 52
1- Hydroksy-2-(4-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 95-100°C
IR (Nujol) : 1610 cm"<1>
NMR (CDCI3, 5) : 1,93 (3H, s), 3,71 (3H, s),
6,68 (2H, d, J=9Hz), 7,18 (1H, dd, J=5Hz, J=8Hz), 7,5-8,0 (4H, m), 8,33 (1H, dd, J=5Hz, J=2Hz), 8,45 (1H, d, J=2Hz)
Eksempel 53
2- (5-Klor-2-metoksy-4-metylfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 130-135°C
IR (Nujol) : 1630, 1565 er1
NMR (DMSO-de, 5) : 2,25 (3H, s), 2,36 (3H, s),
3,79 (3H, s), 7,09 (1H, s), 7,40 (1H, br s),
7,41 (1H, dd, J=8Hz, J=5Hz), 7,93 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,45 (1H, dd, J=5Hz, J=2Hz), 8,69 (1H, d, J=2Hz), 11,40 (1H, br s)
Eksempel 54
2-(3,4-Dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 246-248°C
IR (Nujol) : 1600, 1500 er1
NMR (DMSO-de, 5) : 2,53 (3H, s), 3,82 (3H, s),
3.85 (3H, s), 7,04 (1H, d, J=9Hz), 7,2-7,7 (3H, m), 8,10 (1H, br d, J=8Hz), 8,45 (1H, br d, J=6Hz), 8,92 (1H, br s)
Eksempel 55
2-(3,4-Dimetoksyfenyl)-5-metyl-4-(2-pyridyl)imidazol smeltepunkt : 96-98°C
IR (Nujol) : 3300, 1720, 1590, 1500, 1260 er1
NMR (CDCI3, 5) : 2,62 (3H, s), 3,77 (3H, s),
3.86 (3H, s), 6,18 (1H, d, J=8Hz), 6,9-7,1 (1H, m), 7,39 (1H, dd, J=2Hz, 8Hz), 7,44 (1H, s), 7,5-7,7 (2H, m), 8,40
(1H, d, J=5Hz)
Eksempel 56
2-(3,4-Dimetoksyfenyl)-4-(2-pyridyl)imidazol
smeltepunkt : 80-82°C
IR (Nujol) : 1680, 1590, 1490 er1
NMR (CDCI3 , 6) : 3,83 (3H, s), 3,87 (3H, s),
6,81 (1H, d, J=8Hz), 7,0-7,2 (1H, m), 7,36 (1H, dd, J=2Hz, 8Hz), 7,48 (1H, d, J=2Hz), 7,60 (1H, s), 7,6-7,8 (2H, m), 8,42 (1H, d, J=6Hz)
Massespektrum (m/e) : 281 (M<f>)
Eksempel 57
2-(3,4-Dimetoksyfenyl)-5-metyl-4-(4-pyridyl)imidazol smeltepunkt : 234-236°C
IR (Nujol) : 1600 er1
NMR (CDCI3-CD3 OD, 5) : 2,50 (3H, s), 3,86 (3H, s), 3,91 (3H, s), 6,86 (1H, d, J=8Hz), 7,3-7,7 (4H, m), 8,42
(2H, d, J=6Hz)
Eksempel 58
2-(3,4-Dimetooksyfenyl)-5-etyl-4-(4-pyridyl)imidazol smeltepunkt : 181-182°C (dekomponering)
IR (Nujol) : 1595, 1530, 1410 er<1>
NMR (CDCI3, 5) : 1,31 (3H, t, J=7,5Hz), 2,85 (2H, q, J=7,5Hz), 3,83 (6H, s), 6,77 (1H, d, J=9Hz), 7,37 (1H, dd, J=2Hz, 9Hz), 7,49 (1H, d, J=2Hz), 7,54, 8,44 (4H, ABq, J=6Hz)
Massespektrum (m/e) : 309(M<+>)
Eksempel 59
2-(2,4-Dimetoksyfenyl)-5-metyl-4-(2-pyridyl)imidazol smeltepunkt : 118-120°C
IR (Nujol) : 3260, 1610, 1580, 1490 cm"<1>
NMR (CDCI3, 6) : 2,64 (3H, s), 3,84 (3H, s), 4,01 (3H, s), 6,53 (1H, s), 6,57 (1H, dd, J=2Hz, 9Hz), 7,01 (1H, dd, J=6Hz, 10Hz), 7,5-7,8 (2H, m), 8,23 (1H, d, J=10Hz), 8,50 (1H, d, J=6Hz).
Eksempel 60
2-(3,4-Dimetoksyfenyl)-5-etyl-4-(2-pyridyl)imidazol smeltepunkt : 160-163°C
IR (Nujol) : 1590, 1500, 1270, 1015 cm"<1>
NMR (CDCI3, 5) : 1,35 (3H, t, J=8Hz), 2,99 (2H,
t, J=8Hz), 3,85 (6H, s), 6,80 (1H, d, J=9Hz), 6,9-7,1 (1H, m) , 7,33 (1H, dd, J=2Hz, 9Hz), 7,43 (1H, d, J=2Hz) , 7,5-7,7 (2H, m), 8,43 (1H, d, J=5Hz)
Eksempel 61
2-(2,4-Dimetoksyfenyl)-5-metyl-4-(4-pyridyl)imidazol smeltepunkt : 224-226°C
IR (Nujol) : 1605 cm"<1>
NMR (DMSO-de, 6) : 2,56 (3H, s), 3,85 (3H, s),
3,96 (3H, s), 6,6-6,8 (2H, m), 7,73 (2H, d, J=6Hz), 8,07 (1H, d, J=9Hz), 8,58 (2H, d, J=6Hz), 11-12 (1H, br s)
Eksempel 62
2-(2,4-Dimetoksyfenyl)-5-etyl-4-(4-pyridyl)imidazol smeltepunkt : 212-213°C
IR (Nujol) : 1595, 1530, 1505 cm"<1>
NMR (CDCI3, 6) : 1,36 (3H, t, J=8Hz), 2,93 (2H, q, J=8Hz), 3,83 (3H, s), 3,97 (3H, s), 6,51 (1H, d, J=2Hz), 6,57 (1H, dd, J=2Hz, 10Hz), 7,52 (2H, dd, J=2Hz, 6Hz), 8,23 (1H, d, J=10Hz), 8,50 (1H, dd, J=2Hz, 6Hz) Massespektrum (m/e) : 309 (M<+>)
Eksempel 63
2-(2-Metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 198-200°C
IR (Nujol) : 1600, 1585, 1560 cm"<1>
NMR (DMSO-de, 5) : 2,55 (3H, s), 3,99 (3H, s), 7,6-6,9 (4H, m), 8,0-8,3 (2H, m), 8,46 (1H, dd, J=2Hz, 5Hz), 8,98 (1H, d, J=2Hz), 11,7 (1H, br s)
Eksempel 64
2-(2,4-Dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 164-166°C
IR (Nujol) : 1615, 1590 cnr<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,80 (3H, s),
3,93 (3H, s), 6,64 (1H, dd, J=2Hz, 8Hz), 6,68 (1H, d, J=2Hz), 7,40 (1H, dd, J=5Hz, 8Hz), 7,9-8,2 (2H, m), 8,43 (1H, br d, J=5Hz), 8,94 (1H, br s), 11,5 (1H, br s)
Eksempel 65
2-(2,4-Dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazol smeltepunkt : 148-151°C
IR (Nujol) : 1618, 1590, 1495 er1
NMR (DMSO-de, 5) : 1,25 (3H, t, J=8Hz), 2,85 (2H, q, J=8Hz), 3,80 (3H, s), 3,91 (3H, s), 6,49-6,65 (2H, m) , 6,63 (1H, s), 7,35 (1H, dd, J=8Hz, 4Hz), 7,82-8,01 (2H, m) , 8,35 (1H, m), 8,79 (1H, br s)
Eksempel 66
2-(2,5-Dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 152-154°C
IR (Nujol) : 1590 cm"<1>
NMR (DMSO-de, 5) : 2,53 (3H, s), 3,78 (3H, s), 3,91 (3H, s), 6,88 (1H, dd, J=8Hz, 2Hz), 7,10 (1H, d, J=8Hz), 7,40 (1H, dd, J=4Hz, 8Hz), 7,68 (1H, d, J=2Hz), 8,07 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,44 (1H, br d, J=4Hz), 8,97 (1H, br s)
Eksempel 67
2-(2,3-Dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 125-127°C
IR (Nujol) : 1590, 1555 cm"<1>
NMR (DMSO-de, 5): 2,50 (3H, s), 3,77 (3H, s), 3,84 (3H, s), 6,96 (1H, dd, J=8Hz, 2Hz), 7,06 (1H, dd, J=8Hz, 8Hz), 7,32 (1H, dd, J=8Hz, 4Hz), 7,54 (1H, dd, J=2Hz, 8Hz), 7,97 (1H, ddd, J=2Hz, 2Hz, 8Hz), 8,33 (1H, br d, J=4Hz), 8,83 (1H, br s), 11,73 (1H, br s)
Eksempel 68
2-(2,3,4-Trimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 144-146°C
IR (Nujol) : 1600 cm"<1>
NMR (DMSO-de, 5): 2,47 (3H, s), 3,78 (3H, s), 3,81 (3H, s), 3,83 (3H, s), 6,84 (1H, d, J=9Hz), 7,32 (1H, dd, J=8Hz, 4Hz), 7,62 (1H, d, J=9Hz), 7,96 (1H, br d, J=8Hz), 8,32 (1H, br d, J=4Hz), 8,82 (1H, br s), 11,62 (1H, br s)
Eksempel 69
2-(3,4,5-Trimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 258-260°C
IR (Nujol) : 1590 er1
NMR (CDCI3-CD3OD, 6) : 2,45 (3H, s), 3,84 (3H, s), 3,90 (6H, s), 7,18 (2H, s), 7,33 (1H, dd, J=8Hz, 5Hz), 7,96 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,34 (1H, br d, J=5Hz), 8,72
(1H, br s)
Eksempel 70
2-(4-Klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 145-147°C
IR (Nujol) : 1585, 1595 cm"<1>
NMR (DMSO-de, 5) : 2,54 (3H, s), 4,01 (3H, s), 7,12 (1H, dd, J=8Hz, 2Hz), 7,25 (1H, d, J=2Hz), 7,43 (1H, dd, J=8Hz, 5Hz), 8,08 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,16 (1H, d, J=8Hz), 8,47 (1H, dd, J=2Hz, 5Hz), 8,99 (1H, d, J=2Hz), 11,75 (1H, br s)
Eksempel 71
2-(4-Acetamido-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol
smeltepunkt : 239-240°C
IR (Nujol) : 3400, 1680, 1590, 1520, 1490 cm"<1>
NMR (DMSO-de, 5) : 2,14 (3H, s), 2,50 (3H, s), 3,91 (3H, s) , 7,35 (1H, dd, J=5Hz, 8Hz), 7,63 (1H, s), 8,02 (1H, s), 8,02 (1H, dt, J=2Hz, 8Hz), 8,35 (1H, dd, J=2Hz, 5Hz), 8,82 (1H, d, J=2Hz), 9,40 (1H, s), 11,63 (1H, s)
Massespektrum (m/e) : 356 (M<+>)
Eksempel 72
2-(4-Acetamido-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 215-218°C
IR (Nujol) : 1675, 1600 cm"<1>
NMR (DMSO-de, 5) : 2,06 (3H, s), 2,49 (3H, s), 3,90 (3H, s), 7,14 (1H, dd, J=8Hz, 2Hz), 7,33 (1H, dd, J=8Hz, 5Hz), 7,48 (1H, d, J=2Hz), 7,92 (1H, d, J=8Hz), 7,96 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,33 (1H, br d, J=5Hz), 8,82 (1H, br s), 9,99 (1H, s), 11,45 (1H, br s)
Eksempel 73
2-Fenyl-5-metyl-4-(3-pyridyl)imidazol
smeltepunkt : 206-208°C
IR (Nujol) : 1600, 1590, 1575 cm"<1>
NMR (DMSO-de, 5) : 2,48 (3H, s), 7,2-7,6 (4H, m), 7,8-8,1 (3H, m), 8,35 (1H, br d, J=4Hz), 8,83 (1H, br s), 12,39
(1H, br s)
Eksempel 74
2-(2-Metoksy-4-nitrofenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 203-207°C
IR (Nujol) : 1580 cm"<1>
NMR (DMSO-de, 5) : 2,58 (3H, s), 4,11 (3H, s), 7,37 (1H, m), 7,75-8,14 (4H, m), 8,37 (1H, m), 8,88 (1H, br s), 11,93 (1H, br s)
Eksempel 75
2-(2-Metoksy-4-metyltiofenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 153-156°C
IR (Nujol) : 1600, 1580, 1565 er<1>
NMR (DMSO-de, 6) : 2,48 (3H, s), 2,52 (3H, s), 3,94 (3H, s), 6,89 (1H, dd, J=8Hz, 2Hz), 6,94 (1H, d, J=2Hz), 7,34 (1H, dd, J=8Hz, J=4Hz), 7,96 (1H, d, J=8Hz), 7,98 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,34 (1H, dd, J=4Hz, 2Hz), 8,84 (1H, d, J=2Hz), 11,45 (1H, br s)
Eksempel 76
2-(2,4-Dimetoksyfenyl)-5-hydroksymetyl-4-(3-pyridyl)imidazol smeltepunkt : 192-195°C
IR (Nujol) : 1615, 1595 cm"<1>
NMR (DMSO-de, 5) : 3,83 (3H, s), 3,97 (3H, s), 4,70 (2H, br s), 5,26 (1H, br s), 6,66 (1H, dd, J=7Hz, 2Hz), 6,74 (1H, d, J=2Hz), 7,24 (1H, dd, J=5Hz, 8Hz), 7,9-8,3 (2H, m), 8,47 (1H, dd, J=2Hz, 5Hz), 9,02 (1H, br s)
Eksempel 77
2-(2-Metoksy-4-metyltiofenyl)-5-hydroksymetyl-4-(3-pyridyl)imidazol
smeltepunkt : 199-201°C
IR (Nujol) : 1605, 1590, 1575 er1
NMR (DMSO-de, 5) : 2,52 (3H, s), 3,94 (3H, s), 4,61 (2H, d, J=4Hz), 5,20 (1H, br t, J=4Hz), 6,88 (1H, dd, J=8Hz, 2Hz), 6,93 (1H, d, J=2Hz), 7,35 (1H, dd, J=8Hz, 4Hz), 7,97 (1H, d, J=8Hz), 8,06 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,37 (1H, br d, J=4Hz), 8,90 (1H, br s), 11,57 (1H, br s)
Eksempel 78
2-(4-Amino-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 178-180°C
IR (Nujol) : 3480, 3280, 3150, 1630, 1600, 1560 enr<1>
NMR (DMSO-de, 5) : 2,50 (3H, s), 3,87 (3H, s), 5,58 (2H, s), 6,52 (1H, s), 7,32 (1H, dd, J=5Hz, 8Hz), 7,80 (1H, s), 7,98 (1H, d t, J=2Hz, 8Hz), 8,34 (1H, dd, J=2Hz, 5Hz), 8,82 (1H, d, J=2Hz), 11,30 (1H br s)
Massespektrum (m/e) : 314 (M<*>)
Eksempel 79
2-(4-Amino-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 95-100°C
IR (Nujol) : 1615 cm"<1>
NMR (DMSO-de, 5) : 2,45 (3H, s), 3,83 (3H, s), 5,32 (2H, br s), 6,18 (1H, dd, J=8Hz, 2Hz), 6,24 (1H, d, J=2Hz), 7.30 (1H, dd, J=8Hz, 4Hz), 7,67 (1H, d, J=8Hz), 7,94 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,30 (1H, dd, J=4Hz, 2Hz), 8,80 (1H, d, J=2Hz), 11,13 (1H, br s)
Eksempel 80
2-(2,4-Dimetoksyfenyl)-1,5-dimetyl-4-(3-pyridyl)imidazol smeltepunkt : 129-131°C
IR (Nujol) : 1615, 1595, 1580 er1
NMR (DMSO-de, 5) : 2,40 (3H, s), 3,30 (3H, s), 3,76 (3H, s), 3,80 (3H, s), 6,4-6,7 (2H, m), 7,20 (1H, d, J=8Hz), 7.31 (1H, dd, J=4Hz, 8Hz), 7,89 (1H, br d, J=8Hz), 8,32 (1H, br d, J-4Hz), 8,74 (1H, br s)
Eksempel 81
2-(2-Metoksy-4-metylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 125-128°C
IR (Nujol) : 1615, 1590 cm"<1>
Eksempel 82
2-(3-Metoksy-4-metyltiofenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 226-228°C
IR (Nujol) : 1605, 1570 cml
Eksempel 83
2-(2,6-Dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 185-187°C
IR (Nujol) : 1608, 1590 cm"<1>
Eksempel 84
2-(3-Metoksy-4-metyltiofenyl)-4-metyl-5-(4-pyridyl)imidazol smeltepunkt : 283-285°C
IR (Nujol) : 1600 cm"<1>
Eksempel 85
2-(2-Metoksy-4-metyltiofenyl)-4-metyl-5-(4-pyridyl)imidazol smeltepunkt : 192-194°C
IR (Nujol) : 1606, 1565 er1
Eksempel 86
4-Metyl-2-(2-nitrofenyl)-5-(3-pyridyl)imidazol
smeltepunkt : 229-230°C
IR (Nujol) : 1613, 1601, 1578, 1539, 1497 cm-<1>
Eksempel 87
4-Metyl-2-(o-tolyl)-5-(3-pyridyl)imidazol
smeltepunkt : 129-130°C
IR (Nujol) : 1604, 1570, 1494 cm"<1>
Eksempel 88
2-(4-Klorfenyl)-4-mety1-5-(3-pyridyl)imidazol
smeltepunkt : 229-231°C
IR (Nujol) : 1600, 1574, 1492 enr<1>
Eksempel 89
2-[4-(N-Acetyl-N-metylamino)-5-klor-2-metoksyfenyl]-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 220-221°C
IR (Nujol) : 1672, 1599, 1563, 1525, 1490 cm-<1>
Eksempel 90
2-(2-Klorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 108-109°C
IR (Nujol) : 1590, 1562, 1480 cm"<1>
Eksempel 91
2-(3,4-Diklorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 269°C
IR (Nujol) : 1600, 1574 cm"<1>
Eksempel 92
2-(4-Fluorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 123-124°C
IR (Nujol) : 1600, 1570, 1539, 1502 cm"<1>
Eksempel 93
2-(3-Klorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 242-243°C
IR (Nujol) : 1607, 1587, 1574, 1489 cm"<1>
Eksempel 94
2-(2-Fluorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 194-195°C
IR (Nujol) : 1599, 1590, 1567, 1525, 1485 er<1>
Eksempel 95
2-(2,4-Diklorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 160-161°C
IR (Nujol) : 1590, 1569, 1556, 1484 enr<1>
Eksempel 96
2-(5-Klor-2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 241-244°C
IR (Nujol) : 1610, 1590, 1565 cm-<1>
Eksempel 97
2-(5-Klor-2-metoksy-4-metylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 185-187°C
IR (Nujol) : 1600, 1580, 1560 cm"<1>
Eksempel 98
2-(4-Metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 199-201°C
IR (Nujol) : 1615, 1600 cm"<1>
Eksempel 99
4-Metyl-5-(3-pyridyl)-2-(2,4,6-trimetoksyfenyl)imidazol smeltepunkt : 65-75°C
IR (Nujol) : 1610, 1590 er1
Eksempel 100
4-Metyl-5-(3-pyridyl)-2-(2,4,5-trimetoksyfenyl)imidazol smeltepunkt : 189-191°C
IR (Nujol) : 1615, 1600 cm"<1>
Eksempel 101
2-(4-Benzyloksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 160-162°C
IR (Nujol) : 1615, 1590 cm"<1>
Eksempel 102
2-(4-Etoksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 151-153°C
IR (Nujol) : 1615, 1590 er1
Eksempel 103
2-(5-Klor-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 193-195°C
IR (Nujol) : 1600, 1586, 1565, 1619 cm"<1>
Eksempel 104
2-(4-Hydroksy-3-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 278-279°C
IR (Nujol) : 1609, 1575, 1508, 1490 cm"<1>
Eksempel 105
2-(3-Hydroksy-4-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 267-269°C
IR (Nujol) : 1595, 1574, 1505 cm"<1>
Eksempel 106
2-(3-Klor-4,5-dimetooksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 215-216°C
IR (Nujol) : 1573, 1497 er1
Eksempel 107
2-(3-Klor-4-hydroksy-5-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 251-253°C
IR (Nujol) : 1575, 1504 cm"<1>
Eksempel 108
4-Metyl-2-(2-metoksy-5-nitrofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 220-223°C
IR (Nujol) : 1593, 1534, 1508, 1490 cr<1>
Eksempel 109
4-Metyl-2-(2-metoksy-3-nitrofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 145-150°C
IR (Nujol) : 1600, 1566, 1535 cm"<1>
Eksempel 110
2-(2-Metoksy-4-metylsulfinylfenyl)-4-metyl-5-(3-pyridyl)imidazol
IR (Nujol) : 1660, 1600 cm"<1>
Eksempel 111
2-(2-Metoksy-4-metylsulfonylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 115-118°C
IR (Nujol) : 1600, 1590 cm"<1>
Eksempel 112
2-(2-Aminofenyl)-4-mety1-5-(3-pyridyl)imidazol
smeltepunkt : 221-222°C
IR (Nujol) : 3450, 1618, 1602, 1573, 1600 cm"<1>
Eksempel 113
2-(5-Amino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 172-173°C
IR (Nujol) : 3430, 1598, 1569, 1530, 1495 cm"<1>
Eksempel 114
4-Metyl-2-(4-metylamino-2-metoksyfenyl)-5-(3-pyridyl)imidazol smeltepunkt : 54-56°C
IR (Nujol) : 1612, 1580, 1560 cm'<1>
Eksempel 115
2-(2-Acetamidofenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 270-271°C
IR (Nujol) : 1700, 1620, 1598, 1580, 1545, 1495 cm"<1>
Eksempel 116
4-Metyl-2-[2-(3-metylureido)fenyl]-5-(3-pyridyl)imidazol smeltepunkt : 230-231°C
IR (Nujol) : 3270, 1684, 1658, 1618, 1589, 1493 er1
Eksempel 117
2-(4-Hydroksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 237-240°C
IR (Nujol) : 1610 cm"<1>
Eksempel 118
2-(5-Brom-2,4-dimetoksyfenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 246-248°C
IR (Nujol) : 1600, 1580 cm'<1>
Eksempel 119
2-(5-Klor-4-metylamino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 205-206°C
IR (Nujol) : 1616, 1570, 1546, 1498 cm"<1>
Eksempel 120
Til en suspensjon av l-hydroksy-2-(3,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,68 g) i metylenklorid (9 ml) ble satt fosfortriklorid (0,76 ml) ved omgivelsestemperatur. Blandingen ble oppvarmet under tilbakeløpskjøling i 1 time og avkjølt. Blandingen ble innstilt på en pH-verdi på 7,8 med vandig natriumkarbonat. Den organiske fase ble skilt fra, vasket med saltvann, tørret over magnesiumsulfat og inndampet. Residuet ble utgnidd med diisopropyleter, hvilket ga 2-(3,4-di-metoksyf enyl ) -4-metyl-5- ( 3-pyridyl ) imidazol (0,39 g).
smeltepunkt : 246-248°C
IR (Nujol) : 1600, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,53 (3H, s), 3,82 (3H, s), 3,85 (3H, s), 7,04 (1H, d, J=9Hz), 7,2-7,7 (3H, m), 8,10 (1H, br d, J=8Hz), 8,45 (1H, br d, J=6Hz), 8,92 (1H, br s)
Eksempel 121
Til en oppløsning av l-hydroksy-2-(2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,5 g) i N,N-dimetylformamid (10 ml) ble satt fosfortriklorid (0,31 ml) under isavkjøling. Blandingen ble omrørt i 2 timer ved 5-10°C. Blandingen ble hellet i vann (100 ml) og nøytralisert med vandig natriumhydrogenkarbonat. Bunnfallet ble oppsamlet, vasket med vann og tørret, hvilket ga 2-(2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (0,31 g).
smeltepunkt : 198-200°C
IR (Nujol) : 1600, 1585, 1560 er<1>
NMR (DMSO-de, 5) : 2,55 (3H, s), 3,99 (3H, s), 6,9-7,6 (4H, m), 8,0-8,3 (2H, m), 8,46 (1H, dd, J=2Hz, 5Hz), 8,98 (1H, d, J=2Hz), 11,7 (1H, br s)
Eksempel 122
Til en oppløsning av l-hydroksy-2-(2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (6,6 g) i N,N-dimetylformamid (130 ml) ble satt fosfortriklorid (3,7 ml) under isavkjøling. Blandingen ble omrørt i 2 timer ved 5-10°C. Reaksjonsblandingen ble hellet i vann, nøytralisert med vandig natriumhydrogenkarbonat og ekstrahert med etylacetat. Ekstrakten ble vasket med vann, tørret og inndampet. Residuet ble underkastet kolonnekromatografi på silikagel under eluering med en blanding av kloroform og metanol (metanol 0-15%). Fraksjonene ble samlet og inndampet, hvilket ga 2-(2,4-dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (2,82 g).
smeltepunkt : 164-166°C
IR (Nujol) : 1615, 1590 cm"<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,80 (3H, s), 3,93 (3H, s), 6,64 (1H, dd, J=2Hz, 8Hz), 6,68 (1H, d, J=2Hz), 7,40 (1H, dd, J=5Hz, 8Hz), 7,9-8,2 (2H, m), 8,43 (1H, br d, J=5Hz), 8,94 (1H, br s), 11,5 (1H, br s)
Andre fraksjoner ble samlet og inndampet, hvilket ga 2-(2,4-dimetoksyfenyl)-5-hydroksymetyl-4-(3-pyridyl)imidazol (1,26 g).
smeltepunkt : 192-195°C
IR (Nujol) : 1615, 1595 cm"<1>
NMR (DMSO-de, 5) : 3,83 (3H, s), 3,97 (3H, s), 4,70 (2H, br s), 5,26 (1H, br s), 6,66 (1H, dd, J=7Hz, 2Hz), 6,74 (1H, d, J=2Hz), 7,24 (1H, dd, J=5Hz, 8Hz), 7,9-8,3 (2H, m), 8,47 (1H, dd, J=2Hz, 5Hz), 9,02 (1H, br s)
Eksempel 123
Til en oppløsning av l-hydroksy-2-(2-metoksy-4-metylfenyl)--4-metyl-5-(3-pyridyl)imidazol (1,40 g) i N,N-dimetylformamid (28 ml) ble satt fosfortriklorid (0,83 ml), og blandingen ble omrørt i 2 timer ved omgivelsestemperatur. Derefter ble oppløsningen hellet i vann (150 ml) og omrørt i en time ved omgivelsestemperatur. Efter nøytralisering med vandig natriumhydrogenkarbonat ble det resulterende bunnfall oppsamlet ved filtrering. Bunnfallet ble tørret, oppløst i kloroform og kromatografert på silikagel under eluering med en blanding av kloroform og metanol. Fraksjonene ble samlet, inndampet og utgnidd i diisopropyleter, hvilket ga 2-(2-metoksy-4-metyl-fenyl)-4-metyl-5-(3-pyridyl)imidazol (0,82 g).
smeltepunkt : 125-128°C
IR (Nujol) : 1615, 1590 er1
NMR (DMSO-de, 5) : 2,37 (3H, s), 2,51 (3H, s), 3,95 (3H, s), 7,1-6,8 (2H, m) , 7,42 (1H, dd, J=4Hz, J=8Hz), 8,00 (1H, d, J=7Hz), 8,06 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,44 (1H, dd, J=4Hz, J=2Hz), 8,94 (1H, d, J=2Hz) Massespektrum (M/Z) : 279 (M<+>)
Eksempel 124
Til en oppløsning av l-hydroksy-2-(3-metoksy-4-metyltio-fenyl)-4-metyl-5-(3-pyridyl)imidazol (0,98 g) i N,N-dimetyl-formamid (10 ml) ble satt trietylfosfitt (1,03 ml), og blandingen ble omrørt ved 90°C i 3 timer. Derefter ble opp-løsningen hellet i vann (60 ml) og omrørt ved omgivelsestemperatur i en time. Det resulterende bunnfall ble filtrert, vasket med vann og omkrystallisert fra etanol (6 ml), hvilket ga 2-(3-metoksy-4-metyltiofenyl)-4-metyl-5-(3-pyridyl)imidazol (0,58 g).
smeltepunkt : 226-228°C
IR (Nujol) : 1605, 1570 cm"<1>
NMR (DMSO-de, 5) : 2,43 (3H, s), 2,51 (3H, s), 3,91 (3H, s), 7,18 (1H, d, J=9Hz), 7,37 (1H, dd, J=8Hz, J=4Hz), 7,7-7,45 (2H, m), 8,03 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,38 (1H, dd, J=4Hz, J=2Hz), 8,88 (1H, d, J=2Hz), 12,4
(1H, br s)
massespektrum (M/Z) : 311 (M<+>)
Følgende forbindelser (eksempel 125-183) ble erholdt på lignende måte som de i eksempel 120, 121, 122, 123 og 124 beskrevne.
Eksempel 125
2-(3,4-Dimetoksyfenyl)-5-metyl-4-(2-pyridyl)imidazol smeltepunkt : 96-98°C
IR (Nujol) : 3300, 1720, 1590, 1500, 1260 cm"<1>
NMR (CDCI3, 5) : 2,62 (3H, s), 3,77 (3H, s), 3,86 (3H, s), 6,18 (1H, d, J=8Hz), 6,9-7,1 (1H, m), 7,39 (1H, dd, J=2Hz, 8Hz), 7,44 (1H, s), 7,5-7,7 (2H, m) , 8,40 (1H, d, J=5Hz)
Eksempel 126
2-(3,4-Dimetoksyfenyl)-4-(2-pyridyl)imidazol
smeltepunkt : 80-82°C
IR (Nujol) : 1680, 1590, 1490 cm"<1>
NMR (CDCI3, 5): 3,83 (3H, s), 3,87 (3H, s), 6,81 (1H, d, J=8Hz), 7,0-7,2 (1H, m), 7,36 (1H, dd, J=2Hz, 8Hz), 7,48 (1H, d, J=2Hz), 7,60 (1H, s), 7,6-7,8 (2H, m), 8,42 (1H, d, J=6Hz)
Massespektrum (m/e) : 281 (M<+>)
Eksempel 127
2-(3,4-Dimetoksyfenyl)-5-metyl-4-(4-pyridyl)imidazol smeltepunkt : 234-236°C
IR (Nujol) : 1600 cm"<1>
NMR (CDCI3-CD3 OD, 5) : 2,50 (3H, s), 3,86 (3H, s), 3,91 (3H, s), 6,86 (1H, d, J=8Hz), 7,7-7,3 (4H, m), 8,42 (2H, d, J=6Hz)
Eksempel 128
2-(3,4-Dimetoksyfenyl)-5-etyl-4-(4-pyridyl)imidazol smeltepunkt : 181-182°C (dekomponering)
IR (Nujol) : 1595, 1530, 1410 er<1>
NMR (CDCI3 , 6) : 1,31 (3H, t, J=7,5Hz), 2,85 (2H, q, J=7,5Hz), 3,83 (6H, s), 6,77 (1H, d, J=9Hz), 7,37 (1H, dd, J=2Hz, 9Hz), 7,49 (1H, d, J=2Hz), 7,54, 8,44 (4H, ABq, J=6Hz)
Massespektrum (m/e) : 309 (M<+>)
Eksempel 129
2-(2,4-Dimetoksyfenyl)-5-metyl-4-(2-pyridyl)imidazol smeltepunkt : 118-120°C
IR (Nujol) : 3260, 1610, 1580, 1490 cm"<1>
NMR (CDCI3, 5) : 2,64 (3H, s), 3,84 (3H, s), 4,01 (3H, s), 6,53 (1H, s), 6,57 (1H, dd, J=2Hz, 9Hz), 7,01 (1H, dd, J=6Hz, 10Hz), 7,5-7,8 (2H, m), 8,23 (1H, d, J=10Hz), 8,50
(1H, d, J=6Hz)
Eksempel 130
2-(3,4-Dimetoksyfenyl)-5-etyl-4-(2-pyridyl)imidazol smeltepunkt : 160-163°C
IR (Nujol) : 1590, 1500, 1270, 1015 cm"<1>
NMR (CDCI3, 5) : 1,35 (3H, t, J=8Hz), 2,99 (2H, t, J=8Hz), 3,85 (6H, s), 6,80 (1H, d, J=9Hz), 6,9-7,1 (1H, m), 7,33 (1H, dd, J=2Hz, 9Hz), 7,43 (1H, d, J=2Hz), 7,5-7,7 (2H, m), 8,43 (1H, d, J=5Hz)
Eksempel 131
2-(2,4-Dimetoksyfenyl)-5-metyl-4-(4-pyridyl)imidazol smeltepunkt : 224-226°C
IR (Nujol) : 1605 cm"<1>
NMR (DMSO-de, 5) : 2,56 (3H, s), 3,85 (3H, s), 3,96 (3H, s), 6,6-6,8 (2H, m), 7,73 (2H, d, J=6Hz), 8,07 (1H, d, J=9Hz), 8,58 (2H, d, J=6Hz), 11-12 (1H, br s)
Eksempel 132
2-(2,4-Dimetoksyfenyl)-5-etyl-4-(4-pyridyl)imidazol smeltepunkt : 212-213°C
IR (Nujol) : 1595, 1530, 1505 cm"<1>
NMR (CDCI3, 5) : 1,36 (3H, t, J=8Hz), 2,93 (2H, q, J=8Hz), 3,83 (3H, s), 3,97 (3H, s), 6,51 (1H, d, J=2Hz), 6,57 (1H, dd, J=2Hz, 10Hz), 7,52 (2H, dd, J=2Hz, 6Hz), 8,23 (1H, d, J=10Hz), 8,50 (1H, dd, J=2Hz, 6Hz)
Massespektrum (m/e) : 309 (M<+>)
Eksempel 133
2-(2,4-Dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazol smeltepunkt : 148-151°C
IR (Nujol) : 1618, 1590, 1495 er1
NMR (DMSO-de, 5) : 1,25 (3H, t, J=8Hz), 2,85 (2H, q, J=8Hz), 3,80 (3H, s), 3,91 (3H, s), 6,49-6,65 (2H, m), 6,63 (1H, s), 7,35 (1H, dd, J=8Hz, 4Hz), 7,82-8,01 (2H, m), 8,35 (1H, m), 8,79 (1H, br s)
Eksempel 134
2-(2,5-Dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 152-154°C
IR (Nujol) : 1590 er1
NMR (DMSO-de, 5) : 2,53 (3H, s), 3,78 (3H, s), 3,91 (3H, s), 6,88 (1H, dd, J=8Hz, 2Hz),'7,10 (1H, d, J=8Hz), 7,40 (1H, dd, J=4Hz, 8Hz), 7,68 (1H, d, J=2Hz), 8,07 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,44 (1H, br d, J=4Hz), 8,97 (1H, br s)
Eksempel 135
2-(2,3-Dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 125-127°C
IR (Nujol) : 1590, 1555 er<1>
NMR (DMSO-de, 5) : 2,50 (3H, s), 3,77 (3H, s), 3,84 (3H, s), 6,96 (1H, dd, J=8Hz, 2Hz), 7,06 (1H, dd, J=8Hz, 8Hz), 7,32 (1H, dd, J=8Hz, 4Hz), 7,54 (1H, dd, J=2Hz, 8Hz), 7,97 (1H, ddd, J=2Hz, 2Hz, 8Hz), 8,33 (1H, br d, J=4Hz), 8,83 (1H, br s), 11,73 (1H, br s)
Eksempel 136
2-(2,3,4-Trimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt 144-146°C
IR (Nujol) : 1600 cm"<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,78 (3H, s), 3,81 (3H, s), 3,83 (3H, s), 6,84 (1H, d, J=9Hz), 7,32 (1H, dd, J=8Hz, 4Hz), 7,62 (1H, d, J=9Hz), 7,96 (1H, br d, J=8Hz), 8,32 (1H, br d, J=4Hz), 8,82 (1H, br s), 11,62 (1H, br s)
Eksempel 137
2-(3,4,5-Trimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 258-260°C
IR (Nujol) : 1590 cm"<1>
NMR (CDC13-CD3OD, 5) : 2,45 (3H, s), 3,84 (3H, s), 3,90 (6H, s), 7,18 (2H, s), 7,33 (1H, dd, J=8Hz, 5Hz), 7,96 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,34 (1H, br d, J=5Hz), 8,72
(1H, br s)
Eksempel 138
2-(4-Klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 145-147°C
IR (Nujol) : 1585, 1595 cm"<1>
NMR (DMSO-de, 5) : 2,54 (3H, s), 4,01 (3H, s), 7,12 (1H, dd, J=8Hz, 2Hz), 7,25 (1H, d, J=2Hz), 7,43 (1H, dd, J=8Hz, 5Hz), 8,08 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,16 (1H, d, J=8Hz), 8,47 (1H, dd, J=2Hz, 5Hz), 8,99 (1H, d, J=2Hz), 11,75 (1H, br s)
Eksempel 139
2-(4-Acetamido-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol
smeltepunkt : 239-240°C
IR (Nujol) : 3400, 1680, 1590, 1520, 1490 cm"<1>
NMR (DMSO-de, 5) : 2,14 (3H, s), 2,50 (3H, s), 3,91 (3H, s), 7,35 (1H, dd, J=5Hz, 8Hz), 7,63 (1H, s), 8,02 (1H, s), 8,02 (1H, dt, J=2Hz, 8Hz), 8,35 (1H, dd, J=2Hz, 5Hz), 8,82 (1H, d, J=2Hz), 9,40 (1H, s), 11,63 (1H, s)
Massespektrum (m/e) : 356 (M<+>)
Eksempel 140
2-(4-Acetamido-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 215-218°C
IR (Nujol) : 1675, 1600 er1
NMR (DMSO-de, 5) : 2,06 (3H, s), 2,49 (3H, s), 3,90 (3H, s), 7,14 (1H, dd, J=8Hz, 2Hz), 7,33 (1H, dd, J=8Hz, 5Hz), 7,48 (1H, d, J=2Hz), 7,92 (1H, d, J=8Hz), 7,96 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,33 (1H, br d, J=5Hz), 8,82 (1H, br s), 9,99 (1H, s), 11,45 (1H, br s)
Eksempel 141
2-Fenyl-5-metyl-4-(3-pyridyl)imidazol
smeltepunkt : 206-208°C
IR (Nujol) : 1600, 1590, 1575 cm"<1>
NMR (DMSO-de, 5) : 2,48 (3H, s), 7,2-7,6 (4H, m), 7,8-8,1 (3H, m), 8,35 (1H, br d, J=4Hz), 8,83 (1H, br s), 12,39
(1H, br s)
Eksempel 142
2-(2-Metoksy-4-nitrofenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 203-207°C
IR (Nujol) : 1580 cm"<1>
NMR (DMSO-de, 5) : 2,58 (3H, s), 4,11 (3H, s), 7,37 (1H, m), 7,75-8,14 (4H, m), 8,37 (1H, m), 8,88 (1H, br s), 11,93 (1H, br s)
Eksempel 143
2-(2-Metoksy-4-metyltiofenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 153-156°C
IR (Nujol) : 1600, 1580, 1565 cm"<1>
NMR (DMSO-de, 5) : 2,48 (3H, s) , 2,52 (3H, s) 3,94 (3H, s) , 6,89 (1H, dd, J=8Hz, J=2Hz), 6,94 (1H, d, J=2Hz), 7,34 (1H, dd, J=8Hz, J=4Hz), 7,96 (1H, d, J=8Hz), 7,98 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,34 (1H, dd, J=4Hz, J=2Hz), 8,84 (1H, d, J=2Hz), 11,45 (1H, br s)
Eksempel 144
2-(2-Metoksy-4-metyltiofenyl)-5-hydroksymetyl-4-(3-pyridyl)imidazol
smeltepunkt : 199-201°C
IR (Nujol) : 1605, 1590, 1575 er<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 3,94 (3H, s), 4,61 (2H, d, J=4Hz), 5,20 (1H, br t, J=4Hz), 6,88 (1H, dd, J=8Hz, 2Hz), 6,93 (1H, d, J=2Hz), 7,35 (1H, dd, J=8Hz, J=4Hz), 7,97 (1H, d, J=8Hz), 8,06 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,37 (1H, br d, J=4Hz), 8,90 (1H, br s), 11,57 (1H, br s)
Ekcempel 145
2- (4-A.mino-5-klor-2-metoksyf enyl) -5-metyl-4- (3-pyridyl) imidazol smeltepunkt : 178-180°C
IR (Nujol) : 3480, 3280, 3150, 1630, 1600, 1560 cm"<1>
NMR (DMSO-de, 5) : 2,50 (3H, s), 3,87 (3H, s), 5,58 (2H, s), 6,52 (1H, s), 7,32 (1H, dd, J=5Hz, 8Hz), 7,80 (1H, s), 7,98 (1H, dt, J=2Hz, 8Hz), 8,34 (1H, dd, J=2Hz, 5Hz), 8,82 (1H, d, J=2Hz), 11,30 (1H, br s)
Massespektrum (m/e) : 314 (M<+>)
Eksempel 146
2-(4-Amino-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 95-100°C
IR (Nujol) : 1615 cm"<1>
NMR (DMSO-d6, 5) : 2,45 (3H, s), 3,83 (3H, s), 5,32 (2H, br s), 6,18 (1H, dd, J=8Hz, 2Hz), 6,24 (1H, d, J=2Hz), 7,30 (1H, dd, J=8Hz, 4Hz), 7,67 (1H, d, J=8Hz), 7,94 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,30 (1H, dd, J=4Hz, 2Hz), 8,80 (1H, d, J=2Hz), 11,13 (1H, br s)
Eksempel 147
2-(2,6-Dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 185-187°C
IR (Nujol) : 1608, 1590 er1
NMR (DMSO-de, 5) : 2,44 (3H, s), 3,72 (6H, s), 6,74 (2H, d, J=8Hz), 7,55-7,25 (2H, m), 7,98 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,38 (1H, dd, J=5Hz, J=2Hz), 8,85 (1H, d, J=2Hz), 11,9 (1H, br s)
Massespektrum (M/Z) : 295 (M<+>)
Eksempel 148
2-(3-Metoksy-4-metyltiofenyl)-4-metyl-5-(4-pyridyl)imidazol smeltepunkt : 283-285°C
IR (Nujol) : 1600 er1
NMR (DMSO-de, 5) : 2,43 (3H, s), 2,53 (3H, s), 3,93 (3H, s), 7,22 (1H, d, J=8Hz), 7,8-7,4 (4H, m), 8,54 (2H, d, J=8Hz), 12,50 (1H, br s)
Massespektrum (M/Z) : 311 (M<*>)
Eksempel 149
2-(2-Metoksy-4-metyltiofenyl)-4-metyl-5-(4-pyridyl)imidazol smeltepunkt : 192-194°C
IR (Nujol) : 1606, 1565 er1
NMR (DMSO-de, 5) : 2,56 (3H, s), 2,58 (3H, s), 4,00 (3H, s), 6,99 (1H, dd, J=9Hz, J=2Hz), 7,04 (1H, d, J=2Hz), 7,73 (2H, d, J=6Hz), 8,09 (1H, d, J=9Hz), 8,57 (2H, d, J=6Hz), 11,55 (1H, br s)
Massespektrum (M/Z) :311 (M<+>)
Eksempel 150
4-Metyl-2-(2-nitrofenyl)-5-(3-pyridyl)imidazol
smeltepunkt : 229-230°C
IR (Nujol) : 1613, 1601, 1578, 1539, 1497 er1
NMR (DMSO-de, 5) : 2,51 (3H, s), 7,40 (1H, dd, J=8Hz, 5Hz), 7,54-8,06 (5H, m), 8,45 (1H, dd, J=5Hz, J=2Hz), 8,87 (1H, d, J=2Hz), 12,7 (1H, br s)
Massespektrum (M/Z) : 280 (M<+>)
Eksempel 151
4-Metyl-2-(o-tolyl)-5-(3-pyridyl)imidazol
smeltepunkt : 129-130°C
IR (Nujol) : 1604, 1570, 1494 cm"<1>
NMR (DMSO-de, 5) : 2,57 (3H, s), 2,72 (3H, s), 7,3-7,9 (5H, m), 8,18 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,52 (1H, dd, J=5Hz, 2Hz), 9,08 (1H, d, J=2Hz)
Massespektrum (M/Z) : 249 (M<+>)
Eksempel 152
2-(4-Klorfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 229-231°C
IR (Nujol) : 1600, 1574, 1492 cm"<1>
NMR (DMSO-de, 5) : 2,48 (3H, s), 7,32-7,58 (3H, m), 7,89-8,13 (3H, m), 8,43 (1H, dd, J=5Hz, 2Hz), 8,88 (1H, d, J=2Hz)
Massespektrum (M/Z) : 269 (M<+>)
Eksempel 153
2-[4-(N-Acetyl-N-metylamino)-5-klor-2-metoksyfenyl]-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 220-221°C
IR (Nujol) : 1672, 1599, 1563, 1525, 1490 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 2,79 (3H, s), 3,14 (3H, s), 4,01 (3H, s), 7,28-7,56 (2H, m), 7,95-8,26 (2H, m), 8,44 (1H, dd, J=5Hz, 2Hz), 8,91 (1H, d, J=2Hz) Massespektrum (M/Z) : 370 (M<+>)
Eksempel 154
2-(2-Klorfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 108-109°C
IR (Nujol) : 1590, 1562, 1480 er1
NMR (DMSO-de, 5) : 2,51 (3H, s), 7,25-7,9 (5H, m), 8,09 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,43 (1H, dd, J=5Hz, 2Hz), 8,92 (1H, d, J=2Hz), 12,2 (1H, br s)
Massespektrum (M/Z) : 269 (M<+>)
Eksempel 155
2-(3,4-Diklorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 269°C
IR (Nujol) : 1600, 1574 cm"<1>
NMR (DMSO-de, 5) : 2,51 (3H, s), 7,46 (1H, dd, J=8Hz, 5Hz), 7,71 (1H, d, J=8Hz), 7,8-8,25 (3H, m), 8,45 (1H, d, J=5Hz), 8,93 (1H, s), 12,68 (1H, br s)
Massespektrum (M/Z) : 303 (M-l)
Eksempel 156
2-(4-Fluorfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 123-124°C
IR (Nujol) : 1600, 1570, 1539, 1502 er<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 7,16-7,53 (3H, m), 7,87-8,19 (3H, m), 8,48 (1H, dd, J=5Hz, 2Hz), 8,97 (1H, d, J=2Hz)
Massespektrum (M/Z) : 253 (M<+>)
Eksempel 157
2-(3-Klorfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 242-243°C
IR (Nujol) : 1607, 1587, 1574, 1489 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 7,22-7,56 (3H, m), 7,79-8,21 (3H, m), 8,47 (1H, d, J=5Hz), 8,95 (1H, s) Massespektrum (M/Z) : 269 (M<+>)
Eksempel 158
2-(2-Fluorfenyl)-4-mety1-5-(3-pyridyl)imidazol
smeltepunkt : 194-195°C
IR (Nujol) : 1599, 1590, 1567, 1525, 1485 cm"<1>
NMR (DMSO-de, 5) : 2,60 (3H, s), 7,24-7,63 (4H, m), 7,95-8,36 (2H, m), 8,53 (1H, dd, J=5Hz, 2Hz), 9,08 (1H, d, J=2Hz)
Massespektrum (M/Z) :253 (M<+>)
Eksempel 159
2-(2,4-Diklorfenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 160-161°C
IR (Nujol) : 1590, 1569, 1556, 1484 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 7,38 (1H, dd, J=8Hz, 5Hz), 7,49 (1H, dd, J=8Hz, 2Hz), 7,69 (1H, d, J=2Hz), 7,83 (1H, d, J=8Hz), 8,04 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,43 (1H, d, J=5Hz), 8,91 (1H, s), 12,46 (1H, br s) Massespektrum (M/Z) : 303 (M-l)
Eksempel 160
2-(5-Klor-2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 241-244°C
IR (Nujol) : 1610, 1590, 1565 cm"<1>
NMR (CDCI3-CD3 OD, 5) : 2,50 (3H, s), 3,86 (3H, s), 3,94 (3H, s), 6,61 (1H, s), 7,38 (1H, dd, J=8Hz, J=4Hz), 8,2-7,8 (2H, m), 8,36 (1H, br d, J=4Hz), 8,74 {1H, br s) Massespektrum (M/Z) : 329 (M<+>)
Eksempel 161
2-(5-Klor-2-metoksy-4-metylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 185-187°C
IR (Nujol) : 1600, 1580, 1560 cm"<1>
NMR (DMSO-de, 5) : 2,37 (3H, s), 2,52 (3H, s), 3,94 (3H, s), 7,13 (1H, s), 7,36 (1H, dd, J=8Hz, J=4Hz), 8,00 (1H, s), 8,03 (1H, ddd, J=2Hz, J=2Hz, J=8Hz), 8,37 (1H, dd, J=2Hz, J=4Hz), 8,87 (1H, d, J=2Hz), 11,63 (1H, br s) Massespektrum (M/Z) : 313 (M<+>)
Eksempel 162
2-(4-Metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 199-201°C
IR (Nujol) : 1615, 1600 cm"<1>
NMR (DMSO-de, 6) : 2,51 (3H, s), 3,83 (3H, s), 7,05 (2H, d, J=9Hz), 7,42 (1H, dd, J=5Hz, J=8Hz), 7,8-8,2 (3H, m), 8,45 (1H, dd, J=5Hz, J=2Hz), 8,94 (1H, d, J=2Hz), 12,1
(1H, br s)
Massespektrum (M/Z) : 265 (M<+>)
Eksempel 163
4-Metyl-5-(3-pyridyl)-2-(2,4,6-trimetoksyfenyl)imidazol smeltepunkt : 65-75°C
IR (Nujol) : 1610, 1590 cm"<1>
NMR (DMSO-de, 5) : 2,42 (3H, s), 3,69 (3H, s), 3,83 (3H, s), 6,28 (2H, s), 7,33 (1H, dd, J=8Hz, J=4Hz), 7,93 (1H, br d J=8Hz), 8,32 (1H, br d, J=4Hz), 8,80 (1H, br s) Massespektrum (M/Z) : 325 (M<+>)
Eksempel 164
4-Metyl-5-(3-pyridyl)-2-(2,4,5-trimetoksyfenyl)imidazol smeltepunkt : 189-191°C
IR (Nujol) : 1615, 1600 cm"<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,76 (3H, s), 3,83 (3H, s), 3,93 (3H, s), 6,74 (1H, s), 7,35 (1H, dd, J=8Hz, J=4Hz), 7,60 (1H, s), 7,99 (1H, ddd, J=2Hz, 2Hz, 8Hz), 8,46 (1H, dd, J=2Hz, J=4Hz), 8,85 (1H, d, J=2Hz) Massespektrum (M/Z) :325 (M<+>)
Eksempel 165
2-(4-Benzyloksy-2-metoksyfenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 160-162°C
IR (Nujol) : 1615, 1590 cm"<1>
NMR (DMSO-de, 5) : 2,48 (3H, s), 3,92 (3H, s), 5,14 (2H, s), 6,69 (1H, dd, J=8Hz, J=2Hz), 6,74 (1H, d, J=2Hz), 7,6-7,2 (6H, m), 8,1-7,8 (2H, m), 8,36 (1H, br d, J=4Hz), 8,86 (1H, br s)
Massespektrum (M/Z) : 371 (M<+>)
Eksempel 166
2-(4-Etoksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 151-153°C
IR (Nujol) : 1615, 1590 cm"<1>
NMR (DMSO-de, 5) : 1,36 (3H, t, J=7Hz), 2,53 (3H, s), 3,94 (3H, s), 4,10 (2H, q, J=7Hz), 6,63 (1H, dd, J=2Hz, J=7Hz), 6,68 (1H, d, J=2Hz), 7,41 (1H, dd, J=8Hz, J=4Hz), 7,8-8,3 (2H, m), 8,42 (1H, d, J=4Hz), 8,95 (1H, br s), 11,50 (1H, br s)
Massespektrum (M/Z) : 309 (M<+>)
Eksempel 167
2-(5-Klor-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 193-195°C
IR (Nujol) : 1600, 1586, 1565, 1619 cm"<1>
NMR (DMSO-de, 5) : 2,53 (3H, s), 3,95 (3H, s), 7,11 (1H, d, J=8Hz), 7,21-7,48 (2H, m), 7,89-8,13 (2H, m), 8,39 (1H, d, J=5Hz), 8,88 (1H, s), 11,72 (1H, br s)
Massespektrum (M/Z) : 298 (M<+>)
Eksempel 168
2-(4-Hydroksy-3-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 278-279°C
IR (Nujol) : 1609, 1575, 1508, 1490 er1
NMR (DMSO-de, 5) : 2,43 (3H, s), 3,83 (3H, s), 6,79 (1H, d, J=8Hz), 7,2-7,55 (3H, m), 7,97 (1H, d, J=8Hz), 8,35 (1H, s), 8,83 (1H, s), 9,13 (1H, s)
Massespektrum (M/Z) : 281 (M<+>)
Eksempel 169
2-(3-Hydroksy-4-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 267-269°C
IR (Nujol) : 1595, 1574, 1505 cm"<1>
NMR (DMSO-de, 5) : 2,45 (3H, s), 3,82 (3H, s), 7,00 (1H, d, J=8Hz), 7,26-7,56 (3H, m), 8,05 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,40 (1H, dd, J=5Hz, 2Hz), 8,86 (1H, d, J=2Hz), 9,08 (1H, s), 12,10 (1H, br s)
Massespektrum (M/Z) :281 (M<+>)
Eksempel 170
2-(3-Klor-4,5-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 215-216°C
IR (Nujol) : 1573, 1497 cm"<1>
NMR (DMSO-de, 6) : 2,50 (3H, s), 3,90 (3H, s), 3,96 (3H, s), 7,42 (1H, dd, J=8Hz, 5Hz), 7,67 (2H, s), 8,10 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,47 (1H, dd, J=5Hz, 2Hz), 8,93 (1H, d, J=2Hz)
Massespektrum (M/Z) : 329 (M<+>)
Eksempel 171
2-(3-Klor-4-hydroksy-5-metoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 251-253°C
IR (Nujol) : 1575, 1504 cm"<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,93 (3H, s), 7,42 (1H, br s), 7,54 (1H, s), 7,57 (1H, s), 8,05 (1H, d, J=8Hz), 8,42 (1H, s), 8,90 (1H, s), 9,62 (1H, s), 12,33 (1H, br s) Massespektrum (M/Z) : 315 (M<+>)
Eksempel 172
4-Metyl-2-(2-metoksy-5-nitrofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 220-223°C
IR (Nujol) : 1593, 1534, 1508, 1490 er<1>
NMR (DMSO-de, 6) : 2,52 (3H, s), 4,07 (3H, s), 7,18-7,46 (2H, m), 7,85-8,12 (2H, m), 8,47 (1H, d, J=5Hz), 8,77-8,91 (2H, m), 11,86 (1H, br s)
Massespektrum (M/Z) : 310 (M<+>)
Eksempel 173
4-Metyl-2-(2-metoksy-3-nitrofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 145-150°C
IR (Nujol) : 1600, 1566, 1535 cm"<1>
NMR (DMSO-de, 6) : 2,53 (3H, s), 3,78 (3H, s), 7,2-7,5
(2H, m), 7,83 (1H, dd, J=8Hz, 2Hz), 8,02 (1H, d, J=8Hz), 8,18 (1H, dd, J=8Hz, 2Hz), 8,36 (1H, d, J=5Hz), 8,87 (1H, s), 12,24 (1H, br s)
Massespektrum (M/Z) :310 (M<+>)
Eksempel 174
2-(2-Metoksy-4-metylsulfinylfenyl)-4-metyl-5-(3-pyridyl)imidazol IR (Nujol) : 1660, 1600 cm"<1>
Eksempel 175
2-(2-Metoksy-4-metylsulfonylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 115-118°C
IR (Nujol) : 1600, 1590 er1
Eksempel 176
2-(2-Aminofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 221-222°C
IR (Nujol) : 3450, 1618, 1602, 1573, 1600 cm"<1>
Eksempel 177
2-(5-Amino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 172-173°C
IR (Nujol) : 3430, 1598, 1569, 1530, 1495 cm"<1>
Eksempel 178
4-Metyl-2-(4-metylamino-2-metylfenyl)-5-(3-pyridyl)imidazol smeltepunkt : 54-56°C
IR (Nujol) : 1612, 1580, 1560 cm"<1>
Eksempel 179
2-(2-Acetamidofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 270-271°C
IR (Nujol) : 1700, 1620, 1598, 1580, 1545, 1495 cm"<1>
Eksempel 180
4-Metyl-2-[2-(3-metylureido)fenyl]-5-(3-pyridyl)imidazol smeltepunkt : 230-231°C
IR (Nujol) : 3270, 1684, 1658, 1618, 1589, 1493 cm"<1>
Eksempel 181
2-(4-Hydroksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 237-240°C
IR (Nujol) : 1610 er1
Eksempel 182
2-(5-Brom-2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 246-248°C
IR (Nujol) : 1600, 1580 cm"<1>
Eksempel 183
2-(5-Klor-4-metylamino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 205-206°C
IR (Nujol) : 1616, 1570, 1546, 1498 er1
Eksempel 184
Til en oppløsning av l-hydroksy-2-(3,4-dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazol (1,86 g) i N,N-dimetylformamid (38 ml) ble satt fosfortriklorid (0,10 ml) under isavkjøling. Blandingen ble omrørt i 2 timer ved 5-10°C. Reaksjonsblandingen ble hellet i vann, nøytralisert med vandig natriumhydrogenkarbonat og ekstrahert med etylacetat. Ekstrakten ble vasket med vann, tørret og inndampet. Residuet ble underkastet kolonnekromatografi på silikagel under eluering med en blanding av kloroform og metanol (metanol 1-5%). Fraksjonene ble samlet og inndampet, hvilket ga 2-(3,4-dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazol (0,89 g), som ble fortynnet med metanol (8 ml). 1,2 ekvivalent hydrogenkloridgass ble boblet igjennom,
og dietyleter ble satt til blandingen under avkjøling. Bunnfallet ble oppsamlet og tørret, hvilket ga 2-(3,4-dimetoksyfenyl)-4-etyl-5-(3-pyridyl)imidazolhydroklorid (0,43 g).
smeltepunkt : 245-248°C
IR (Nujol) : 1650, 1605, 1515 cm"<1>
NMR (DMSO-de, 6) : 1,33 (3H, t, J=8Hz), 2,76 (2H, q, J=8Hz), 3,71 (3H, s), 3,81 (3H, s), 6,82 (1H, d, J=8Hz), 7,16 (1H, s), 7,10-7,30 (1H, m), 7,72 (1H, dd, J=8Hz, 4Hz), 8,15
(1H, d, J=8Hz), 8,45-8,70 (2H, br s)
Eksempel 185
Til en oppløsning av 2-(2,4-dimetoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (0,80 g) i N,N-dimetylformamid (12 ml) ble satt natriumhydrid (0,13 g, 60% suspensjon i olje), og blandingen ble omrørt i 10 minutter. Derefter ble det tilsatt metyljodid (0,34 ml), og reaksjonen ble omrørt ved omgivelsestemperatur i 5 timer. Oppløsningen ble hellet i vann (100 ml) og ekstrahert med etylacetat. Ekstrakten ble vasket med vann, tørret over natriumsulfat og kromatografert på silikagel (25 g) under eluering med kloroform. Fraksjonene ble samlet og inndampet, og residuet ble utgnidd med en blanding av etylacetat og diisopropyleter (1:1 volum/volum), hvilket ga 2-(2,4-dimetoksyfenyl)-1,5-dimetyl-4-(3-pyridyl)imidazol (70 mg),
smeltepunkt : 129-131°C
IR (Nujol) : 1615, 1595, 1580 cm"<1>
NMR (DMSO-de, 6) : 2,40 (3H, s), 3,30 (3H, s), 3,76 (3H, s), 3,80 (3H, s), 6,7-6,4 (2H, m), 7,20 (1H, d, J=8Hz), 7,31 (1H, dd, J=4Hz, 8Hz), 7,89 (1H, br d, J=8Hz), 8,32 (1H,
br d, J=4Hz), 8,74 (1H, br s)
Eksempel 186
En oppløsning av 2-(2-Aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,7 g) og 2-metyltio-2-imidazolinhydrojodid (1,23 g)
i N,N-dimetylformamid (10 ml) ble omrørt ved 1000C i 24 timer. Det resulterende bunnfall ble oppsamlet ved filtrering og
vasket suksessivt med N,N-dimetylformamid og etylacetat. Til en oppløsning av residuet i etanol (10 ml) ble satt en oppløsning av 20% hydrogenklorid i etanol (2 ml) ved omgivelsestemperatur, og det ble inndampet under redusert trykk. Bunnfallet ble utgnidd i etanol og dietyleter, hvilket ga 2-(2-aminofenyl)-
1,5-dimetyl-4-(3-pyridyl)imidazoldihydroklorid (0,13 g).
smeltepunkt : 285-286°C
IR (Nujol) : 1587, 1512 cm'<1>
NMR (D20, 5) : 2,59 (3H, s), 4,48 (3H, s), 7,10-7,68 (4H, m), 8,05 (1H, dd, J=8Hz, 6Hz), 8,53-8,76 (2H, m), 8,99
(1H, s)
massespektrum (M/Z) : 264 (M+ , fri)
Eksempel 187
En oppløsning av 2-(4-acetamido-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (1,0 g) i 10% saltsyre (30 ml) ble omrørt ved 80-85°C i 4 timer. Reaksjonsblandingen ble hellet i vann (100 ml) og vasket med etylacetat. Oppløsningen ble innstilt på en pH-verdi på 8,0 med 20% kaliumkarbonat og ekstrahert med etylacetat. Ekstrakten ble vasket med saltvann og tørret over magnesiumsulfat. Oppløsningsmidlet ble avdampet i vakuum, og residuet ble krystallisert fra en blanding av etylacetat og dietyleter, hvilket ga 2-(4-amino-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (0,63 g).
smeltepunkt : 178-180°C
IR (Nujol) : 3480, 3280, 3150, 1630, 1600, 1560 cm"<1>
NMR (DMSO-de, 5) : 2,50 (3H, s), 3,87 (3H, s), 5,58 (2H,
s), 6,52 (1H, s), 7,32 (1H, dd, J=5Hz, 8Hz), 7,80 (1H, s), 7,98 (1H, dt, J=2Hz, 8Hz), 8,34 (1H, dd, J=2Hz, 5Hz), 8,82 (1H, d, J=2Hz), 11,30 (1H, br s)
massespektrum (m/e) : 314 (M<+>)
Eksempel 188
En oppløsning av 2-(4-acetamido-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (0,55 g) i IN saltsyre (25 ml) ble oppvarmet under tilbakeløpskjøling i 5,5 time og avkjølet.
Efter nøytralisering med vandig natriumhydrogenkarbonat ble blandingen ekstrahert med kloroform. Ekstrakten ble tørret over natriumsulfat og inndampet, og residuet ble utgnidd med en blanding av metanol og diisopropyleter, hvilket ga 2-(4-amino-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol (0,24 g).
smeltepunkt : 95-100°C
IR (Nujol) : 1615 er1
NMR (DMSO-de, 5) : 2,45 (3H, s), 3,83 (3H, s), 5,32 (2H, br s), 6,18 (1H, dd, J=8Hz, 2Hz), 6,24 (1H, d, J=2Hz), 7,30 (1H, dd, J=8Hz, 4Hz), 7,67 (1H, d, J=8Hz), 7,94 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,30 (1H, dd, J=4Hz, 2Hz), 8,80 (1H, d, J=2Hz), 11,13 (1H, brs)
Eksempel 189
En oppløsning av 2-[4-[N-acetyl-N-metylamino)-5-klor-2-metoksyfenyl]-4-metyl-5-(3-pyridyl)imidazol (0,70 g) og konsentrert saltsyre (7 ml) i en blanding av vann (7 ml) og etanol (7 ml) ble oppvarmet under tilbakeløpskjøling i 7 timer under omrøring. Blandingen fikk avkjøles til omgivelsestemperatur, hvorefter den ble inndampet under redusert trykk. Den resulterende olje ble hellet i vann (20 ml). Efter nøytral-isering med vandig kaliumhydrogenkarbonat ble blandingen ekstrahert med etylacetat. Den organiske fase ble vasket med saltvann og tørret over magnesiumsulfat. Oppløsningsmidlet ble destillert fra, hvilket ga 2-(5-klor-4-metylamino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,58 g).
smeltepunkt : 205-206°C
IR (Nujol) : 1616, 1570, 1546, 1498 er<1>
NMR (DMSO-de, 5) : 2,51 (3H, s), 2,87 (3H, d, J=6Hz), 3,97 (3H, s), 5,77 (1H, d, J=6Hz), 6,32 (1H, s), 7,39 (1H, dd, J=8Hz, 5Hz), 7,92 (1H, s), 8,07 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,40 (1H, d, J=5Hz), 8,92 (1H, s), 11,38 (1H, br s)
Eksempel 190
Til en oppløsning av 2-(2-metoksy-4-metyltiofenyl)-4-metyl-5-(3-pyridyl)imidazol (1,0 g) i kloroform (50 ml) og etanol (25 ml) ble satt en oppløsning av m-klorperbenzoesyre (0,53 g, 80% rent) i kloroform (5,3 ml) ved -30 til -40°C. Blandingen ble omrørt ved samme temperatur i 4 timer og derefter oppvarmet til omgivelsestemperatur. Reaksjonsblandingen ble fortynnet med kloroform (100 ml) og vasket suksessivt med vandig natriumhydrogenkarbonat og saltvann. Efter tørring over natriumsulfat ble blandingen kromatografert på silikagel under eluering med en blanding av kloroform og metanol, hvilket ga 2-(2-metoksy-4-metylsulfinylfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,82 g).
IR (Nujol) : 1660, 1600 er1
NMR (CDCI3, 5) : 2,48 (3H, s), 2,72 (3H, s), 3,98 (3H, s), 7,16 (1H, dd, J=8Hz, J=2Hz), 7,25 (1H, dd, J=8Hz, J=5Hz), 7,33 (1H, d, J=2Hz), 7,98 (1H, br d, J=8Hz), 8,35 (1H, d, J=8Hz), 8,37 (1H, dd, J=2Hz, J=5Hz), 8,84 (1H, br s),
10,68 (1H, br s)
Eksempel 191
Til en oppløsning av 2-(2-metoksy-4-metyltiofenyl)-4-metyl-5-(3-pyridyl)imidazol (0,93 g) i eddiksyre (10 ml) ble satt vandig kaliumpermanganat (0,80 g i 15 ml) ved omgivelsestemperatur, og blandingen ble omrørt ved omgivelsestemperatur i 3 timer. Efter nøytralisering med vandig natriumhydrogenkarbonat ble blandingen ekstrahert med kloroform. Den organiske fase ble vasket med vann, tørret over natriumsulfat og konsentrert. Residuet ble kromatografert på silikagel under eluering med en blanding av kloroform og metanol, hvilket ga 2-(2-metoksy-4-metylsulfonylfenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,16 g).
smeltepunkt : 115-118°C
IR (Nujol) : 1600, 1590 er1
NMR (DMSO-de, 6) : 2,53 (3H, s), 3,25 (3H, s), 4,05 (3H, s), 7,7-7,2 (3H, m), 7,8-8,5 (3H, m), 8,85 (1H, br s), 11,85 (1H, br s)
massespektrum (M/Z) :343 (M<+>)
Eksempel 192
En blanding av 4-metyl-2-(2-nitrofenyl)-5-(3-pyridyl)-imidazol (4,99 g) og 10% palladium på kull (1,0 g) i en blanding av tetrahydrofuran (150 ml) og metanol (150 ml) ble hydrogenert ved omgivelsestemperatur under atmosfærisk hydrogengasstrykk. Efter fjernelse av katalysatoren ved filtrering ble filtratet inndampet under redusert trykk. Residuet ble omkrystallisert fra etanol, hvilket ga 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (4,22 g).
smeltepunkt : 221-222°C
IR (Nujol) : 3450, 1618, 1602, 1573, 1600 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 6,54-7,23 (3H, m), 7,45 (1H, dd, J=8Hz, 5Hz), 7,64 (1H, d, J=8Hz), 8,10 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,48 (1H, dd, J=5Hz, 2Hz), 8,95 (1H, d, J=2Hz)
massespektrum (M/Z) : 250 (M<+>)
Eksempel 193
2-(5-Amino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol ble erholdt på lignende måte som den i eksempel 192 beskrevne,
smeltepunkt : 172-173°C
IR (Nujol) : 3430, 1598, 1569, 1530, 1495 er1
NMR (DMSO-de, 6) : 2,49 (3H, s), 3,82 (3H, s), 6,53 (1H, dd, J=8Hz, 2Hz), 6,83 (1H, d, J=8Hz), 7,22-7,48 (2H, m), 7,98 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,36 (1H, dd, J=5Hz,
2Hz), 8,87 (1H, d, J=2Hz)
massespektrum (M/Z) : 280 (M<+>)
Eksempel 194
En blanding av 2-(5-klor-4-metylamino-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,50 g) og 10% palladium på kull (7,5 g) i en blanding av trietylamin (0,64 ml) og metanol (20 ml) ble hydrogenert ved omgivelsestemperatur under atmosfærisk trykk av hydrogengass. Efter fjernelse av det uoppløselige stoff ved filtrering ble filtratet inndampet under redusert trykk. Residuet ble utgnidd i diisopropyleter, hvilket ga 4-metyl-2-(4-metylamino-2-metoksyfenyl)-5-(3-pyridyl)imidazol (0,10 g).
smeltepunkt : 54-56°C
IR (Nujol) : 1612, 1580, 1560 cm"<1>
NMR (DMSO-de, 6) : 2,48 (3H, s), 2,75 (3H, d, J=6Hz), 3,92 (3H, s), 5,94 (1H, d, J=6Hz), 6,15-6,35 (2H, m), 7,38 (1H, dd, J=8Hz, 5Hz), 7,81 (1H, d, J=8Hz), 8,02 (1H, d, J=8Hz), 8,37 (1H, d, J=5Hz), 8,88 (1H, s), 11,22 (1H, br s) massespektrum (M/Z) : 294 (M<+>)
Eksempel 195
En oppløsning av 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,5 g) og eddiksyreanhydrid (0,38 ml) i eddiksyre (5 ml) ble omrørt ved omgivelsestemperatur i 1,5 time. Det resulterende bunnfall ble oppsamlet ved filtrering og omkrystallisert fra etanol, hvilket ga 2-(2-acetamidofenyl)-4-metyl-5-(3-pyridyl)imidazol (0,55 g).
smeltepunkt : 270-271°C
IR (Nujol) : 1700, 1620, 1598, 1580, 1545, 1495 cm"<1>
NMR (DMSO-de, 6) : 2,21 (3H, s), 2,52 (3H, s), 7,0-7,6
(3H, m), 7,85 (1H, s), 8,10 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,4-8,75 (2H, m), 8,97 (1H, d, J=2Hz)
massespektrum : (M/Z) : 292 (M<+>)
Eksempel 196
En oppløsning av 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,5 g) og metylisocyanat (0,15 ml) i en blanding av tetrahydrofuran (5 ml) og metanol (2 ml) ble omrørt ved omgivelsestemperatur i 5 timer. Det resulterende bunnfall ble oppsamlet ved filtrering, vasket med en blanding av etanol og kloroform og tørret i vakuum, hvilket ga 4-metyl-2-[2-(3-metylureido)fenyl]-5-(3-pyridyl)imidazol (0,51 g).
smeltepunkt : 230-231°C
IR (Nujol) : 3270, 1684, 1658, 1618, 1589, 1493 er1
NMR (DzO-DCl, 5) : 2,62 (3H, s), 2,70 (3H, s) 7,38-7,95 (4H, m), 8,38 (1H, dd, J=8Hz, 5Hz), 8,8-9,1 (2H, m), 9,21
(1H, d, J=2Hz)
massespektrum (M/Z) : 307 (M<+>)
Eksempel 197
Til en oppløsning av 2-(4-benzyloksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (1,18 g) i metanol (12 ml) og tetrahydrofuran (6 ml) ble satt 10% palladium på kull (vått ca. 50%, 0,30 g), og blandingen ble omrørt i 7 timer ved omgivelsestemperatur under atmosfærisk trykk av hydrogengass. Blandingen ble filtrert, og filtratet ble inndampet. Residuet ble oppløst i metanol (20 ml), og hydrogenert igjen på palladium på kull (vått, 0,50 g) i 5 timer. Efter filtrering ble filtratet inndampet, og residuet ble utgnidd i en blanding av diisopropyleter og isopropanol (1:1 volum/volum), hvilket ga 2-(4-hydroksy-2-metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,25 g).
smeltepunkt : 237-240°C
IR (Nujol) : 1610 cm"<1>
NMR (DMSO-de, 5) : 2,47 (3H, s), 3,89 (3H, s), 6,53 (1H,
dd, J=8Hz, J=2Hz), 6,60 (1H, d, J=2Hz), 7,46 (1H, dd,
J=8Hz, J=5Hz), 7,89 (1H, d, J=8Hz), 8,07 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,51 (1H, dd, J=5Hz, J=2Hz), 8,92 (1H, d, J=2Hz), 10,0 (1H, br s)
massespektrum (M/Z) : 281 (M<*>)
Eksempel 198
Til en oppløsning av 2-(2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (1,0 g) i eddiksyre (10 ml) ble satt en oppløsning av hydrogenbromid i eddiksyre (28%, 0,2 ml) og pyridiniumhydrobromidperbromid (1,49 g) og omrørt ved omgivelsestemperatur i 19 timer. Derefter ble blandingen hellet i isvann (100 ml), innstilt på en pH-verdi på 4,8 med 8N natriumhydroksyd og ekstrahert med kloroform. Den organiske fase ble vasket med vandig natriumhydrogenkarbonat og inndampet, og residuet ble utgnidd i diisopropyleter, hvilket ga 2-(5-brom-2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,92 g).
smeltepunkt : 246-248°C
IR (Nujol) : 1600, 1580 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 2,96 (3H, s), 3,96 (3H,
s), 4,03 (3H, s), 6,89 (1H, s), 7,43 (1H, dd, J=8Hz, J=5Hz), 8,11 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,24 (1H, s), 8,47
(1H, dd, J=2Hz, J=5Hz), 8,97 (1H, d, J=2Hz), 11,6 (1H, br s)
massespektrum (M/Z) : 373 (M<+>)
Eksempel 199
Til en oppløsning av 2-(2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol (0,9 g) i etanol (20 ml) ble satt konsentrert saltsyre (0,6 ml), og blandingen ble inndampet. Den resulterende sirup ble utgnidd i etanol, hvilket ga 2-(2,4-dimetoksyfenyl)-4-metyl-5-(3-pyridyl)imidazoldihydroklorid (1,02 g).
smeltepunkt : 247-248°C
IR (Nujol) : 1615, 1580 er1
NMR (DMSO-de, 5) : 2,56 (3H, s), 3,91 (3H, s), 4,01 (3H,
s), 6,78 (1H, dd, J=7Hz, J=2Hz), 6,86 (1H, d, J=2Hz), 8,3-7,8 (2H, m), 8,65 (1H, ddd, J=8Hz, J=2Hz, J=2Hz), 8,87 (1H, dd, J=5Hz, J=2Hz), 9,20 (1H, d, J=2Hz)
Eksempel 200
2-(2-Metoksy-4-metylsulfinylfenyl)-4-mety1-5-(3-pyridyl)-imidazoldihydroklorid ble erholdt på lignende måte som den i eksempel 199 beskrevne.
smeltepunkt: 212-215°C
IR (Nujol) : 1640, 1600, 1580 cm"<1>
NMR (DMSO-de, 5) : 2,55 (3H, s), 2,84 (3H, s), 4,03 (3H, s), 7,41 (1H, dd, J=8Hz, J=2Hz), 7,49 (1H, d, J=2Hz), 7,66
(1H, dd, J=5Hz, J=8Hz), 8,19 (1H, d, J=8Hz), 8,28 (1H,
ddd, J=2Hz, J=2Hz, J=8Hz), 8,62 (1H, dd, J=2Hz, J=5Hz), 8,91 (1H, d, J=2Hz)
massespektrum (M/Z) : 327 (M+ , fri)
Eksempel 201
2- [4-(Dimetylamino)-2-metoksyfenyl]-4-metyl-5-(3-pyridyl)-imidazol ble erholdt på lignende måte som den i eksempel 124 beskrevne. Derefter ble dihydrokloridet derav erholdt på lignende måte som den i eksempel 199 beskrevne.
De følgende fysiske data angår dihydrokloridet.
smeltepunkt : 218-220°C
IR (Nujol) : 1612, 1519, 1495 er1
NMR (D20, 5) : 2,58 (3H, s), 3,22 (6H, s), 4,10 (3H, s), 6,83-7,09 (2H, m), 7,85 (1H, d, J=9Hz), 8,37 (1H, dd, J=8Hz, 5Hz), 8,70-8,98 (2H, m), 9,10 (1H, s)
Eksempel 202
2-(2-Aminofenyl)-1,5-dimetyl-4-(3-pyridyl)imidazoldihydro-klorid ble erholdt på lignende måte som den i eksempel 199 beskrevne.
smeltepunkt : 285-286°C
IR (Nujol) : 1587, 1512 er1
Eksempel 203
Til en oppløsning av 1-hydroksyimino-l-(3-pyridyl)aceton (0,5 g) i eddiksyre (10 ml) ble satt 2-fluorbenzaldehyd (0,76 g) og ammoniumacetat (2,35 g), og det ble oppvarmet under tilbakeløpskjøling i 30 minutter. Derefter ble oppløsningen hellet i vann (75 ml), nøytralisert med vandig kaliumkarbonat og ekstrahert med etylacetat. Ekstrakten ble tørret over magnesiumsulfat og konsentrert, og residuet ble utgnidd med diisopropyleter, hvilket ga 2-(2-fluorfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol (0,23 g).
smeltepunkt : 65-75°C
IR (Nujol) : 1640, 1572, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,25 (3H, s), 7,12-7,80 (5H, m), 7,99 (1H, dd, J=8Hz, 2Hz, 2Hz), 8,40-8,92 (2H, m) massespektrum : (M/Z) : 269 (M<+>)
Eksempel 204
De følgende forbindelser ble erholdt på lignende måte som den i eksempel 1, 2, 3, 4, 5 eller 203 beskrevne.
(1) l-Hydroksy-2-(4-metoksykarbonylfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 105-113°C
IR (Nujol) : 1723, 1611 er1
NMR (DMSO-de, 5) : 2,25 (3H, s), 3,90 (3H, s), 7,46 (1H,
dd, J=8Hz, 5Hz), 7,86-8,34 (5H, m), 8,58 (1H, dd, J=5Hz, 2Hz), 8,78 (1H, d, J=2Hz)
(2) l-Hydroksy-2-(2-mesylaminofenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 158-163°C
IR (Nujol) : 1583, 1495 er1
NMR (DMSO-de, 5) : 2,46 (3H, s), 2,97 (3H, s), 7,20-7,95 (5H, m), 8,20 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,60 (1H, dd, J=5Hz, 2Hz), 8,91 (1H, d, J=2Hz)
(3) 2-(4-Karboksyfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 188-192°C
IR (Nujol) : 1708, 1609 er1
NMR (D2O-DCI, 5) : 2,60 (3H, s), 8,15-8,26 (4H, m), 8,39 (1H, dd, J=8Hz, 5Hz), 8,95-9,20 (2H, m), 9,29 (1H, s), Massespektrum (M/Z) : 295 (M<+>)
(4) l-Hydroksy-2-(2-hydroksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 201-202°C
IR (Nujol) : 1629, 1592, 1572, 1486 cm"<1>
NMR (DMSO-de, 5) : 2,42 (3H, s), 6,80-7,81 (5H, m), 8,19 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,62 (1H, dd, J=5Hz, 2Hz),
8,90 (1H, d, J=2Hz)
(5) l-Hydroksy-4-metyl-5-(3-pyridyl)-2-(2-trifluor-metylfenyl)-imidazol
smeltepunkt : 100-106°C
IR (Nujol) : 1608, 1560, 1482 cm"<1>
NMR (DMSO-de, 6) : 2,32 (3H, s), 7,35-8,13 (6H, m) , 8,58 (1H, dd, J=5Hz, 2Hz), 8,80 (1H, d, J=2Hz)
(6) l-Hydroksy-5-metyl-2-(2-metyltiofenyl)-4-(3-pyridyl)imidazol smeltepunkt : 80-90° C
IR (Nujol) : 1590, 1550, 1540 cm"<1>
NMR (DMSO-de, 6) : 2,42 (3H, s), 2,48 (3H, s), 7,20-7,70 (5H, m), 8,15 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,49 (1H, d, J=5Hz), 8,96 (1H, d, J=2Hz)
Massespektrum (M/Z) : 297 (M<+>)
(7) l-Hydroksy-4-metyl-5-(3-pyridyl)-2-(4-trifluormetylfenyl)-imidazol
NMR (DMSO-de, 5) : 2,28 (3H, s), 7,50 (1H, dd, J=8Hz,
5Hz), 7,70-8,40 (5H, m), 8,56 (1H, m), 8,80 (1H, s)
(8) 2-(4-Acetamidofenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 156-161°C
IR (Nujol) : 1690, 1672, 1600, 1530, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,09 (3H, s), 2,21 (3H, s), 7,45 (1H,
dd, J=8Hz, 5Hz), 7,50-8,20 (5H, m), 8,52 (1H, dd, J=5Hz, 2Hz), 8,75 (1H, d, J=2Hz), 10,16 (1H, s)
(9) l-Hydroksy-4-metyl-2-(4-nitrofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 113-121°C
IR (Nujol) : 1600, 1510 er1
NMR (DMSO-de, 5) : 2,38 (3H, s), 7,65 (1H, dd, J=8Hz, 5Hz), 8,00-8,55 (5H, m), 8,70 (1H, dd, J=5Hz, 2Hz), 8,85 (1H, d, J=2Hz)
(10) 2-[2-(4-Klorbenzyloksy)fenyl]-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 201-203°C
IR (Nujol) : 1620, 1600 cm"<1>
NMR (DMSO-de, 5) : 2,27 (3H, s), 5,20 (2H, s), 6,86-7,77 (9H, m), 7,93 (1H, dt, J=2, 8Hz), 8,55 (1H, dd, J=2, 5Hz), 8,75 (1H, d, J=2Hz)
(11) l-Hydroksy-4-metyl-2-(2-metyl-4-acetamidofenyl)-5-(3-pyridyl)imidazol
smeltepunkt : 200-204°C (dekomponering)
IR (Nujol) : 1670, 1610, 1590, 1530 cm"<1>
(12) 2-(3-Klor-4-acetamidofenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 157-159°C (dekomponering)
IR (Nujol) : 3250, 1700, 1625, 1565, 1505 cnr 1
NMR (DMSO-de, 5) : 2,17 (3H, s), 2,22 (3H, s), 7,47 (1H, dd, J=5, 8Hz), 7,73-8,17 (3H, m), 8,18 (1H, d, J=2Hz), 8,55 (1H, dd, J=2, 5Hz), 8,75 (1H, d, J=2Hz), 9,57 (1H, s) Massespektrum (m/e) : 342 (M<+>)
(13) l-Hydroksy-2-(2-metoksy-4-acetamido-5-nitrofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 182-183°C
IR (Nujol) : 3470, 3340, 1695, 1620, 1595, 1500 cm"<1>
NMR (D20 + DC1, 6) : 2,43 (3H, s), 2,63 (3H, s), 4,12 (3H, s), 8,17 (1H, s), 8,48 (1H, dd, J=5Hz, 8Hz), 8,83-9,27 (2H, m), 9,05 (1H, s), 9,32 (1H, d, J=2Hz)
(14) l-Hydroksy-2-(2-metoksy-4-klor-5-nitrofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 171-172°C (dekomponering)
IR (Nujol) : 1620, 1600, 1565, 1530, 1520 cm"<1>
NMR (D2O + DC1, 5) : 2,67 (3H, s), 4,20 (3H, s), 7,67 (1H, s), 8,45 (1H, dd, J=5Hz, 8Hz), 8,87 (1H, s), 8,90-9,23 (2H, m), 9,32 (1H, d, J=2Hz)
(15) 2-(2-Etoksyfenyl)-l-hydroksy-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 101-103°C
IR (Nujol) : 3350, 1620, 1585, 1250 cm"<1>
NMR (CDCI3+ CD3OD, 5) : 1,37 (3H, t, J=7Hz), 2,24 (3H, s) , 4,06 (2H, q, J=7Hz), 6,8-7,1 (2H, m) , 7,2-7,5 (2H, m), 8,01 (1H, dd, J=2Hz, 7Hz), 8,17 (1H, dd, J=2Hz, 7Hz), 8,48 (1H, dd, J=2Hz, 5Hz), 8,61 (1H, d, J=2Hz)
(16) l-Hydroksy-2-(2-isopropoksyfenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 158-160°C
IR (Nujol) : 3400, 1600, 1570 er1
NMR (CDCI3+ CD3OD, 5) : 1,41 (6H, d, J=6Hz), 4,72 (1H, septett, J=6Hz), 7,0-7,6 (4H, m), 8,1-8,3 (1H, m), 8,5-8,8
(3H, m)
(17) l-Hydroksy-4-metyl-2-[2-(2-propynyloksy)fenyl]-5-(3-pyridyl)imidazol
smeltepunkt: 148-150°C
IR (Nujol) : 1600, 1580 er1
NMR (CDCI3+ CDsOD, 5) : 2,25 (3H, s), 2,62 (1H, t, J=2Hz), 4,76 (2H, d, J=2Hz), 6,8-7,6 (4H, m), 7,8-8,8 (4H, m)
(18) 2-(2-Fluorfenyl)-l-hydroksy-4-metyl-5-(2-pyridyl)-imidazol
smeltepunkt : 244-249°C (dekomponering)
IR (Nujol) : 1590, 1580 cm"<1>
NMR (CDCls-CD3 OD, 5) : 2,55 (3H, s), 6,9-7,5 (4H, m) , 7,6-7,8 (2H, m), 7,8-8,2 (1H, m), 8,5-8,7 (1H, m)
(19) 2-(2-Fluorfenyl)-l-hydroksy-4-metyl-5-(4-pyridyl)-imidazol
smeltepunkt : 249-251°C
IR (Nujol) : 1600, 1210 er1
NMR (DMSO-de, 5) : 2,52 (3H, s), 7,2-7,7 (4H, m), 7,82 (2H, dd, J=2Hz, 5Hz), 8,52 (2H, dd, J=2Hz, 5Hz)
(20) 2-(2-Metoksy-4-klor-5-nitrofenyl)-4-metyl-5-(3-pyridyl) imidazol
smeltepunkt : 234-6°C (dekomponering)
IR (Nujol) : 1600, 1570, 1510 cm"<1>
(21) 2-[2-(4-Klorbenzyloksy)fenyl]-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 106-108°C
IR (Nujol) : 3410, 1600, 1585, 1550, 1530 cm"<1>
(22) 4-Metyl-2-(2-metyl-4-acetamidofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 285-287°C
IR (Nujol) : 3220, 1675, 1620, 1550, 1500 cnr 1
(23) 2-(2-Metoksy-4-acetamido-5-nitrofenyl)-4-metyl-5- (3-pyridyl)imidazol
smeltepunkt : 220-221°C
IR (Nujol) : 3360, 3330, 1695, 1620, 1590, 1535 er1
(24) 2-(2-Etoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 166-168°C
IR (Nujol) : 3230, 1590, 1555, 1520 cm"<1>
(25) 2-(2-Isopropoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 168-169°C
IR (Nujol) : 3420, 1590, 1560, 1235 er1
(26) 4-Metyl-2-[2-(2-propynyloksy)fenyl]-5-(3-pyridyl)imidazol smeltepunkt : 167-169°C
IR (Nujol) : 3320, 1590, 1560, 1510 er1
(27) 2-(2-Fluorfenyl)-4-metyl-5-(2-pyridyl)imidazol smeltepunkt : 128-130°C
IR (Nujol) : 1600, 1590, 1490 citi"1
(28) 2-(2-Fluorfenyl)-4-metyl-5-(4-pyridyl)imidazol smeltepunkt : 192-193°C
IR (Nujol) : 1595, 1570 cm"<1>
(29) 2-(2-Fluorfenyl)-4-(3-pyridyl)imidazol smeltepunkt : 144-145°C
IR (Nujol) : 1605, 1586, 1556, 1485 cm"<1>
(30) 2- {2-Hydroksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 265-266°C
IR (Nujol) : 1600, 1575, 1494 cm"<1>
(31) 2-(2-Mesylaminofenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 245-246°C
IR (Nujol) : 1600, 1577, 1497 er1
(32) 2-(4-Metoksykarbonylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 160-168°C
IR (Nujol) : 1733, 1616, 1600, 1569 er<1>
(33) 2-(4-Karboksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : >280°C
IR (Nujol) : 1675, 1611, 1568 cm"<1>
(34) 4-Metyl-2-(2-metyltiofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 200-201°C
IR (Nujol) : 1600, 1576, 1489 cr1
(35) 4-Metyl-5-(3-pyridyl)-2-(2-trifluormetylfenyl)imidazol smeltepunkt : 131-132°C
IR (Nujol) : 1609, 1575, 1500 cm-<1>
(36) 2-(4-Acetamido-3-klorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 262-264°C
IR (Nujol) : 3210, 1665, 1580, 1540 cm"<1>
(37) 2-(2-Metoksy-4-klor-5-aminofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 173-175°C
IR (Nujol) : 3300, 3200, 1630, 1580, 1565, 1520 er1
(38) 2-(2-Metoksy-4-klor-5-acetamidofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 274-276°C (dekomponering)
IR (Nujol) : 3250, 1660, 1600, 1590, 1570, 1535 cm"<1>
(39) l-Hydroksy-4-metyl-5-(3-pyridyl)-2-(2-tosylaminofenyl)-imidazol
smeltepunkt : 103-113°C
IR (Nujol) : 3520, 1658, 1590 cm-<1>
NMR (DMSO-de, 5) : 2,32 (6H, s), 7,10-7,78 (9H, m), 8,24 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,65 (1H, dd, J=5Hz, 2Hz), 8,95 (1H, d, J=2Hz)
(40) 4-Metyl-5-(3-pyridyl)-2-{2-tosylaminofenyl)imidazol smeltepunkt : 282-284°C
IR (Nujol) : 3530, 1665, 1599, 1570, 1495 cm"<1>
(41) 4-Metyl-2-[2-(3-nitrobenzoylamino)fenyl]-5-(3-pyridyl)imidazol
smeltepunkt: 257-259°C
IR (Nujol) : 1675, 1625, 1600, 1525, 1490 cm"<1>
(42) 4-Metyl-2-[2-(3-metyltioureido)fenyl]-5-(3-pyridyl)imidazol
smeltepunkt: 192-193°C
IR (Nujol) : 1570, 1520, 1490 er1
(43) 2-[2-(3-benzoyltioureido)fenyl]-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt: 159-161°C
IR (Nujol) : 3405, 3180, 2070, 1680, 1615, 1582, 1510 er1
(44) 2-(2-metoksykarbonylaminofenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt: 221-223°C
IR (Nujol) : 1732, 1599, 1570, 1538, 1490 er1
Eksempel 205
En blanding av l-hydroksy-2-(2-metoksy-4-klor-5-nitro-fenyl)-4-metyl-5-(3-pyridyl)imidazol (9,7 g) og trietylfosfitt (8,9 g) i N,N-dimetylformamid (100 ml) ble omrørt ved 80-90°C i 1 time. Reaksjonsblandingen ble hellet i vann, og den resul terende blanding ble omrørt ved omgivelsestemperatur i 1 time. Bunnfallet ble oppsamlet ved filtrering, vasket med vann og etylacetat og tørret, hvilket ga 2-(2-metoksy-4-klor-5-nitro-fenyl)-4-metyl-5-(3-pyridyl)imidazol (7,6 g).
smeltepunkt : 234-236°C (dekomponering)
IR (Nujol) : 1600, 1570, 1510 er1
NMR (D20 + DC1, 6) : 2,68 (3H, s), 4,22 (3H, s), 7,63 (1H, s), 8,38 (1H, dd, J=5Hz, 8Hz), 8,78 (1H, s), 8,92-9,17 (2H, m), 9,28 (1H, d, J=2Hz)
massespektrum (m/e) : 344 (M<+>)
Eksempel 206
Følgende forbindelser ble erholdt på lignende måte som den i eksempel 120, 121, 122, 123, 124 eller 205 beskrevne.
(1) 2-[2-(4-Klorbenzyloksy)fenyl]-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 106-108°C (omkrystallisert fra en blanding av
etylacetat og dietyleter)
IR (Nujol) : 3410, 1600, 1585, 1550, 1530 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 5,36 (2H, s), 6,85-7,63 (9H, m), 8,03 (1H, dd, J=2Hz, 8Hz), 8,40 (1H, dd, J=2Hz, 5Hz), 8,90 (1H, d, J=2Hz), 11,70 (1H, br s)
massespektrum (m/e) : 375 (M<*>)
(2) 4-Metyl-2-(2-metyl-4-acetamidofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 285-287°C (omkrystallisert fra en blanding av
metanol og etylacetat)
IR (Nujol) : 3220, 1675, 1620, 1550, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,06 (3H, s), 2,47 (3H, s), 2,60 (3H, s), 7,36 (1H, dd, J=5Hz, 8Hz), 7,43-7,60 (3H, m), 8,00
(1H, dt, J=2Hz, 8Hz), 8,37 (1H, dd, J=2Hz, 5Hz), 8,86 (1H, d, J=2Hz), 9,66 (1H, s), 12,10 (1H, br s)
massespektrum (m/e): 306 (M4 )
(3) 2-(2-Metoksy-4-acetamido-5-nitrofenyl)-4-metyl-5-(3-pyridyl)imidazol
smeltepunkt : 220-221°C
IR (Nujol) : 3360, 3330, 1695, 1620, 1590, 1535 cm"<1>
NMR (DMSO-de, 5) : 2,20 (3H, s), 2,53 (3H, s), 4,11 (3H, s), 7,47 (1H, dd, J=5Hz, 8Hz), 7,90 (1H, s), 8,12 (1H, dt, J=2Hz, 8Hz), 8,48 (1H, dd, J=2Hz, 5Hz), 8,77 (1H, s), 8,95 (1H, d, J=2Hz), 10,42 (1H, br s), 11,70 (1H, m)
(4) 2-(2-Etoksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 166-168°C
IR (Nujol) : 3230, 1590, 1555, 1520 cm"<1>
NMR (CDCI3+ CD3OD, 6) : 1,56 (3H, t, J=7Hz), 2,47 (3H, s), 4,24 (2H, q, J=7Hz), 6,9-7,6 (4H, m), 7,9-8,5 (3H, m), 8,85 (1H, d, J=2Hz)
Massespektrum (m/e) : 279 (M<+>)
(5) 2-(2-Isopropoksyfenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 168-169°C
IR (Nujol) : 3420, 1590, 1560, 1235 cm"<1>
NMR (CD3OD+CDCI3 , 5) : 1,35 (6H, d, J=6,5Hz), 2,53 (3H, s), 4,80 (1H, sep, J=6,5Hz), 6,9-7,6 (4H, m), 7,9-8,5 (3H, m) , 8,84 (1H, d, J=3Hz)
Massespektrum (m/e) : 293 (M<*>)
(6) 4-Metyl-2-[2-(2-propynyloksy)fenyl]-5-(3-pyridyl)imidazol smeltepunkt : 167-169°C
IR (Nujol) : 3320, 1590, 1560, 1510 cm"<1>
NMR (CDCI3+ CDsOD, 5) : 2,51 (3H, s), 2,77 (1H, t, J=2Hz), 4,86 (2H, d, J=2Hz), 6,9-7,5 (4H, m), 7,9-8,5 (3H, m) , 8,83 (1H, d, J=2Hz)
Massespektrum (m/e): 289 (M<+>)
(7) 2-(2-Fluorfenyl)-4-metyl-5-(2-pyridyl)imidazol smeltepunkt : 128-130°C
IR (Nujol) : 1600, 1590, 1490 cm"<1>
NMR (CDCI3+ CD3OD, 5) : 2,61 (3H, s), 5,40 (1H, br s), 6,9-7,4 (4H, m), 7,6-7,8 (2H, m) , 8,0-8,4 (1H, m), 8,4-8,6
(1H, m)
Massespektrum (m/e) : 253 (M<+>)
(8) 2-(2-Fluorfenyl)-4-metyl-5-(4-pyridyl)imidazol smeltepunkt : 192-193° C
IR (Nujol) : 1595, 1570 cm"<1>
NMR (CDCI3+ CD3OD, 6) : 2,52 (3H, s), 6,9-7,4 (3H, m), 7,65 (2H, dd, J=2Hz, 5Hz), 8,53 (2H, dd, J=2Hz, 5Hz), 8,0-8,4 (1H, m)
Massespektrum (m/e) : 253 (M<+>)
(9) 2-(2-Fluorfenyl)-4-(3-pyridyl)imidazol smeltepunkt : 144-145°C
IR (Nujol) : 1605, 1586, 1556, 1485 cm"<1>
NMR (DMSO-de, 6) : 7,25-7,68 (4H, m), 8,00-8,20 (2H, m), 8,28 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,48 (1H, dd, J=5Hz, 2Hz), 9,22 (1H, d, J=2Hz)
Massespektrum (M/Z) : 239 (M<+>)
(10) 2-(2-Hydroksyfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 265-266°C
IR (Nujol) : 1600, 1575, 1494 cm-<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 6,75-7,03 (2H, m), 7,20 (1H, dd, J=8Hz, 2Hz), 7,44 (1H, dd, J=8Hz, 5Hz), 7,70-8,11 (2H, m), 8,46 (1H, dd, J=5Hz, 2Hz), 8,85 (1H, d, J=2Hz) Massespektrum (M/Z) : 251 (MM
(11) 2-(2-Mesylaminofenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 245-246°C
IR (Nujol) : 1600, 1577, 1497 er1
NMR (DMSO-de, 5) : 2,54 (3H, s), 3,11 (3H, s), 7,08-7,68 (4H, m), 7,81-8,11 (2H, m), 8,47 (1H, dd, J=3Hz, 2Hz), 8,93 (1H, d, J=2Hz), 12,83 (1H, br s)
(12) 2-(4-Metoksykarbonylfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 160-168°C
IR (Nujol) : 1733, 1616, 1600, 1569 cm"<1>
NMR (DMSO-de, 6) : 2,56 (3H, s), 3,90 (3H, s), 7,42 (1H, dd, J=8Hz, 5Hz), 7,88-8,30 (5H, m) , 8,43 (1H, dd, J=5Hz, 2Hz), 8,92 (1H, d, J=2Hz)
Massespektrum (M/Z) : 293 (M<+>)
(13) 2-(4-Karboksyfenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : >280°C
IR (Nujol) : 1675, 1611, 1568 er1
NMR (DMSO-de, 5) : 2,69 (3H, s), 7,61 (1H, dd, J=8Hz, 5Hz), 8,05-8,40 (5H, m), 8,61 (1H, d, J=5Hz), 9,09 (1H, s) Massespektrum (M/Z) : 279 (M<+>)
(14) 4-Metyl-2-(2-metyltiofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 200-201° C
IR (Nujol) : 1600, 1576, 1489 cm"<1>
NMR (DMSO-de, 5) : 2,40 (3H, s), 2,50 (3H, s), 7,12-7,76 (5H, m), 8,09 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,42 (1H, dd, J=5Hz, 2Hz), 8,96 (1H, d, J=2Hz)
Massespektrum (M/Z) : 281 (M<+>)
(15) 4-Metyl-5-(3-pyridyl)-2-(2-trifluormetylfenyl)imidazol smeltepunkt : 131-132°C
IR (Nujol) : 1609, 1575, 1500 cm"<1>
NMR (DMSO-de, 5) : 2,52 (3H, s), 7,45 (1H, dd, J=8Hz, 5Hz), 7,60-8,00 (4H, m), 8,10 (1H, ddd, J=8Hz, 2Hz, 2Hz), 8,45 (1H, dd, J=5Hz, 2Hz), 8,95 (1H, d, J=2Hz) Massespektrum (M/Z) : 303 (M<+>)
(16) 2-(4-Acetamido-3-klorfenyl)-4-mety1-5-(3-pyridyl)imidazol smeltepunkt : 262-264°C
IR (Nujol) : 3210, 1665, 1580, 1540 cm"<1>
NMR (DMSO-de, 5) : 2,16 (3H, s), 2,52 (3H, s), 7,40 (1H, dd, J=5, 8Hz), 7,87 (2H, s), 8,84 (2H, br s), 8,43 (1H, d, J=5Hz), 8,91 (1H, br s), 9,50 (1H, s), 12,53 (1H, br s)
(17) 4-Metyl-5-(3-pyridyl)-2-(2-tosylaminofenyl)imidazol smeltepunkt : 282-284°C
IR (Nujol) : 3530, 1665, 1599, 1570, 1495 cm"<1>
NMR (DMSO-de, 6) : 2,24 (3H, s), 2,50 (3H, s) , 6,9.5-7,91 (9H, m), 8,04 (1H, d, J=8Hz), 8,48 (1H, d, J=5Hz), 8,95
(1H, s), 13,00 (1H, br s)
(18) 2-(2-Metoksy-4-klor-5-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt : 173-175° C
IR (Nujol) : 3300, 3200, 1630, 1580, 1565, 1520 cr1
(19) 2-(2-Metoksy-4-klor-5-acetamidofenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt: 274-276°C (dekomponering)
IR (Nujol) : 3250, 1660, 1600, 1590, 1570, 1535 cm"<1>
(20) 4-Metyl-2-[2-(3-nitrobenzoylamino)fenyl]-5-(3-pyridyl)-imidazol
smeltepunkt: 257-259°C
IR (Nujol) : 1675, 1625, 1600, 1525, 1490 cm"<1>
(21) 4-Metyl-2-[2-(3-metyltioureido)fenyl]-5-(3-pyridyl)imidazol smeltepunkt: 192-193°C
IR (Nujol) : 1570, 1520, 1490 cnr<1>
(22) 2-[2-(3-benzoyltioureido)fenyl]-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt: 159-161°C
IR (Nujol) : 3405, 3180, 2070, 1680, 1615, 1582, 1510 er1
(23) 2-(2-metoksykarbonylaminofenyl)-4-metyl-5-(3-pyridyl)-imidazol
smeltepunkt: 221-223°C
IR (Nujol) : 1732, 1599, 1570, 1538, 1490 cm-1
Eksempel 207
En blanding av 2-(2-metoksy-4-klor-5-nitrofenyl)-4-metyl-5-(3-pyridyl)imidazol (6,4 g), IN saltsyre (37 ml) og 10% palladium på kull (3 g) i metanol (100 ml) ble underkastet katalytisk reduksjon ved omgivelsestemperatur under atmosfærisk hydrogengasstrykk i 3 timer. Reaksjonsblandingen ble filtrert, og filtratet ble inndampet i vakuum. Residuet ble oppløst i vann, og oppløsningen ble innstilt på en pH-verdi på 8,0 med 20% vandig kaliumkarbonat. Den resulterende blanding ble ekstrahert med etylacetat, og ekstrakten ble tørret over magnesiumsulfat. Oppløsningsmidlet ble avdampet i vakuum, og residuet ble underkastet kolonnekromatografi på silikagel under eluering med en blanding av kloroform og metanol (96:4 volum/volum). Fraksjonene inneholdende denønskede forbindelse ble inndampet i vakuum, og residuet ble omkrystallisert fra en blanding av etylacetat og diisopropyleter, hvilket ga 2-(2-metoksy-4-klor-5-aminofenyl)-4-metyl-5-(3-pyridyl)imidazol (2,1 g).
smeltepunkt : 173-175°C
IR (Nujol) : 3300, 3200, 1630, 1580, 1565, 1520 cm"<1>
NMR (DMSO-de, 5) : 2,55 (3H, s), 3,90 (3H, s), 5,03 (2H, s), 7,09 (1H, s), 7,45 (1H, dd, J=5Hz, 8Hz), 7,70 (1H, s), 8,08 (1H, dt, J=2Hz, 8Hz), 8,45 (1H, dd, J=2Hz, 5Hz), 8,97 (1H, d, J=2Hz), 11,50 (1H, br s)
massespektrum (m/e) : 314 (M<*>)
Eksempel 208
En oppløsning av 2-(2-metoksy-4-klor-5-aminofenyl)-4-metyl-5-(3-pyridyl)imidazol (1,0 g) og eddiksyreanhydrid (2 ml) i en blanding av etylacetat (20 ml) og tetrahydrofuran (10 ml) ble opvarmet under tilbakeløpskjøling i 2 timer. Reaksjonsblandingen ble avkjølt med isvann, og det krystallinske residuum ble oppsamlet ved filtrering, hvilket ga 2-(2-metoksy-4-klor-5-acetamidofenyl)-4-metyl-5-(3-pyridyl)imidazol (0,7 g).
smeltepunkt : 274-276°C (dekomponering)
IR (Nujol) : 3250, 1660, 1600, 1590, 1570, 1535 er1
NMR (D20 + DC1, 5) : 2,30 (3H, s), 2,65 (3H, s), 4,06 (3H, s), 7,45 (1H, s), 8,06 (1H, s), 5,70 (1H, dd, J=5Hz, 7Hz), 8,83-9,06 (2H, m) , 9,21 (1H, d, J=2Hz)
massespektrum (m/e) : 356 (M<+>)
Eksempel 209
Følgende forbindelser ble erholdt på lignende måte som den
i eksempel 195 eller 208 beskrevne.
(1) 2-(4-Acetamido-5-klor-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol
smeltepunkt : 239-240°C
IR (Nujol) : 3400, 1680, 1590, 1520, 1490 er1
(2) 2-(4-Acetamido-2-metoksyfenyl)-5-metyl-4-(3-pyridyl)imidazol smeltepunkt : 215-218°C
IR (Nujol) : 1675, 1600 cm"<1>
(3) 4-Metyl-2-(2-metyl-4-acetamidofenyl)-5-(3-pyridyl)imidazol smeltepunkt : 285-287°C
IR (Nujol) : 3220, 1675, 1620, 1550, 1500 cm"<1>
(4) 2-(2-Metoksy-4-acetamido-5-nitrofenyl)-4-metyl-5-(3- * pyridyl)imidazol
smeltepunkt : 220-221°C
IR (Nujol) : 3360, 3330, 1695, 1620, 1590, 1535 cm"<1>
(5) 2-(4-Acetamido-3-klorfenyl)-4-metyl-5-(3-pyridyl)imidazol smeltepunkt : 262-264°C
IR (Nujol) : 3210, 1665, 1580, 1540 cm"<1>
Eksempel 210
2-(2-Metoksyfenyl)-4-metyl-5-(3-pyridyl)imidazoldihydro-klorid ble erholdt på lignende måte som den i eksempel 199 beskrevne.
smeltepunkt : 228-230°C
IR (Nujol) : 1630, 1580 cm"<1>
NMR (DMSO-de, 5) : 2,60 (3H, s), 4,01 (3H, s), 8,4-7,0
(5H, m), 9,0-8,6 (2H, m), 9,24 (1H, d, J=2Hz)
Eksempel 211
Til en oppløsning av 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,8 g) og trietylamin (0,49 ml) i metylenklorid (10 ml) ble satt en oppløsning av 3-nitrobenzoylklorid (0,65 g) i metylenklorid (5 ml) under isavkjøling. Reaksjonsoppløsningen ble omrørt i 1 time. Reaksjonsblandingen ble hellet i vann (50 ml), ekstrahert med en blanding av kloroform og metanol og tørret over magnesiumsulfat. Oppløsningsmidlet ble destillert fra, og residuet ble utgnidd med etylacetat, bvilket ga 4-mety1-2-[2-(3-nitrobenzoylamino)fenyl]-5-(3-pyridyl)imidazol (0,95 g).
smeltepunkt : 257-259°C
IR (Nujol) : 1675, 1625, 1600, 1525, 1490 cm"<1>
NMR (DMSO-de, 5) : 2,51 (3H, s), 7,10-8,20 (6H, m), 8,31-8,95 (6H, m)
Eksempel 212
Til en oppløsning av 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,8 g) i tetrahydrofuran (10 ml) ble satt metylisotio-cyanat (0,33 ml) ved omgivelsestemperatur. Reaksjonsblandingen ble omrørt ved omgivelsestemperatur i 1 time og oppvarmet under tilbakeløpskjøling i 20 timer. Det resulterende bunnfall ble oppsamlet ved filtrering og vasket med tetrahydrofuran og dietyleter, hvilket ga 4-metyl-2-[2-(3-metyltioureido)fenyl]-5-(3-pyridyl)imidazol (0,71 g).
smeltepunkt : 192-193°C
IR (Nujol) : 1570, 1520, 1490 er1
NMR (DMSO-de, 5) : 2,50 (3H, s), 2,95 (3H, d, J=5Hz), 6,98-7,52 (3H, m), 7,68-8,60 (5H, m), 8,99 (1H, s), 14,30 (1H, s), 15,07 (1H, s)
Eksempel 213
Til en oppløsning av 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl ) imidazol (1,60 g) i metylenklorid (20 ml) ble satt en oppløsning av benzoylisotiocyanat (1,04 g) i metylenklorid (5 ml) ved omgivelsestemperatur. Reaksjonsblandingen ble omrørt ved omgivelsestemperatur i 1 time. Det resulterende bunnfall ble oppsamlet ved filtrering. Bunnfallet ble vasket med metylenklorid, etanol og dietyleter, hvilket ga 2-[2-(3-benzoyltioureido)fenyl]-4-metyl-5-(3-pyridyl)imidazol (1,95 g).
smeltepunkt : 159-161°C
IR (Nujol) : 3405, 3180, 2070, 1680, 1615, 1582, 1510 cm"<1>NMR (DMSO-de, 6) : 2,50 (3H, s), 7,00-8,49 (12H, m), 8,97 (1H, s), 11,38 (1H, s)
Eksempel 214
Til en suspensjon av 2-(2-aminofenyl)-4-metyl-5-(3-pyridyl)-imidazol (0,80 g) og trietylamin (0,49 ml) i metylenklorid (10 ml) ble satt metylklorformiat (0,27 ml) under isavkjøling. Reaksjonsblandingen ble omrørt ved omgivelsestemperatur i 1 time, og det resulterende bunnfall ble oppsamlet ved filtrering og utgnidd ved hjelp av vann og etylacetat. Residuet ble omkrystallisert fra etanol, hvilket ga 2-(2-metoksykarbonyl-aminofenyl)-4-metyl-5-(3-pyridyl)imidazol (0,50 g).
smeltepunkt : 221-223°C
IR (Nujol) : 1732, 1599, 1570, 1538, 1490 cm"<1>
NMR (DMSO-de, 5) : 2,50 (3H, s), 3,73 (3H, s), 7,00-7,55 (3H, m), 7,80-8,11 (2H, m), 8,20-8,54 (2H, m), 8,94 (1H,
s)
Claims (9)
1. Fremgangsmåte for fremstilling av en forbindelse med formel I
hvor
R 1 er pyridyl,
R <2> er hydrogen, lavere alkyl eller hydroksy(lavere)alkyl,
R <3> er hydrogen, hydroksy eller lavere alkyl, og R <4> er aryl, som eventuelt er substituert med én eller flere
substituenter valgt fra gruppen bestående av lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, nitro, amino, substituert amino, hydroksy, lavere alkoksy, lavere alkynyloksy, substituert eller usubstituert ar(lavere)alkoksy, halogen, halogen(lavere)alkyl, karboksy og forestret karboksy
eller et salt derav,
karakterisert ved at den omfatter følgende trinn:a) en forbindelse med formel II
hvor en av X <1> og X <2> er 0 og den annen er en gruppe med formelen:=N-R3 , hvor R <3> har den ovenfor angitte betydning, og R <1> og R <2> hver har den ovenfor angitte betydning, eller et salt derav, omsettes med en forbindelse med formel II
hvor R <4> har den ovenfor angitte betydning, eller et salt derav,
i nærvær av ammoniakk eller et middel som frigjø r ammoniakk,
for å danne en forbindelse med formel I
hvorR 1, R <2> , R <3> og R <4> hver har den ovenfor angitte betydning,
eller et salt derav, ellerb) en forbindelse med formel Ia
hvor R1 , R <2> og R <4> hver har den ovenfor angitte betydning, eller et salt derav, reduseres for å danne en forbindelse med formel
Ib
hvor R <1> , R <2> og R <4> hver har den ovenfor angitte betydning, eller et salt derav, ellerc) en forbindelse med formel Ib
hvor R <1> , R <2> og R <4> hver har den ovenfor angitte betydning, eller et salt derav, underkastes en lavere alkyleringsreaksjon for å
danne en forbindelse med formel Ic
hvor R <3>a er lavere alkyl, og R <1> , R <2> og R <4> hver har den ovenfor angitte betydning, eller et salt derav, ellerd) en forbindelse med formel Id
hvor R <4>a er aryl substituert med acylamino og lavere alkoksy,
med acylamino, lavere alkoksy og halogen, eller med N-acyl-N-lavere alkylamino, lavere alkoksy og halogen, og R1 , R <2> ogR<3> hver har den ovenfor angitte betydning, eller et salt derav,
underkastes en reaksjon for eliminering av acylgruppen for å
danne en forbindelse med formel le
hvor R <4>b er aryl substituert med amino og lavere alkoksy, med amino, lavere alkoksy og halogen, eller med lavere alkylamino,
lavere alkoksy og halogen, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt derav, ellere) en forbindelse med formel If
hvor R <4>c er aryl substituert med amino, med amino og lavere alkyl, med amino og lavere alkoksy, med amino og halogen, med amino, lavere alkoksy og nitro, eller med amino, lavere alkoksy og halogen, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt derav, omsettes med et acyleringsmiddel
for å danne en forbindelse med formel lg
hvor R <4>a er aryl substituert med acylamino, med acylamino og lavere alkyl, med acylamino og lavere alkoksy, med acylamino og halogen, med acylamino, lavere alkoksy og nitro, eller med acylamino, lavere alkoksy og halogen, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt derav, ellerf) en forbindelse med formel Ih
hvor R <4>e er aryl substituert med lavere alkyltio og lavere alkoksy, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning,
eller et salt derav, oksyderes for å danne en forbindelse med formel li
hvor R <4>f er aryl substituert med lavere alkylsulfinyl og lavere alkoksy, eller med lavere alkylsulfonyl og lavere alkoksy, og R1 , R <2> og R <3> hver har den ovenfor angitte betydning, eller et
salt derav, ellerg) en forbindelse med formel Ij
hvor R <4> g er aryl substituert med nitro, med nitro og lavere alkoksy, eller med nitro, lavere alkoksy og halogen, og R1 , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt
derav, reduseres for å danne en forbindelse med formel Ik
hvor R <4>h er aryl substituert med amino, med amino og lavere alkoksy, eller med amino, lavere alkoksy og halogen, og R1 , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt derav, ellerh) en forbindelse med formel II
hvor R <3> er halogen, R <6> og R <7> er hver lavere alkoksy eller substituert amino, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt derav, reduseres for å danne en
forbindelse med formel Im
hvor R <1> , R <2> , R <3> , R <6> og R <7> hver har den ovenfor angitte betydning,
eller et salt derav, elleri) en forbindelse med formel In
hvor R <8> og R <9> hver er lavere alkoksy, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning, eller et salt derav, halogeneres
for å danne en forbindelse med formel Io
hvor R1 , R2 , R3 , R3 , R <8> og R <9> hver har den ovenfor angitte betydning, eller et salt derav, ellerj) en forbindelse med formel lp
hvor R4 i er aryl substituert med ar(lavere)alkoksy og lavere alkoksy, og R <1> , R <2> og R <3> hver har den ovenfor angitte betydning,
eller et salt derav, reduseres for å danne en forbindelse med
formel Iq
hvor R <4>j er aryl substituert med hydroksy og lavere alkoksy, og R1 , R <2> og R <3> hver har den ovenfor angitte betydning, eller et
salt derav.
2. Fremgangsmåte ifølge krav 1, karakterisert ved at det fremstilles forbindelser, i hvilke R <4> er fenyl, som kan være substituert med én eller flere substituenter valgt fra gruppen bestående av lavere alkyl, lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, nitro, amino, mono- eller di(lavere)alkylamino, lavere alkanoylamino, nitro-substituert eller usubstituert benzoylamino, lavere alkoksykarbonylamino, fenyl(lavere)alkoksykarbonylamino, lavere alkansulfonylamino, lavere alkyl-substituert benzensulfonylamino, ureido, tioureido, lavere alkylureido, lavere alkyltioureido, N-lavere alkanoyl-N-lavere alkylamino, hydroksy, benzoyltioureido, lavere alkoksy, lavere alkynyloksy, halogen-substituert eller usubstituert fenyl(lavere)alkoksy, halogen, halogen(lavere)alkyl, karboksy og lavere alkoksykarbonyl.
3. Fremgangsmåte ifølge krav 2, karakterisert ved at det fremstilles forbindelser, i hvilke R <2> er lavere alkyl, R <3> er hydrogen, og R <4> er fenyl substituert med én eller flere substituenter valgt fra gruppen bestående av lavere alkyltio, lavere alkanoylamino, lavere alkoksy og halogen.
4. Fremgangsmåte ifølge krav 3, karakterisert ved at det fremstilles forbindelser hvor R <4> er fenyl substituert med lavere alkoksy.
5. Fremgangsmåte ifølge krav 4, karakterisert ved at det fremstilles en forbindelse hvor R <1> er 3-pyridyl, R <2> er metyl og R <4> er 2-metoksyfenyl.
6. Fremgangsmåte ifølge krav 3, karakterisert ved at det fremstilles forbindelser hvor R <4> er fenyl substituert med lavere alkanoylamino.
7. Fremgangsmåte ifølge krav 6, karakterisert ved at det fremstilles en forbindelse hvor R <1> er 3-pyridiyl, R <2> er metyl og R <4> er 2-acetamidofenyl.
8. Fremgangsmåte ifølge krav 3, karakterisert ved at det fremstilles forbindelser hvor R <4> er fenyl substituert med lavere alkanoylamino, lavere alkoksy og halogen.
9. Fremgangsmåte ifølge krav 8, karakterisert ved at det fremstilles en forbindelse hvor R <1> er 3-pyridyl, R <2> er metyl og R <4> er 4-acetamido-5-klor-2-metoksyfenyl.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB868619971A GB8619971D0 (en) | 1986-08-15 | 1986-08-15 | Imidazole compounds |
GB878715932A GB8715932D0 (en) | 1987-07-07 | 1987-07-07 | Imidazole compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
NO873432D0 NO873432D0 (no) | 1987-08-14 |
NO873432L true NO873432L (no) | 1988-02-16 |
Family
ID=26291182
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO873432A NO873432L (no) | 1986-08-15 | 1987-08-14 | Fremgangsmaate for fremstilling av imidazolforbindelser. |
Country Status (12)
Country | Link |
---|---|
US (1) | US4822805A (no) |
EP (1) | EP0257897A1 (no) |
KR (1) | KR880002840A (no) |
CN (1) | CN87105680A (no) |
AU (1) | AU7682587A (no) |
DK (1) | DK425887A (no) |
FI (1) | FI873509A (no) |
HU (1) | HUT44779A (no) |
IL (1) | IL83467A0 (no) |
NO (1) | NO873432L (no) |
OA (1) | OA08647A (no) |
PT (1) | PT85531B (no) |
Families Citing this family (61)
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US5616601A (en) * | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
JP2636819B2 (ja) | 1994-12-20 | 1997-07-30 | 日本たばこ産業株式会社 | オキサゾール系複素環式芳香族化合物 |
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AP9700912A0 (en) | 1996-01-11 | 1997-01-31 | Smithkline Beecham Corp | Novel cycloalkyl substituted imidazoles |
KR19990077164A (ko) * | 1996-01-11 | 1999-10-25 | 스티븐 베네티아너 | 신규 치환된 이미다졸 화합물 |
JP2000507558A (ja) * | 1996-03-25 | 2000-06-20 | スミスクライン・ビーチャム・コーポレイション | Cns損傷についての新規な治療 |
US6677364B2 (en) | 1998-04-20 | 2004-01-13 | G.D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
WO1998007425A1 (en) | 1996-08-21 | 1998-02-26 | Smithkline Beecham Corporation | Imidazole compounds, compositions and use |
US5929076A (en) * | 1997-01-10 | 1999-07-27 | Smithkline Beecham Corporation | Cycloalkyl substituted imidazoles |
WO1998056377A1 (en) | 1997-06-13 | 1998-12-17 | Smithkline Beecham Corporation | Novel pyrazole and pyrazoline substituted compounds |
US6610695B1 (en) | 1997-06-19 | 2003-08-26 | Smithkline Beecham Corporation | Aryloxy substituted pyrimidine imidazole compounds |
TW517055B (en) | 1997-07-02 | 2003-01-11 | Smithkline Beecham Corp | Novel substituted imidazole compounds |
US6489325B1 (en) | 1998-07-01 | 2002-12-03 | Smithkline Beecham Corporation | Substituted imidazole compounds |
US7301021B2 (en) * | 1997-07-02 | 2007-11-27 | Smithkline Beecham Corporation | Substituted imidazole compounds |
AR016294A1 (es) * | 1997-07-02 | 2001-07-04 | Smithkline Beecham Corp | Compuesto de imidazol sustituido, composicion farmaceutica que la contiene, su uso en la fabricacion de un medicamento y procedimiento para supreparacion |
US6562832B1 (en) | 1997-07-02 | 2003-05-13 | Smithkline Beecham Corporation | Substituted imidazole compounds |
WO1999001452A1 (en) | 1997-07-02 | 1999-01-14 | Smithkline Beecham Corporation | Novel cycloalkyl substituted imidazoles |
CA2294898A1 (en) * | 1997-07-03 | 1999-01-14 | Neurogen Corporation | Certain diarylimidazole derivatives; a new class of npy specific ligands |
JP2001518507A (ja) | 1997-10-08 | 2001-10-16 | スミスクライン・ビーチャム・コーポレイション | 新規シクロアルケニル置換化合物 |
AU1924699A (en) | 1997-12-19 | 1999-07-12 | Smithkline Beecham Corporation | Compounds of heteroaryl substituted imidazole, their pharmaceutical compositionsand uses |
CN1548436A (zh) | 1998-05-22 | 2004-11-24 | ʷ��˿�������ȳ�ķ����˾ | 新的2-烷基取代咪唑化合物 |
US6858617B2 (en) | 1998-05-26 | 2005-02-22 | Smithkline Beecham Corporation | Substituted imidazole compounds |
CA2341370A1 (en) * | 1998-08-20 | 2000-03-02 | Smithkline Beecham Corporation | Novel substituted triazole compounds |
US6548503B1 (en) | 1998-11-04 | 2003-04-15 | Smithkline Beecham Corporation | Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines |
US6239279B1 (en) | 1998-12-16 | 2001-05-29 | Smithkline Beecham Corporation | Synthesis for 4-aryl-5-pyrimidine imidazole substituted derivatives |
US7053098B1 (en) | 1999-11-23 | 2006-05-30 | Smithkline Beecham Corporation | 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors |
ES2249309T3 (es) | 1999-11-23 | 2006-04-01 | Smithkline Beecham Corp | Compuestos de 3,4-dihidro-(1h)quinazolin-2-ona como inhibidores de csbp/p39 kinasa. |
EP1235814B1 (en) | 1999-11-23 | 2004-11-03 | Smithkline Beecham Corporation | 3,4-DIHYDRO-(1H)QUINAZOLIN-2-ONE COMPOUNDS AS CSBP/p38 KINASE INHIBITORS |
US6759410B1 (en) | 1999-11-23 | 2004-07-06 | Smithline Beecham Corporation | 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors |
EP1237875B1 (en) | 1999-12-16 | 2005-08-31 | Schering Corporation | Substituted imidazole neuropeptide y y5 receptor antagonists |
US7235551B2 (en) * | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
EP2404603A1 (en) * | 2000-10-23 | 2012-01-11 | Glaxosmithkline LLC | Novel trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds for the treatment of CSBP/p38 kinase mediated diseases |
US20030105144A1 (en) | 2001-04-17 | 2003-06-05 | Ping Gao | Stabilized oral pharmaceutical composition |
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US7329401B2 (en) * | 2002-04-15 | 2008-02-12 | The Regents Of The University Of California | Cyclooxygenase-2 selective agents useful as imaging probes and related methods |
WO2004005264A2 (en) * | 2002-07-05 | 2004-01-15 | Axxima Pharmaceuticals Ag | Imidazole compounds for the treatment of hepatitis c virus infections |
AU2003263404A1 (en) | 2002-09-18 | 2004-04-08 | Pfizer Products Inc. | Novel imidazole compounds as transforming growth factor (tgf) inhibitors |
PA8595001A1 (es) | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
KR20060007008A (ko) * | 2003-05-08 | 2006-01-23 | 아스텔라스세이야쿠 가부시키가이샤 | Cox 저해제 |
MX2007012951A (es) * | 2005-03-25 | 2008-01-11 | Glaxo Group Ltd | Procedimiento para preparar derivados de pirido[2,3-d] pirimidin-7-ona y 3,4-dihidropirimidino[4,5-d]pirimidin-2(1h)-ona. |
MY145281A (en) | 2005-03-25 | 2012-01-13 | Glaxo Group Ltd | Novel compounds |
US7728027B2 (en) * | 2007-08-08 | 2010-06-01 | Bristol-Myers Squibb Company | Process for synthesizing compounds useful for treating hepatitis C |
MX2011003011A (es) | 2008-09-22 | 2011-09-01 | Cayman Chem Co | Compuestos de multiheteroarilo como inhibidores de prostaglandina d sintasa hematopoyetica y su uso para tratar enfermedades mediadas por prostaglandina d2. |
BR112016022043B1 (pt) * | 2014-03-28 | 2020-12-29 | Syngenta Participations Ag | compostos, composição pesticida, método para controle de pragas e método para a proteção de material de propagação de plantas do ataque por pragas |
MA52033A (fr) * | 2014-08-13 | 2021-01-20 | Nippon Soda Co | Composé de diarylimidazole et agent de lutte antiparasitaire |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3707475A (en) * | 1970-11-16 | 1972-12-26 | Pfizer | Antiinflammatory imidazoles |
US3929807A (en) * | 1971-05-10 | 1975-12-30 | Ciba Geigy Corp | 2-Substituted-4(5)-(aryl)-5(4)-(2,3 or -4-pyridyl)-imidazoles |
CH561717A5 (no) * | 1971-05-10 | 1975-05-15 | Ciba Geigy Ag | |
US4440774A (en) * | 1975-03-03 | 1984-04-03 | Merck & Co., Inc. | 3-Amino-2-hydroxypropoxyaryl imidazole derivatives |
SE7601713L (sv) * | 1975-03-03 | 1976-09-06 | Merck & Co Inc | Nya, substituerad imidazoler |
-
1987
- 1987-08-06 IL IL83467A patent/IL83467A0/xx unknown
- 1987-08-07 EP EP87307051A patent/EP0257897A1/en not_active Withdrawn
- 1987-08-12 AU AU76825/87A patent/AU7682587A/en not_active Abandoned
- 1987-08-13 PT PT85531A patent/PT85531B/pt unknown
- 1987-08-13 FI FI873509A patent/FI873509A/fi not_active Application Discontinuation
- 1987-08-13 US US07/084,862 patent/US4822805A/en not_active Expired - Fee Related
- 1987-08-14 DK DK425887A patent/DK425887A/da not_active Application Discontinuation
- 1987-08-14 NO NO873432A patent/NO873432L/no unknown
- 1987-08-14 CN CN198787105680A patent/CN87105680A/zh active Pending
- 1987-08-14 OA OA59177A patent/OA08647A/xx unknown
- 1987-08-14 KR KR1019870008953A patent/KR880002840A/ko not_active Application Discontinuation
- 1987-08-14 HU HU873676A patent/HUT44779A/hu unknown
Also Published As
Publication number | Publication date |
---|---|
IL83467A0 (en) | 1988-01-31 |
NO873432D0 (no) | 1987-08-14 |
PT85531A (en) | 1987-09-01 |
EP0257897A1 (en) | 1988-03-02 |
AU7682587A (en) | 1988-02-18 |
FI873509A0 (fi) | 1987-08-13 |
OA08647A (fr) | 1988-11-30 |
CN87105680A (zh) | 1988-04-27 |
US4822805A (en) | 1989-04-18 |
DK425887A (da) | 1988-02-16 |
FI873509A (fi) | 1988-02-16 |
PT85531B (en) | 1989-12-15 |
DK425887D0 (da) | 1987-08-14 |
KR880002840A (ko) | 1988-05-11 |
HUT44779A (en) | 1988-04-28 |
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