NO180795B - Analogifremgangsmåte for fremstilling av terapeutisk aktive benzimidazolderivater - Google Patents
Analogifremgangsmåte for fremstilling av terapeutisk aktive benzimidazolderivaterInfo
- Publication number
- NO180795B NO180795B NO913728A NO913728A NO180795B NO 180795 B NO180795 B NO 180795B NO 913728 A NO913728 A NO 913728A NO 913728 A NO913728 A NO 913728A NO 180795 B NO180795 B NO 180795B
- Authority
- NO
- Norway
- Prior art keywords
- chloro
- hydrogen
- hydroxyphenyl
- dihydro
- trifluoromethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 7
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title description 2
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 229910004013 NO 2 Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910005965 SO 2 Inorganic materials 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract description 6
- 102000004257 Potassium Channel Human genes 0.000 abstract description 6
- 108020001213 potassium channel Proteins 0.000 abstract description 6
- 241000124008 Mammalia Species 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 2
- 229910052760 oxygen Inorganic materials 0.000 abstract 2
- 229910052717 sulfur Inorganic materials 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 108091006146 Channels Proteins 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000007868 Raney catalyst Substances 0.000 description 14
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 14
- 229910000564 Raney nickel Inorganic materials 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 11
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- TZGFQIXRVUHDLE-UHFFFAOYSA-N 1-chloro-2-nitro-4-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1Cl TZGFQIXRVUHDLE-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- WYLYBVMNGZOYOH-UHFFFAOYSA-N 3-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound OC1=CC=C(Cl)C=C1N1C(=O)NC2=CC(C(F)(F)F)=CC=C21 WYLYBVMNGZOYOH-UHFFFAOYSA-N 0.000 description 5
- TZFWDZFKRBELIQ-UHFFFAOYSA-N chlorzoxazone Chemical compound ClC1=CC=C2OC(O)=NC2=C1 TZFWDZFKRBELIQ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 4
- WBSMIPLNPSCJFS-UHFFFAOYSA-N 5-chloro-2-methoxyaniline Chemical compound COC1=CC=C(Cl)C=C1N WBSMIPLNPSCJFS-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- XRXKXMZZICZXGN-UHFFFAOYSA-N 2-(2-nitroanilino)phenol Chemical compound OC1=CC=CC=C1NC1=CC=CC=C1[N+]([O-])=O XRXKXMZZICZXGN-UHFFFAOYSA-N 0.000 description 3
- HLEFTZPTWXTBQZ-UHFFFAOYSA-N 3-(2-nitrophenyl)-1,3-benzoxazol-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1N1C(=O)OC2=CC=CC=C21 HLEFTZPTWXTBQZ-UHFFFAOYSA-N 0.000 description 3
- TVZCRIROJQEVOT-CABCVRRESA-N Cromakalim Chemical compound N1([C@@H]2C3=CC(=CC=C3OC([C@H]2O)(C)C)C#N)CCCC1=O TVZCRIROJQEVOT-CABCVRRESA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002102 hyperpolarization Effects 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ZYJBTGNUWOMRBG-UHFFFAOYSA-N 1,2,5-trichloro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(Cl)=C1Cl ZYJBTGNUWOMRBG-UHFFFAOYSA-N 0.000 description 2
- FXOCDIKCKFOUDE-UHFFFAOYSA-N 1,2-dichloro-4-fluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=C(Cl)C=C1F FXOCDIKCKFOUDE-UHFFFAOYSA-N 0.000 description 2
- VLVNHMVSVDVAOA-UHFFFAOYSA-N 1,5-dichloro-2-nitro-4-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=C(Cl)C=C1Cl VLVNHMVSVDVAOA-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- DTYBRSLINXBXMP-UHFFFAOYSA-N 2-methoxy-5-phenylaniline Chemical compound C1=C(N)C(OC)=CC=C1C1=CC=CC=C1 DTYBRSLINXBXMP-UHFFFAOYSA-N 0.000 description 2
- BUNCHTGWWPOJFZ-UHFFFAOYSA-N 2-n-(3,5-dichloro-2-methoxyphenyl)benzene-1,2-diamine Chemical compound COC1=C(Cl)C=C(Cl)C=C1NC1=CC=CC=C1N BUNCHTGWWPOJFZ-UHFFFAOYSA-N 0.000 description 2
- CHOYJIAPCQNFES-UHFFFAOYSA-N 2-n-(5-chloro-2-methoxyphenyl)benzene-1,2-diamine Chemical compound COC1=CC=C(Cl)C=C1NC1=CC=CC=C1N CHOYJIAPCQNFES-UHFFFAOYSA-N 0.000 description 2
- IELHLIPYPPRJID-UHFFFAOYSA-N 3-(2-hydroxy-5-phenylphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound C1=C(N2C(NC3=CC(=CC=C32)C(F)(F)F)=O)C(O)=CC=C1C1=CC=CC=C1 IELHLIPYPPRJID-UHFFFAOYSA-N 0.000 description 2
- PIBZOHJUHDVUDG-UHFFFAOYSA-N 3-(2-hydroxyphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound OC1=CC=CC=C1N1C(=O)NC2=CC(C(F)(F)F)=CC=C21 PIBZOHJUHDVUDG-UHFFFAOYSA-N 0.000 description 2
- PPPCMNINJQSLEG-UHFFFAOYSA-N 3-(3-hydroxynaphthalen-2-yl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound C12=CC=C(C(F)(F)F)C=C2NC(=O)N1C1=CC2=CC=CC=C2C=C1O PPPCMNINJQSLEG-UHFFFAOYSA-N 0.000 description 2
- FGCZWOOANMJFIH-UHFFFAOYSA-N 3-(4-benzoyl-2-nitrophenyl)-5-chloro-1,3-benzoxazol-2-one Chemical compound C=1C=C(N2C(OC3=CC=C(Cl)C=C32)=O)C([N+](=O)[O-])=CC=1C(=O)C1=CC=CC=C1 FGCZWOOANMJFIH-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- NMDMHKVCPISZTF-UHFFFAOYSA-N 4-chloro-2-(2,4-dinitroanilino)phenol Chemical compound OC1=CC=C(Cl)C=C1NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O NMDMHKVCPISZTF-UHFFFAOYSA-N 0.000 description 2
- GJXXUHGUCBUXSL-UHFFFAOYSA-N 5-amino-3h-1,3-benzoxazol-2-one Chemical compound NC1=CC=C2OC(=O)NC2=C1 GJXXUHGUCBUXSL-UHFFFAOYSA-N 0.000 description 2
- BZQOGSASRMGQHB-UHFFFAOYSA-N 5-chloro-3-(2,4-dinitrophenyl)-1,3-benzoxazol-2-one Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1N1C(=O)OC2=CC=C(Cl)C=C21 BZQOGSASRMGQHB-UHFFFAOYSA-N 0.000 description 2
- UTQPEXLRBRAERQ-UHFFFAOYSA-N 5-nitro-3h-1,3-benzoxazol-2-one Chemical compound [O-][N+](=O)C1=CC=C2OC(=O)NC2=C1 UTQPEXLRBRAERQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 150000001556 benzimidazoles Chemical class 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 229950004210 cromakalim Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- NVBJVKSEBHBFIY-UHFFFAOYSA-N n-(2-oxo-3h-1,3-benzoxazol-5-yl)acetamide Chemical compound CC(=O)NC1=CC=C2OC(=O)NC2=C1 NVBJVKSEBHBFIY-UHFFFAOYSA-N 0.000 description 2
- KUKFUMZTUGZKDL-UHFFFAOYSA-N n-[3-[2-nitro-4-(trifluoromethyl)phenyl]-2-oxo-1,3-benzoxazol-5-yl]acetamide Chemical compound C12=CC(NC(=O)C)=CC=C2OC(=O)N1C1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O KUKFUMZTUGZKDL-UHFFFAOYSA-N 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000005090 tracheal smooth muscle Anatomy 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- YBDBYPQFIMSFJW-UHFFFAOYSA-N (4-chloro-3-nitrophenyl)-phenylmethanone Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC(C(=O)C=2C=CC=CC=2)=C1 YBDBYPQFIMSFJW-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- AXLDWMVASPWDQF-UHFFFAOYSA-N 1,3-bis(2-methoxyphenyl)urea Chemical compound COC1=CC=CC=C1NC(=O)NC1=CC=CC=C1OC AXLDWMVASPWDQF-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical class C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- OHZHFAITHCZQJD-UHFFFAOYSA-N 1-(2-methoxyphenyl)-n,n-dimethyl-2-oxo-3h-benzimidazole-5-sulfonamide Chemical compound COC1=CC=CC=C1N1C(=O)NC2=CC(S(=O)(=O)N(C)C)=CC=C21 OHZHFAITHCZQJD-UHFFFAOYSA-N 0.000 description 1
- IYSBZDIWGIQMDJ-UHFFFAOYSA-N 1-[2-amino-4-(trifluoromethyl)anilino]naphthalen-2-ol Chemical compound NC1=CC(C(F)(F)F)=CC=C1NC1=C(O)C=CC2=CC=CC=C12 IYSBZDIWGIQMDJ-UHFFFAOYSA-N 0.000 description 1
- NJKHAMDETWXUAY-UHFFFAOYSA-N 1-[2-nitro-4-(trifluoromethyl)anilino]naphthalen-2-ol Chemical compound OC1=CC=C2C=CC=CC2=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O NJKHAMDETWXUAY-UHFFFAOYSA-N 0.000 description 1
- FHMMQQXRSYSWCM-UHFFFAOYSA-N 1-aminonaphthalen-2-ol Chemical compound C1=CC=C2C(N)=C(O)C=CC2=C1 FHMMQQXRSYSWCM-UHFFFAOYSA-N 0.000 description 1
- HISHUMDTGXICEZ-UHFFFAOYSA-N 1-chloro-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Cl)C([N+]([O-])=O)=C1 HISHUMDTGXICEZ-UHFFFAOYSA-N 0.000 description 1
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 1
- HLDFCCHSOZWKAA-UHFFFAOYSA-N 1-fluoro-2-nitro-4-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1F HLDFCCHSOZWKAA-UHFFFAOYSA-N 0.000 description 1
- CULFWMXJHHKFGJ-UHFFFAOYSA-N 1-n-(2-methoxy-5-phenylphenyl)-4-(trifluoromethyl)benzene-1,2-diamine Chemical compound COC1=CC=C(C=2C=CC=CC=2)C=C1NC1=CC=C(C(F)(F)F)C=C1N CULFWMXJHHKFGJ-UHFFFAOYSA-N 0.000 description 1
- OLTNHAVUPCKTQR-UHFFFAOYSA-N 1-n-(5-chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzene-1,2-diamine Chemical compound COC1=CC=C(Cl)C=C1NC1=CC=C(C(F)(F)F)C=C1N OLTNHAVUPCKTQR-UHFFFAOYSA-N 0.000 description 1
- ABFQWFCIHQMUBG-UHFFFAOYSA-N 1-n-(5-chloro-2-methylphenyl)-4-methoxybenzene-1,2-diamine Chemical compound NC1=CC(OC)=CC=C1NC1=CC(Cl)=CC=C1C ABFQWFCIHQMUBG-UHFFFAOYSA-N 0.000 description 1
- NMGHEOHOYKBWEM-UHFFFAOYSA-N 2,4-dichloro-6-methoxyaniline Chemical compound COC1=CC(Cl)=CC(Cl)=C1N NMGHEOHOYKBWEM-UHFFFAOYSA-N 0.000 description 1
- KYAGPEYJRITJLT-UHFFFAOYSA-N 2,4-dichloro-n-(5-chloro-2-methoxyphenyl)-6-nitroaniline Chemical compound COC1=CC=C(Cl)C=C1NC1=C(Cl)C=C(Cl)C=C1[N+]([O-])=O KYAGPEYJRITJLT-UHFFFAOYSA-N 0.000 description 1
- RJXOVESYJFXCGI-UHFFFAOYSA-N 2,4-difluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1F RJXOVESYJFXCGI-UHFFFAOYSA-N 0.000 description 1
- KZZWFUCYTWDCCS-UHFFFAOYSA-N 2-(2,4-dichloro-6-nitroanilino)phenol Chemical compound OC1=CC=CC=C1NC1=C(Cl)C=C(Cl)C=C1[N+]([O-])=O KZZWFUCYTWDCCS-UHFFFAOYSA-N 0.000 description 1
- MDFOQYKZQPTLON-UHFFFAOYSA-N 2-(2-amino-4,5-dichloroanilino)phenol Chemical compound NC1=CC(Cl)=C(Cl)C=C1NC1=CC=CC=C1O MDFOQYKZQPTLON-UHFFFAOYSA-N 0.000 description 1
- OQPZSHIKEMPJIK-UHFFFAOYSA-N 2-(2-amino-4-nitroanilino)-4-chlorophenol;hydrochloride Chemical compound Cl.NC1=CC([N+]([O-])=O)=CC=C1NC1=CC(Cl)=CC=C1O OQPZSHIKEMPJIK-UHFFFAOYSA-N 0.000 description 1
- GWYNFCHWTALUBK-UHFFFAOYSA-N 2-(2-amino-5-fluoroanilino)-4-chlorophenol;hydrochloride Chemical compound Cl.NC1=CC=C(F)C=C1NC1=CC(Cl)=CC=C1O GWYNFCHWTALUBK-UHFFFAOYSA-N 0.000 description 1
- XGKHCLSGQDOGPD-UHFFFAOYSA-N 2-(2-aminoanilino)benzenethiol Chemical compound NC1=CC=CC=C1NC1=CC=CC=C1S XGKHCLSGQDOGPD-UHFFFAOYSA-N 0.000 description 1
- LYEZXOMDMACXMT-UHFFFAOYSA-N 2-(2-aminoanilino)phenol Chemical compound NC1=CC=CC=C1NC1=CC=CC=C1O LYEZXOMDMACXMT-UHFFFAOYSA-N 0.000 description 1
- FUGKSCQGTPYBHW-UHFFFAOYSA-N 2-(2-nitroanilino)benzenethiol Chemical compound [O-][N+](=O)C1=CC=CC=C1NC1=CC=CC=C1S FUGKSCQGTPYBHW-UHFFFAOYSA-N 0.000 description 1
- DANRBUDCZZLSRH-UHFFFAOYSA-N 2-(4,5-dichloro-2-nitroanilino)phenol Chemical compound OC1=CC=CC=C1NC1=CC(Cl)=C(Cl)C=C1[N+]([O-])=O DANRBUDCZZLSRH-UHFFFAOYSA-N 0.000 description 1
- -1 2-Amino-N-(5-chloro-2-hydroxyphenyl)-4-fluoroaniline hydrochloride Chemical compound 0.000 description 1
- BBWXJKOMDHJJPB-UHFFFAOYSA-N 2-[2-amino-4-(trifluoromethyl)anilino]-4-chlorophenol Chemical compound NC1=CC(C(F)(F)F)=CC=C1NC1=CC(Cl)=CC=C1O BBWXJKOMDHJJPB-UHFFFAOYSA-N 0.000 description 1
- KYBYYEPAYASLKJ-UHFFFAOYSA-N 2-[2-amino-4-(trifluoromethyl)anilino]-4-chlorophenol;hydrochloride Chemical compound Cl.NC1=CC(C(F)(F)F)=CC=C1NC1=CC(Cl)=CC=C1O KYBYYEPAYASLKJ-UHFFFAOYSA-N 0.000 description 1
- CUYGIHNJUYDZPV-UHFFFAOYSA-N 2-[2-amino-4-(trifluoromethyl)anilino]phenol Chemical compound NC1=CC(C(F)(F)F)=CC=C1NC1=CC=CC=C1O CUYGIHNJUYDZPV-UHFFFAOYSA-N 0.000 description 1
- LLCCRQPSVBCLPN-UHFFFAOYSA-N 2-[2-amino-4-(trifluoromethyl)anilino]pyridin-3-ol Chemical compound NC1=CC(C(F)(F)F)=CC=C1NC1=NC=CC=C1O LLCCRQPSVBCLPN-UHFFFAOYSA-N 0.000 description 1
- MXPNZJQJBYVKHH-UHFFFAOYSA-N 2-[2-nitro-4-(trifluoromethyl)anilino]phenol Chemical compound OC1=CC=CC=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O MXPNZJQJBYVKHH-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- SWFNPENEBHAHEB-UHFFFAOYSA-N 2-amino-4-chlorophenol Chemical compound NC1=CC(Cl)=CC=C1O SWFNPENEBHAHEB-UHFFFAOYSA-N 0.000 description 1
- VFWWGFYZNFLPTE-UHFFFAOYSA-N 2-methoxy-4-phenylaniline Chemical compound C1=C(N)C(OC)=CC(C=2C=CC=CC=2)=C1 VFWWGFYZNFLPTE-UHFFFAOYSA-N 0.000 description 1
- RKUSRLUGUVDNKP-UHFFFAOYSA-N 2-methoxy-5-(trifluoromethyl)aniline Chemical compound COC1=CC=C(C(F)(F)F)C=C1N RKUSRLUGUVDNKP-UHFFFAOYSA-N 0.000 description 1
- SMXSFWBFEVJOMM-UHFFFAOYSA-N 2-methoxy-n-[2-nitro-4-(trifluoromethyl)phenyl]-4-phenylaniline Chemical compound COC1=CC(C=2C=CC=CC=2)=CC=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O SMXSFWBFEVJOMM-UHFFFAOYSA-N 0.000 description 1
- GSUQXXWDXVDXQB-UHFFFAOYSA-N 2-n-(2-methoxy-5-phenylphenyl)benzene-1,2-diamine Chemical compound COC1=CC=C(C=2C=CC=CC=2)C=C1NC1=CC=CC=C1N GSUQXXWDXVDXQB-UHFFFAOYSA-N 0.000 description 1
- RRMVBUOCCIVITB-UHFFFAOYSA-N 2-n-(2-methoxyphenyl)benzene-1,2-diamine Chemical compound COC1=CC=CC=C1NC1=CC=CC=C1N RRMVBUOCCIVITB-UHFFFAOYSA-N 0.000 description 1
- VQVJMSMIMXHFNL-UHFFFAOYSA-N 2-n-(2-nitrophenyl)benzene-1,2-diamine Chemical compound NC1=CC=CC=C1NC1=CC=CC=C1[N+]([O-])=O VQVJMSMIMXHFNL-UHFFFAOYSA-N 0.000 description 1
- PGBYLHRVUUPEQL-UHFFFAOYSA-N 3,5-dichloro-2-methoxy-n-(2-nitrophenyl)aniline Chemical compound COC1=C(Cl)C=C(Cl)C=C1NC1=CC=CC=C1[N+]([O-])=O PGBYLHRVUUPEQL-UHFFFAOYSA-N 0.000 description 1
- PBNWKXJMRPRROE-UHFFFAOYSA-N 3,5-dichloro-2-n-(5-chloro-2-methoxyphenyl)benzene-1,2-diamine Chemical compound COC1=CC=C(Cl)C=C1NC1=C(N)C=C(Cl)C=C1Cl PBNWKXJMRPRROE-UHFFFAOYSA-N 0.000 description 1
- KBCMPABVTQDUTO-UHFFFAOYSA-N 3-(2-aminoanilino)phenol Chemical compound NC1=CC=CC=C1NC1=CC=CC(O)=C1 KBCMPABVTQDUTO-UHFFFAOYSA-N 0.000 description 1
- FJZLBTBUTOEUKR-UHFFFAOYSA-N 3-(2-hydroxynaphthalen-1-yl)-4-(trifluoromethyl)-1h-imidazol-2-one Chemical compound OC1=CC=C2C=CC=CC2=C1N1C(C(F)(F)F)=CNC1=O FJZLBTBUTOEUKR-UHFFFAOYSA-N 0.000 description 1
- KHLBIUSMSQHRQA-UHFFFAOYSA-N 3-(2-hydroxyphenyl)-6-(trifluoromethyl)-1h-benzimidazole-2-thione Chemical compound OC1=CC=CC=C1N1C(=S)NC2=CC(C(F)(F)F)=CC=C21 KHLBIUSMSQHRQA-UHFFFAOYSA-N 0.000 description 1
- QLALMOIAJGEEPC-UHFFFAOYSA-N 3-(2-methoxy-5-phenylphenyl)-1h-benzimidazol-2-one Chemical compound C1=C(N2C(NC3=CC=CC=C32)=O)C(OC)=CC=C1C1=CC=CC=C1 QLALMOIAJGEEPC-UHFFFAOYSA-N 0.000 description 1
- BLEHBKBOONOFQO-UHFFFAOYSA-N 3-(2-methoxy-5-phenylphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound C1=C(N2C(NC3=CC(=CC=C32)C(F)(F)F)=O)C(OC)=CC=C1C1=CC=CC=C1 BLEHBKBOONOFQO-UHFFFAOYSA-N 0.000 description 1
- SSILWUSDXOOUDQ-UHFFFAOYSA-N 3-(2-methoxyphenyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=CC=C1N1C(=O)NC2=CC=CC=C21 SSILWUSDXOOUDQ-UHFFFAOYSA-N 0.000 description 1
- NOOXVTYJMCWIED-UHFFFAOYSA-N 3-(2-methoxyphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=CC=C1N1C(=O)NC2=CC(C(F)(F)F)=CC=C21 NOOXVTYJMCWIED-UHFFFAOYSA-N 0.000 description 1
- MRCSZHUWNHOTHN-UHFFFAOYSA-N 3-(2-nitroanilino)phenol Chemical compound OC1=CC=CC(NC=2C(=CC=CC=2)[N+]([O-])=O)=C1 MRCSZHUWNHOTHN-UHFFFAOYSA-N 0.000 description 1
- BSPOIJPFILZYTK-UHFFFAOYSA-N 3-(2-nitrophenyl)-1,3-benzothiazol-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1N1C(=O)SC2=CC=CC=C21 BSPOIJPFILZYTK-UHFFFAOYSA-N 0.000 description 1
- IUXJCILKZCQZCL-UHFFFAOYSA-N 3-(2-sulfanylphenyl)-1h-benzimidazol-2-one Chemical compound SC1=CC=CC=C1N1C(=O)NC2=CC=CC=C21 IUXJCILKZCQZCL-UHFFFAOYSA-N 0.000 description 1
- URXZPGJQWCQNPN-UHFFFAOYSA-N 3-(3-hydroxynaphthalen-2-yl)-6-(trifluoromethyl)-1h-benzimidazole-2-thione Chemical compound C12=CC=C(C(F)(F)F)C=C2NC(=S)N1C1=CC2=CC=CC=C2C=C1O URXZPGJQWCQNPN-UHFFFAOYSA-N 0.000 description 1
- SNCKSPDKEMCKHB-UHFFFAOYSA-N 3-(3-hydroxyphenyl)-1h-benzimidazol-2-one Chemical compound OC1=CC=CC(N2C(NC3=CC=CC=C32)=O)=C1 SNCKSPDKEMCKHB-UHFFFAOYSA-N 0.000 description 1
- NTPNHULINJLTRM-UHFFFAOYSA-N 3-(5-chloro-2-hydroxy-3-nitrophenyl)-5-nitro-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound C1=C(Cl)C=C([N+]([O-])=O)C(O)=C1N1C(=O)NC2=CC(C(F)(F)F)=C([N+]([O-])=O)C=C21 NTPNHULINJLTRM-UHFFFAOYSA-N 0.000 description 1
- JGBXEFPNXOUTCJ-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=C(Cl)C=C1N1C(=O)NC2=CC=CC=C21 JGBXEFPNXOUTCJ-UHFFFAOYSA-N 0.000 description 1
- GQEDGOXTKCPGDG-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=C(Cl)C=C1N1C(=O)NC2=CC(C(F)(F)F)=CC=C21 GQEDGOXTKCPGDG-UHFFFAOYSA-N 0.000 description 1
- JIYVZYPAOGXGNH-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-6-(trifluoromethyl)-1h-benzimidazole-2-thione Chemical compound COC1=CC=C(Cl)C=C1N1C(=S)NC2=CC(C(F)(F)F)=CC=C21 JIYVZYPAOGXGNH-UHFFFAOYSA-N 0.000 description 1
- PLWRZACQCYPRSH-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-6-methoxy-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC(OC)=CC=C2N1C1=CC(Cl)=CC=C1OC PLWRZACQCYPRSH-UHFFFAOYSA-N 0.000 description 1
- WUCSRCCLEVKTEQ-UHFFFAOYSA-N 3-[2-amino-4-(trifluoromethyl)anilino]naphthalen-2-ol Chemical compound NC1=CC(C(F)(F)F)=CC=C1NC1=CC2=CC=CC=C2C=C1O WUCSRCCLEVKTEQ-UHFFFAOYSA-N 0.000 description 1
- XOSOSXNGVNKBAE-UHFFFAOYSA-N 3-[2-nitro-4-(trifluoromethyl)anilino]naphthalen-2-ol Chemical compound OC1=CC2=CC=CC=C2C=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O XOSOSXNGVNKBAE-UHFFFAOYSA-N 0.000 description 1
- GJTLCLPHSOWZAF-UHFFFAOYSA-N 3-amino-4-(2-methoxyanilino)-n,n-dimethylbenzenesulfonamide Chemical compound COC1=CC=CC=C1NC1=CC=C(S(=O)(=O)N(C)C)C=C1N GJTLCLPHSOWZAF-UHFFFAOYSA-N 0.000 description 1
- ARJXUDDEURDNQB-UHFFFAOYSA-N 3-amino-4-(5-chloro-2-hydroxyanilino)-n,n-dimethylbenzenesulfonamide Chemical compound NC1=CC(S(=O)(=O)N(C)C)=CC=C1NC1=CC(Cl)=CC=C1O ARJXUDDEURDNQB-UHFFFAOYSA-N 0.000 description 1
- ZHVPTERSBUMMHK-UHFFFAOYSA-N 3-aminonaphthalen-2-ol Chemical compound C1=CC=C2C=C(O)C(N)=CC2=C1 ZHVPTERSBUMMHK-UHFFFAOYSA-N 0.000 description 1
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 1
- 229940018563 3-aminophenol Drugs 0.000 description 1
- SFIUUZGFWXCWSO-UHFFFAOYSA-N 4,5-dichloro-2-n-(2-methoxyphenyl)benzene-1,2-diamine Chemical compound COC1=CC=CC=C1NC1=CC(Cl)=C(Cl)C=C1N SFIUUZGFWXCWSO-UHFFFAOYSA-N 0.000 description 1
- LXEWAOHWXSGFKU-UHFFFAOYSA-N 4,5-dichloro-n-(2-methoxyphenyl)-2-nitroaniline Chemical compound COC1=CC=CC=C1NC1=CC(Cl)=C(Cl)C=C1[N+]([O-])=O LXEWAOHWXSGFKU-UHFFFAOYSA-N 0.000 description 1
- XMOQGDJIEGSVCE-UHFFFAOYSA-N 4,6-dichloro-3-(5-chloro-2-methoxyphenyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=C(Cl)C=C1N1C(=O)NC2=CC(Cl)=CC(Cl)=C21 XMOQGDJIEGSVCE-UHFFFAOYSA-N 0.000 description 1
- XVDJGJAIMHQEEG-UHFFFAOYSA-N 4-(2-aminoanilino)phenol Chemical compound NC1=CC=CC=C1NC1=CC=C(O)C=C1 XVDJGJAIMHQEEG-UHFFFAOYSA-N 0.000 description 1
- LOKQWOIZHSJIMW-UHFFFAOYSA-N 4-(2-methoxyanilino)-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound COC1=CC=CC=C1NC1=CC=C(S(=O)(=O)N(C)C)C=C1[N+]([O-])=O LOKQWOIZHSJIMW-UHFFFAOYSA-N 0.000 description 1
- HSDSBIUUVWRHTM-UHFFFAOYSA-N 4-(2-nitroanilino)phenol Chemical compound C1=CC(O)=CC=C1NC1=CC=CC=C1[N+]([O-])=O HSDSBIUUVWRHTM-UHFFFAOYSA-N 0.000 description 1
- QCJFEBQKBHDDKM-UHFFFAOYSA-N 4-(5-chloro-2-hydroxyanilino)-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(S(=O)(=O)N(C)C)=CC=C1NC1=CC(Cl)=CC=C1O QCJFEBQKBHDDKM-UHFFFAOYSA-N 0.000 description 1
- AKIOXSFQIPXSMK-UHFFFAOYSA-N 4-chloro-2-(4-fluoro-2-nitroanilino)phenol Chemical compound OC1=CC=C(Cl)C=C1NC1=CC=C(F)C=C1[N+]([O-])=O AKIOXSFQIPXSMK-UHFFFAOYSA-N 0.000 description 1
- VMFCFNLFXSQHEO-UHFFFAOYSA-N 4-chloro-2-[2-nitro-4-(trifluoromethyl)anilino]phenol Chemical compound OC1=CC=C(Cl)C=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O VMFCFNLFXSQHEO-UHFFFAOYSA-N 0.000 description 1
- DWULEZSPTCVSOP-UHFFFAOYSA-N 4-chloro-2-n-(2-methoxy-5-phenylphenyl)-5-(trifluoromethyl)benzene-1,2-diamine Chemical compound COC1=CC=C(C=2C=CC=CC=2)C=C1NC1=CC(Cl)=C(C(F)(F)F)C=C1N DWULEZSPTCVSOP-UHFFFAOYSA-N 0.000 description 1
- CNFZPOAGVVMEGS-UHFFFAOYSA-N 4-chloro-2-n-(2-methoxyphenyl)-5-(trifluoromethyl)benzene-1,2-diamine Chemical compound COC1=CC=CC=C1NC1=CC(Cl)=C(C(F)(F)F)C=C1N CNFZPOAGVVMEGS-UHFFFAOYSA-N 0.000 description 1
- KDRZNHUUIQCDDR-UHFFFAOYSA-N 4-chloro-N,N-dimethyl-4-nitrocyclohexa-1,5-diene-1-sulfonamide Chemical compound CN(S(=O)(=O)C=1C=CC(CC=1)([N+](=O)[O-])Cl)C KDRZNHUUIQCDDR-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- KLPGHWMFZPLJEI-UHFFFAOYSA-N 5,6-dichloro-3-(2-hydroxyphenyl)-1h-benzimidazol-2-one Chemical compound OC1=CC=CC=C1N1C(=O)NC2=CC(Cl)=C(Cl)C=C21 KLPGHWMFZPLJEI-UHFFFAOYSA-N 0.000 description 1
- DHBYPSMLTMWYAV-UHFFFAOYSA-N 5,6-dichloro-3-(2-methoxyphenyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=CC=C1N1C(=O)NC2=CC(Cl)=C(Cl)C=C21 DHBYPSMLTMWYAV-UHFFFAOYSA-N 0.000 description 1
- GLXMAFNPBMJOQU-UHFFFAOYSA-N 5,6-dichloro-3-(5-chloro-2-hydroxyphenyl)-1h-benzimidazol-2-one Chemical compound OC1=CC=C(Cl)C=C1N1C(=O)NC2=CC(Cl)=C(Cl)C=C21 GLXMAFNPBMJOQU-UHFFFAOYSA-N 0.000 description 1
- CTTFBOGCKIMQKL-UHFFFAOYSA-N 5-chloro-2-methoxy-n-(2-nitrophenyl)aniline Chemical compound COC1=CC=C(Cl)C=C1NC1=CC=CC=C1[N+]([O-])=O CTTFBOGCKIMQKL-UHFFFAOYSA-N 0.000 description 1
- OYJIIXHHGCQIQV-UHFFFAOYSA-N 5-chloro-3-(2-methoxy-5-phenylphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound C1=C(N2C(NC3=CC(=C(Cl)C=C32)C(F)(F)F)=O)C(OC)=CC=C1C1=CC=CC=C1 OYJIIXHHGCQIQV-UHFFFAOYSA-N 0.000 description 1
- ALTJOHSVHOBQTJ-UHFFFAOYSA-N 5-chloro-3-(2-methoxyphenyl)-6-(trifluoromethyl)-1h-benzimidazol-2-one Chemical compound COC1=CC=CC=C1N1C(=O)NC2=CC(C(F)(F)F)=C(Cl)C=C21 ALTJOHSVHOBQTJ-UHFFFAOYSA-N 0.000 description 1
- JFABRHSZDDCHKK-UHFFFAOYSA-N 5-chloro-3-(4-fluoro-2-nitrophenyl)-1,3-benzoxazol-2-one Chemical compound [O-][N+](=O)C1=CC(F)=CC=C1N1C(=O)OC2=CC=C(Cl)C=C21 JFABRHSZDDCHKK-UHFFFAOYSA-N 0.000 description 1
- XLIXIMKIDSKSAO-UHFFFAOYSA-N 5-chloro-3-[2-nitro-4-(trifluoromethyl)phenyl]-1,3-benzoxazol-2-one Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1N1C(=O)OC2=CC=C(Cl)C=C21 XLIXIMKIDSKSAO-UHFFFAOYSA-N 0.000 description 1
- IWADKCKJKGBMLB-UHFFFAOYSA-N 5-chloro-n-(2-methoxy-4-phenylphenyl)-2-nitro-4-(trifluoromethyl)aniline Chemical compound COC1=CC(C=2C=CC=CC=2)=CC=C1NC1=CC(Cl)=C(C(F)(F)F)C=C1[N+]([O-])=O IWADKCKJKGBMLB-UHFFFAOYSA-N 0.000 description 1
- LZLTZWNPUWWFBZ-UHFFFAOYSA-N 5-chloro-n-(2-methoxyphenyl)-2-nitro-4-(trifluoromethyl)aniline Chemical compound COC1=CC=CC=C1NC1=CC(Cl)=C(C(F)(F)F)C=C1[N+]([O-])=O LZLTZWNPUWWFBZ-UHFFFAOYSA-N 0.000 description 1
- KFFSCSYFRRQOEV-UHFFFAOYSA-N 6-benzoyl-3-(5-chloro-2-hydroxyphenyl)-1h-benzimidazol-2-one Chemical compound OC1=CC=C(Cl)C=C1N1C(=O)NC2=CC(C(=O)C=3C=CC=CC=3)=CC=C21 KFFSCSYFRRQOEV-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 108010023798 Charybdotoxin Proteins 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- RRJGJEAOMJLXEX-UHFFFAOYSA-N [3-amino-4-(5-chloro-2-hydroxyanilino)phenyl]-phenylmethanone Chemical compound NC1=CC(C(=O)C=2C=CC=CC=2)=CC=C1NC1=CC(Cl)=CC=C1O RRJGJEAOMJLXEX-UHFFFAOYSA-N 0.000 description 1
- JGAPEMBTQYQYTH-UHFFFAOYSA-N [4-(5-chloro-2-hydroxyanilino)-3-nitrophenyl]-phenylmethanone Chemical compound OC1=CC=C(Cl)C=C1NC1=CC=C(C(=O)C=2C=CC=CC=2)C=C1[N+]([O-])=O JGAPEMBTQYQYTH-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000005057 airway smooth muscle cell Anatomy 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 230000001262 anti-secretory effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 210000003433 aortic smooth muscle cell Anatomy 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000000782 cerebellar granule cell Anatomy 0.000 description 1
- CNVQLPPZGABUCM-LIGYZCPXSA-N ctx toxin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H]3CSSC[C@@H](C(N[C@@H](CC=4C5=CC=CC=C5NC=4)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC3=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CO)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3NC=NC=3)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N2)C(C)C)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)O)NC1=O)=O)CCSC)C(C)C)[C@@H](C)O)NC(=O)[C@H]1NC(=O)CC1)C1=CC=CC=C1 CNVQLPPZGABUCM-LIGYZCPXSA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- BTVWZWFKMIUSGS-UHFFFAOYSA-N dimethylethyleneglycol Natural products CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- JMNAIXYYUZRIPL-UHFFFAOYSA-N ethyl n-[2-(3,5-dichloro-2-methoxyanilino)phenyl]carbamate Chemical compound CCOC(=O)NC1=CC=CC=C1NC1=CC(Cl)=CC(Cl)=C1OC JMNAIXYYUZRIPL-UHFFFAOYSA-N 0.000 description 1
- CKZBJAURVFZWKP-UHFFFAOYSA-N ethyl n-[2-(5-chloro-2-hydroxyanilino)-5-nitrophenyl]carbamate Chemical compound CCOC(=O)NC1=CC([N+]([O-])=O)=CC=C1NC1=CC(Cl)=CC=C1O CKZBJAURVFZWKP-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JXXWJMUPNZDILL-UHFFFAOYSA-N imidazo[4,5-b]pyridin-2-one Chemical class C1=CC=NC2=NC(=O)N=C21 JXXWJMUPNZDILL-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- CNJVWDMOROJUHE-UHFFFAOYSA-N n-(2-methoxyphenyl)-2-nitro-4-(trifluoromethyl)aniline Chemical compound COC1=CC=CC=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O CNJVWDMOROJUHE-UHFFFAOYSA-N 0.000 description 1
- GLFIGGLPOXATJW-UHFFFAOYSA-N n-(2-methoxyphenyl)-2-nitroaniline Chemical compound COC1=CC=CC=C1NC1=CC=CC=C1[N+]([O-])=O GLFIGGLPOXATJW-UHFFFAOYSA-N 0.000 description 1
- VREBTSQISPRTBY-UHFFFAOYSA-N n-(5-chloro-2-methoxyphenyl)-2-nitro-4-(trifluoromethyl)aniline Chemical compound COC1=CC=C(Cl)C=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O VREBTSQISPRTBY-UHFFFAOYSA-N 0.000 description 1
- LYWSOGYNTPIADZ-UHFFFAOYSA-N n-(5-chloro-2-methoxyphenyl)-4-methoxy-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1NC1=CC(Cl)=CC=C1OC LYWSOGYNTPIADZ-UHFFFAOYSA-N 0.000 description 1
- HVECVVXMHSVSQG-UHFFFAOYSA-N n-[2-methoxy-5-(trifluoromethyl)phenyl]-2-nitro-4-(trifluoromethyl)aniline Chemical compound COC1=CC=C(C(F)(F)F)C=C1NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O HVECVVXMHSVSQG-UHFFFAOYSA-N 0.000 description 1
- DMCMBRHBAMVKJQ-UHFFFAOYSA-N n-[3-[2-amino-4-(trifluoromethyl)anilino]-4-hydroxyphenyl]acetamide Chemical compound CC(=O)NC1=CC=C(O)C(NC=2C(=CC(=CC=2)C(F)(F)F)N)=C1 DMCMBRHBAMVKJQ-UHFFFAOYSA-N 0.000 description 1
- RZMMQCZPRSKRIR-UHFFFAOYSA-N n-[4-hydroxy-3-[2-oxo-5-(trifluoromethyl)-3h-benzimidazol-1-yl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(O)C(N2C(NC3=CC(=CC=C32)C(F)(F)F)=O)=C1 RZMMQCZPRSKRIR-UHFFFAOYSA-N 0.000 description 1
- 208000024696 nocturnal asthma Diseases 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- 108010083133 potassium channel protein I(sk) Proteins 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000036390 resting membrane potential Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/28—Sulfur atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Polyesters Or Polycarbonates (AREA)
- Graft Or Block Polymers (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av nye, terapeutisk aktive ben-zimidazolderivater.
Oppfinnelsens formål
Det er et formål ved foreliggende oppfinnelse å til-veiebringe nye benzimidazolforbindelser som kan anvendes ved behandlingen av sykdommer hos pattedyr, inkludert mennesket, og spesielt ved behandlingen av sykdommer som kan behandles ved å åpne cellemembrankaliumkanaler hos pattedyret.
Oppfinnelsens bakgrunn
I Bianchi et al. i Eur. J. Med. Chem. - Chimica Therapeutica 16 ( 4), 321-326 (1981), beskrives benzimidazolin-2-on-derivater med antimagesår- og antisekretorisk virkning.
I Clark et al. i J. Med. Chem. 21 ( 9), 965-978
(1978), beskrives imidazo[4,5-b]pyridin-2-on-derivater som har analgetisk aktivitet.
Det er generelt godt kjent at åpning av kaliumkanaler (K<+->kanaler) fører til en hyperpolarisering og relaksasjon i celler. De for tiden kjente K<+->kanalåpnere (f.eks. cromakalim og pinacidil) utøver sin effekt hovedsakelig via den ATP-føl-somme K<+->kanal. De har en høy affinitet for vaskulære glattmuskelceller og er således stort sett vasodilatorer. Nyere undersøkelser indikerer imidlertid at K<+->kanalåpnere som hyper-polariserer neuronceller, også har antikonvulsive og antiiske-miske effekter i sentralnervesystemet (CNS) (European Journal of Pharmacology 167, 181-183 (1989), Neuroscience Letters 115, 195-200 (1990), Neuroscience 37 ( 1), 55-60 (1990), The Journal of Pharmacology and Experimental Therapeutics 251 ( 1), 98-104
(1989)). Nyere undersøkelser viser dessuten at kaliumkanal-åpnere som virker på glattmuskelceller i luftveiene (luftrør-glattmuskel), vil ha antiastmatiske effekter (Small et al., K<+->channel opening as a mechanism for relaxing airways smooth muscle i New Anti-Asthma Drugs (s. 89-94) 1988, Birkhåuser Verlag Basel, og Dr. S.G. Dilly, Cromakalim/Lemakalim, Ex-perience in hypertension and nocturnal asthma i Conference Documentation, Potassium Channels '90, The Royal College of Physicians, 6.-7. des. 1990).
Oppsummering av oppfinnelsen
Oppfinnelsen vedrører således en analogifremgangsmåte for fremstilling av en terapeutisk aktiv forbindelse med den generelle formel I
hvor
R<1>er hydrogen, NH2eller Cx.6-alkyl som kan være forgrenet ,
X er 0 eller S,
Y er 0 eller S,
R<4>,R<5>, R6 ogR<7>er uavhengig av hverandre hydrogen, halogen,
CF3, N02, NH2, OH, Ci.g-alkoksy, C(=0)-fenyl eller S02-NRIR<11>, hvor R<1>og R<11>uavhengig av hverandre er hydrogen eller C^-alkyl,
R<11>er hydrogen, halogen, N02eller S02NR'R'', hvor R' og R'' uavhengig av hverandre er hydrogen eller C^-alkyl,
R<13>er hydrogen, halogen, fenyl, CF3eller N02,
R<12>er hydrogen eller danner sammen med R<13>en C4_7-<k>arbo-syklisk ring som kan være aromatisk eller delvis
mettet,
R<14>er hydrogen eller danner sammen med R<13>en C4.7-<k>arbo-syklisk ring som kan være aromatisk eller delvis
mettet,
som er kjennetegnet ved at
a) for fremstilling av en forbindelse med formel (I) hvor X = 0, omsettes en forbindelse med formel
hvorR<1>,R4, R5,R<6>,R<7>, Y, R<11>, R<1>2,R1<3>og R<14>har de ovenfor angitte betydninger, med fosgen eller urea, og b) for fremstilling av en forbindelse med formel (I) hvor X = S, omsettes en forbindelse med formel
hvorR<1>,R4,R<5>,R<6>,R<7>, Y, R<11>, R<1>2,R1<3>og R<14>har de ovenfor angitte betydninger, med tiokarbonyldiimidazol.
Blant forbindelsene fremstilt ifølge oppfinnelsen er de følgende særlig foretrukket på grunn av sin gunstige tera-peutiske virkning: 5-trifluormetyl-2,3-dihydro-l-(5-klor-2-hydroksyfenyl)-lH-2-okso-benzimidazol,
5-trifluormetyl-2,3-dihydro-l-(5-fenyl-2-hydroksyfenyl)-lH-2-okso-benzimidazol og
5-trifluormetyl-6-nitro-2,3-dihydro-l-(3-nitro-5-klor-2-hydroksyfenyl)-lH-2-okso-benzimidazol.
Biologisk aktivitet
Forbindelsene fremstilt ifølge foreliggende oppfinnelse er sterke åpnere av den kalsiumaktiverte K<+->kanal med høy elektrisk ledningsevne, noen ganger henvist til som den store K<+->kanal eller BKCa-kanalen. BKCa-kanalen er til stede i de fleste neuronceller, i luftvei- og vaskulærglattmuskel-celler samt i (3-celler i bukspyttkjertel.
Evnen til forbindelsene fremstilt ifølge foreliggende oppfinnelse når det gjelder å åpne BKCa-kanalen, kan vises på flere forskjellige måter.
Alle forsøkene ble utført med "patch-clamp"-teknikk (Hamill et al., Pflugers Arch. 391, 85-100 (1981)). Ionesam-mensetningen i den interne oppløsning var (i mM) 4 NaCl, 140 KC1, 1 CaCl2, 1 MgCl2, 2 EGTA, 10 HEPES, og den eksterne opp-løsning inneholdt 140 NaCl, 4 KC1, 2 CaCl2, 1 MgCl2og 10
HEPES.
Helcellemålinger
Membranpotensialet til N1E-115 neuroblastomceller ble bestemt i helcellemålinger under anvendelse av vanlig klamme-måte (HEKA EPC-9 "patch-clamp"-forsterker). På grunn av høy-motstandskapselen og den store størrelsen til disse cellene forble det målte membranpotensial stabilt i tidsrom på 30-60 minutter, riktignok ved noe depolariserte verdier (-15 til
-60 Mv).
Administrering av f.eks. l-(5-klor-2-hydroksyfenyl)-5-trifluormetyl-1,3-dihydro-2H-benzimidazol-2-on (30 uM) til badet, hyperpolariserte cellene etter en forsinkelse på 1-3 minutter. Den gjennomsnittlige hyperpolarisering var -14 Mv (SD = -5 Mv, n = 8), og effekten var størst i de cellene som ble mest depolarisert før administrering av forbindelsen.
Likevektspotensialet for K<+>, Cl" og Na<+>i disse for-søkene var hhv. -90 mV, 0 mV og +90 mV (jf. ionesammensetning ovenfor). Ettersom kalium er det eneste ion med et revers-potensial som er mer negativt enn hvilemembranpotensialet, må den observerte hyperpolarisering indusert av testforbindelsen forklares gjennom en økt kaliumkonduktans.
Énkanalforsøk
I stykker av lillehjernegranulcellemembran med inn-siden ut ble enkle BKCa-kanaler aktivert ved hjelp av f.eks. 5-trifluormetyl-1-(5-klor-2-hydroksyfenyl)-1,3-dihydro-2H-benzimidazol-2-on (3-10 uM), 5-trifluormetyl-1-(2-hydroksyfenyl)-l,3-dihydro-2H-benzimidazol-2-on (10-30 uM), 5-tri-fluormetyl-1-(5-fenyl-2-hydroksyfenyl)-1,3-dihydro-2H-benzimidazol-2-on (3-30 uM). Alle forbindelsene økte den åpne sannsynlighet for BKCa-kanalen med flere hundre prosent. Det ble ikke funnet noen effekt på den forsinkede likeretter-K<+->kanal eller på Cl~-kanalene, som også er til stede i stykkene.
BKCa-kanalene i granulceller er blitt undersøkt i symmetrisk 144 mM K<+>, og under disse betingelsene er den gjennomsnittlige konduktans 154 pS (76 pS med 4 mM ekstern K<+>). Charybdotoksin blokkerer kanalen i stykker med utsiden ut med det karakteristiske blokkerende mønster for stille perioder, avbrutt med perioder med lav eller normal aktivitet, hvorved identiteten til kanalen aktivert ved hjelp av forbindelsene ifølge oppfinnelsen bekreftes.
I dyrkede bovine aortaglattmuskelceller hvor BKCaer den overveiende K<*->kanal, aktiverte f.eks. 1,3-dihydro-l-(5-klor-2-hydroksyfenyl)-5,6-diklor-2H-benzimidazol-2-on (3-30 uM), 1,3-dihydro-l-(3-hydroksy-2-naftyl)-5-trifluormetyl-2H-benzimidazol-2-on (3-30 uM), 5-trifluormetyl-1-(5-klor-2-hydroksyfenyl)-l,3-dihydro-2H-benzimidazol-2-on (3-30 uM), 5-trifluormetyl-1,3-dihydro-l-(2-hydroksy-5-fenylfenyl)-2H-benzimidazol-2-on (3-30 uM), 1,3-dihydro-l-(3-nitro-5-klor-2-hydroksyfenyl)-5-trifluormetyl-6-nitro-2H-benzimidazol-2-on (1-3 uM) og 1,3-dihydro-l-(2-hydroksyfenyl)-5-trifluormetyl-2H-benzimidazol-2-tion (3-30 uM) BKCa-kanalen signifikant.
Likeledes, i dyrkede marsvintrakealglattmuskelceller hvor en 160-180 pS BKCa-kanal uttrykkes, aktiverte f.eks. 1,3-dihydro—l-(5-klor-2-hydroksyfenyl)-5-trifluormetyl-2H-benzimidazol-2-on BKCasterkt.
Farmasøytiske preparater
Forbindelsene fremstilt ifølge oppfinnelsen, sammen med en konvensjonell adjuvans, bærer eller fortynner, kan plasseres i form av farmasøytiske preparater og enhetsdoser derav, og kan i en slik form anvendes som faststoffer, slik som tabletter eller fylte kapsler, eller væsker, slik som opp-løsninger, suspensjoner, emulsjoner, eliksirer eller kapsler fylt med slike, alt for oral bruk, i form av suppositorier for rektal administrering, eller i form av sterile, injiserbare oppløsninger for parenteral (inkludert subkutan) bruk. Slike farmasøytiske preparater og enhetsdoseringsformer derav kan omfatte konvensjonelle bestanddeler i konvensjonelle mengde-forhold, med eller uten ytterligere aktive forbindelser eller prinsipper, og slike enhetsdoseformer kan inneholde enhver egnet effektiv mengde av den aktive bestanddel sammen med det påtenkte daglige doseringsområde som skal anvendes. Tabletter som inneholder 10 mg aktive bestanddeler eller, bredere, 0,1 til ett hundre (100) mg pr. tablett, er følgelig egnede repre-sentative enhetsdoseformer.
Behandlinqsmetode
Forbindelsene fremstilt ifølge oppfinnelsen er svært anvendbare ved behandlingen av sykdommer hos pattedyr på grunn av deres sterke kaliumkanalaktiveringsegenskaper. Disse egen-skapene gjør forbindelsene ifølge oppfinnelsen ekstremt anvendbare ved behandlingen av konvulsjoner, astma, hypertensjon, iskemi og andre sykdommer som er følsomme for kalium-kanalaktiveringsaktivitet. Forbindelsene fremstilt ifølge oppfinnelsen kan følgelig administreres til et individ, inkludert mennesket, som trenger behandling, lindring eller fjerning av en indikasjon forbundet med kaliumkanalene. Dette omfatter spesielt konvulsjoner og enhver form for epilepsi, astma, hypertensjon og iskemi.
Egnet doseområde er 0,1-1000 mg daglig, 10-500 mg daglig, og spesielt 30-100 mg daglig, som vanlig avhengig av den nøyaktige administråsjonsmåte, form som det administreres i, indikasjonen som administreringen er rettet mot, det involverte individ og kroppsvekten til det involverte individ, og videre preferansen og erfaringen til behandlende lege eller veterinær.
De følgende eksempler vil illustrere oppfinnelsen nærmere.
Eksempel 1
a) N-( 2- hvdroksvfenvl)- 2- nitroanilin
En oppløsning av 2-nitrofluorbenzen (2 g, 20 mmol),
2-aminofenol (2,2 g, 20 mol) og trietylamin (2,8 ml) i tetrahydrofuran ble omrørt i 16 timer ved 100 °C og så i 48 timer ved værelsestemperatur. Reaksjonsblandingen ble så helt over i en blanding av 50 ml vann og 50 ml heksan. Fasene ble sepa-rert, og vannfasen ble ekstrahert med eter. Den erholdte organiske oppløsning ble ekstrahert med 20 ml 2 N natrium-hydroksid. Vannfasen ble nøytralisert og surgjort med saltsyre. Utfellingen ble ekstrahert med eter som ble tørket med MgS04. Den organiske oppløsning ble inndampet, hvorved man fikk en orange olje som krystalliserte i løpet av et kort tidsrom. Utbytte: 0,6 g av tittelforbindelsen, sm.p. 132-134 °C. De følgende forbindelser ble fremstilt på en lignende måte.
N-(4-hydroksyfenyl)-2-nitroanilin, sm.p. olje ved værelsestemperatur, ved omsetning mellom 2-fluor-nitrobenzen og 4-aminofenol.
N-(3-hydroksyfenyl)-2-nitroanilin, sm.p. 128-129 °C, ved omsetning mellom 2-fluornitrobenzen og 3-aminofenol.
N-(2-hydroksyfenyl)-2-nitro-4,6-dikloranilin, sm.p. 182-184 °C, ved omsetning mellom 2,3,5-triklor-nitrobenzen og 2-aminofenol.
N-(2-hydroksyfenyl)-2-nitro-4-trifluormetylanilin, sm.p. olje ved værelsestemperatur, ved omsetning mellom 2-aminofenol og 2-klor-5-trifluormetylnitrobenzen.
N-(2-metoksy-5-klorfenyl)-2-nitroanilin, sm.p. 107-108 °C, ved omsetning mellom 2-fluornitrobenzen og 2-metoksy-5-kloranilin.
N-(2-metoksy-5-klorfenyl)-4-trifluormetyl-2-nitroanilin, sm.p. 133-136 °C, ved omsetning mellom 2-klor-5-trifluor-metylnitrobenzen og 2-metoksy-5-kloranilin.
N-(2-metoksy-5-klorfenyl)-2-nitro-4,6-dikloranilin, sm.p. 60-61 °C, ved omsetning mellom 2,3,5-triklornitrobenzen
og 2-metoksy-5-kloranilin.
N-(2-metoksyfenyl)-2-nitroanilin, sm.p. 80-82 "C, ved omsetning mellom 2-metoksyanilin og 2-fluornitrobenzen.
N-2-nitrofenyl-o-fenylendiamin, sm.p. 95-98 °C, ved omsetning mellom o-fenylendiamin og 2-fluornitrobenzen.
b) N-( 2- metoksv- 4- fenylfenyl)- 2- nitroanilin
Til en omrørt oppløsning av 2-fluornitrobenzen
(10 mmol, 1 ml) og 2-metoksy-4-fenylanilin (10 mmol, 2,0 g) i tetrahydrofuran (50 ml) ble det tilsatt natriumhydrid (10 mmol, 380 mg, 60 % i mineralolje). Reaksjonsblandingen ble omrørt ved reflukstemperatur i 8 timer og ble så inndampet under vakuum. Resten ble fordelt mellom eter (100 ml) og 1 N saltsyre (50 ml). Den organiske fase ble tørket og inndampet under vakuum. Resten ble ekstrahert flere ganger ved værelsestemperatur med petroleter for å fjerne gjenværende 2-fluor-nitrobenzen. Denne behandlingen etterlot tittelforbindelsen som en mørkegul olje.
De følgende forbindelser ble fremstilt på en lignende måte.
N-(2-metoksyfenyl)-2-nitro-4-trifluormetylanilin, sm.p. 112-114 °C, ved omsetning mellom o-anisidin og 4-klor-3-nitrobenzotrifluorid.
N-(2-metoksy-5-trifluormetylfenyl)-2-nitro-4-tri-fluormetylanilin, sm.p. 90-95 °C, ved omsetning mellom 3-amino-4-metoksybenzotrifluorid og 4-klor-3-nitrobenzo-trifluorid.
N-(2-metoksyfenyl)-2-nitro-4-dimetylsulfamoylanilin, sm.p. 136-138 °C, ved omsetning mellom 2-metoksyanilin og 5-dimetylsulfamoyl-2-klor-nitrobenzen.
N-(2-metoksyfenyl)-2-nitro-4,5-dikloranilin, sm.p. 145-148 °C, ved omsetning mellom 2-metoksyanilin og 2-fluor-4,5-diklornitrobenzen.
N-(3-hydroksy-2-naftyl)-2-nitro-4-trifluormetyl-anilin, ved omsetning mellom 3-hydroksy-2-aminonaftalen og 2-klor-5-trifluormetylnitrobenzen.
N-(2-hydroksy-l-naftyl)-2-nitro-4-trifluormetyl-anilin, sm.p. 187-190 °C, ved omsetning mellom 2-klor-5-tri-fluormetylnitrobenzen og 2-hydroksy-l-aminonaftalen.
N-(5-klor-2-metoksyfenyl)-2-nitro-4-metoksyanilin, sm.p. 112-114 °C, ved omsetning mellom 2-metoksy-5-kloranilin og 2-nitro-4-metoksyklorbenzen.
N-(2-metoksyfenyl)-2-nitro-4-trifluormetyl-5-klor-anilin, sm.p. 142-145 °C, ved omsetning mellom 2-metoksyanilin og 2-klor-4-klor-5-trifluormetylnitrobenzen.
c) 4, 5- diklor- 2- nitro- N-( 2- hydroksvfenyl)- anilin, sm. p. 193- 194 °C
En oppløsning av 4,5-diklor-2-fluornitrobenzen
(2,1 g, 10 mmol) og o-aminofenol (2,1 g, 19 mmol) i en blanding av dimetylformamid (25 ml) og pyridin ble omrørt over natten ved 60 °C. Oppløsningsmidlene ble inndampet, og resten ble fordelt mellom eter (100 ml) og 1 N HC1 (100 ml). Den organiske fase ble vasket med vann, tørket og inndampet. Dette gav en krystallinsk rest av det urene produkt som ble rekrystallisert i metanol, sm.p. 193-194 °C.
På en lignende måte ble den følgende forbindelse fremstilt: 2-nitro-4-dimetylsulfamoyl-N- (5-klor-2-hydroksyfenyl)-anilin, olje ved værelsestemperatur, ved å omsette 2-klor-5-dimetylsulfamoylnitrobenzen og 2-amino-4-klorfenol.
Eksempel 2
a) 2- benzoksazolinon
1,09 g 2-aminofenol ble oppløst i tørt tetrahydrofuran (25 ml) og trietylamin (3,09 g). Så ble fosgen (5,5 ml) dråpevis tilsatt, og den resulterende blanding ble kokt under tilbakeløpskjøling i 4 timer og hensatt over natten ved værelsestemperatur. Reaksjonsblandingen ble filtrert og filtratet inndampet. Utbytte: 0,75 g tittelforbindelse, sm.p. 137-
138 °C.
De følgende forbindelser ble fremstilt på en lignende måte.
5-klor-2-benzoksazolinon, sm.p. 190-192 °C. 5-nitro-2-benzoksazolinon, sm.p. 207-210 °C.
b) 5- amino- 2- benzoksazolinon. sm. p. 205- 210 °C Forbindelsen ble erholdt etter reduksjon av 5-nitro- 2-benzoksazolinon under standardbetingelser og anvendelse av 5 % Pd/C som katalysator og etanol som oppløsningsmiddel.
c) 5- acetamino- 2- benzoksazolinon
Til en omrørt suspensjon av 5-amino-2-benzoksazolinon
(3,39 g, 22,5 mmol) og trietylamin (3,17 ml, 22,5 mmol) i tørt tetrahydrofuran (50 ml) ble det dråpevis tilsatt acetylklorid (1,6 ml, 22,6 mmol). Reaksjonsblandingen ble omrørt i ytterligere 2 timer ved værelsestemperatur, hvoretter utfellingen ble frafiltrert. Krystallene ble behandlet med 100 ml vann, frafiltrert og vasket med vann. Denne behandlingen etterlot produktet som hvite krystaller, sm.p. 295-300 °C.
d) N-( 2- nitrofenyl)- 2- benzoksazolinon
0,7 g 2-benzoksazolinon ble oppløst i 5 ml dimetylformamid, og 0,52 ml 2-fluornitrobenzen ble tilsatt. Så ble 0,27 g natriumhydrid (60 % oljesuspensjon) tilsatt. Blandingen ble omrørt ved værelsestemperatur inntil gassutviklingen stanset og deretter ved 80 "Ci 1 time. Reaksjonsblandingen ble avkjølt og helt over i 25 ml vann og 1 ml iseddik. Utfellingen ble frafiltrert og vasket med vann og dietyleter. Utbytte: 1,0 g av tittelforbindelsen, sm.p. 153-155 °C.
De følgende forbindelser ble fremstilt på en lignende måte.
N-(2-nitro-4-trifluormetylfenyl) -5-klor-2-benzoksazolinon, sm.p. 177-179 °C, ved omsetning mellom 2-klor-5-tri-fluornitrobenzen og 5-klor-2-benzoksazolinon.
5-acetamino-N-(2-nitro-4-trifluormetylfenyl)-2-benzoksazolinon, sm.p. 215-217 °C, ved omsetning mellom 5-acetamino-2-benzoksazolinon og 4-klor-3-nitrobenzotrifluorid.
N-(2-nitrofenyl)-2-benzotiazolinon, sm.p. 92-95 °C, ved omsetning mellom 2-fluornitrobenzen og 2-benzotiazolinon.
N-(2-nitro-4-trifluorfenyl)-5-klor-2-benzoksazolinon ved omsetning mellom 2,4-difluornitrobenzen og 5-klor-2-benzoksazolinon. Produktet ble brukt uten ytterligere rensing.
N-(2-nitro-4-trifluormetylfenyl)-5-fenyl-o-anisidin, ved omsetning mellom 2-fluor-5-trifluormetylnitrobenzen og 5-fenyl-o-anisidin. Produktet ble brukt uten ytterligere rensing.
N-(2-nitro-4-trifluormetyl-5-klorfenyl)-5-fenyl-o-anisidin, ved omsetning mellom 2-klor-4-klor-5-trifluormetyl-nitrobenzen og 5-fenyl-o-anisidin. Produktet ble brukt uten ytterligere rensing.
N-(2-nitrofenyl)-3,5-diklor-2-metoksyanilin, ved omsetning mellom 2-fluornitrobenzen og 3,5-diklor-o-anisidin, brune krystaller, sm.p. 104-105 °C.
N-(2-nitro-4-benzoylfenyl)-5-klor-2-benzoksazolinon, ved omsetning mellom 4-klor-3-nitrobenzofenon og 5-klor-2-benzoksazolinon. Produktet ble brukt uten ytterligere rensing.
N-(2,4-dinitrofenyl)-5-klor-2-benzoksazolinon, ved omsetning mellom 2,4-dinitroklorbenzen og 5-klor-2-benzoksazolinon. Produktet ble brukt uten ytterligere rensing.
e) N-( 2- hydroksyfenyl)- 2- nitroanilin
0,23 g N-(2-nitrofenyl)-2-benzoksazolinon ble varmet
opp ved 70 °C i 1 time i en blanding av 2 ml 4 N natrium-hydroksid og 5 ml 96 % etanol. Reaksjonsblandingen ble så av-kjølt og nøytralisert med saltsyre. Den røde utfelling ble isolert ved filtrering eller ekstraksjon med dietyleter, etterfulgt av inndamping. Utbytte: 180 mg tittelforbindelse, sm.p. 133-135 °C.
De følgende forbindelser ble fremstilt på en lignende måte.
2-nitro-N-(5-klor-2-hydroksyfenyl)-4-trifluormetyl-anilin, sm.p. 67-70 °C, fra N-(2-nitro-4-trifluormetylfenyl)-5-acetamido-2-benzoksazolinon.
N-(2-merkaptofenyl)-2-nitroanilin, sm.p. 105-110 °C, fra N-(2-nitrofenyl)-2-benzoksazolinon.
N-(5-klor-2-hydroksyfenyl)-4-fluor-2-nitroanilin fra N-(2-nitro-4-fluorfenyl)-5-klor-2-benzoksazolinon. Produktet ble brukt uten ytterligere rensing.
N-(5-klor-2-hydroksyfenyl)-4-benzoyl-2-nitroanilin fra N-(2-nitro-4-benzoylfenyl)-5-klor-2-benzoksazolinon. Produktet ble brukt uten ytterligere rensing.
N-(5-klor-2-hydroksyfenyl)-2,4-dinitroanilin fra N-(2,4-dinitrofenyl)-5-klor-2-benzoksazolinon. Produktet ble brukt uten ytterligere rensing.
Eksempel 3
2- amino- N- ( 5- klor- 2- hydroksyfenyl) - 4- nitroanilin- hydroklorid
En blanding av N-(5-klor-2-hydroksyfenyl)-2,4-di-nitroanilin (7,9 g, 25,6 mmol), ammoniumklorid (5,2 g, 98 mmol) og natriumsulfid-nonahydrat (23,5 g, 98 mmol) i metanol (350 ml) ble kokt under tilbakeløpskjøling i 1 time. Reaksjonsblandingen ble filtrert etter avkjøling til værelsestemperatur, og filtratet ble oppkonsentrert under vakuum. Remanencen ble oppløst i etanol, surgjort med konsentrert saltsyre, og blandingen ble oppkonsentrert under vakuum. Til sist ble det urene produkt triturert med dietyleter, hvorved man fikk tittelforbindelsen som rødbrune krystaller. Produktet ble brukt uten ytterligere rensing.
Eksempel 4
N- ( 2- hydroksyfenyl)- 2- fenylendiamin- hydroklorid
1,5 g N-(2-hydroksyfenyl)-2-nitroanilin ble hydro-genert under standardbetingelser (1 atm.) med 0,5 g 5 % Pd/C som katalysator, 100 ml etanol som oppløsningsmiddel og 0,6 ml konsentrert saltsyre, hvorved man fikk tittelforbindelsen som en olje som ble krystallisert i løpet av et kort tidsrom. Utbytte: 1,1 g grønnaktige krystaller av tittelforbindelsen, sm.p. 220-223 °C.
De følgende forbindelser ble fremstilt på en lignende måte. I tilfeller hvor de frie basene ble isolert, ble tilset-ning av saltsyre unngått under hydrogeneringen.
N-(2-metoksyfenyl)-2-amino-4-trifluoranilin, hydroklorid, sm.p. 258-260 °C.
2-amino-N-(2-hydroksyfenyl)-4-trifluormetylanilin, sm.p. 108-109 °C.
2-amino-N-(2-metoksy-5-klorfenyl)-anilin, sm.p. olje ved værelsestemperatur. Raney-nikkel ble brukt som katalysator.
2-amino-4-trifluormetyl-N-(2-metoksy-5-klorfenyl )-anilin, sm.p. olje ved værelsestemperatur. Raney-nikkel ble brukt som katalysator.
2-amino-N-(2-metoksyfenyl)-anilin, sm.p. olje ved værelsestemperatur.
2-amino-4, 6-diklor-N-( 2-metoksy-5-klorf enyl)-anilin,
sm.p. olje ved værelsestemperatur. Raney-nikkel ble brukt som katalysator.
N-(4-hydroksyfenyl)-2-aminoanilin, sm.p. olje ved værelsestemperatur.
N-(3-hydroksyfenyl)-2-aminoanilin, sm.p. olje ved værelsestemperatur.
2-amino-N-(5-klor-2-hydroksyfenyl)-4-trifluormetyl-anilin- hydroklor id, sm.p. 192-195 °C. Raney-nikkel ble brukt som katalysator.
N-(2-metoksy-5-fenylfenyl)-2-aminoanilin, hydroklorid, olje ved værelsestemperatur.
N-(2-hydroksyfenyl)-4,5-diklor-2-aminoanilin, sm.p. 132-133 °C. Raney-nikkel ble brukt som katalysator.
N-(5-acetamino-2-hydroksyfenyl)-4-trifluormetyl-2-aminoanilin, sm.p. 185-190 °C.
N-(2-merkaptofenyl)-2-aminoanilin, olje ved værelsestemperatur .
2-(2-amino-4-trif luormetylf enyl )amino-3-hydroksy-pyridin, sm.p. 160-165 °C.
N-(5-klor-2-metoksyfenyl)-2-aminoanilin. Raney-nikkel ble brukt som katalysator, olje ved værelsestemperatur.
N-(5-klor-2-metylfenyl)-2-amino-4-metoksyanilin, sm.p. olje ved værelsestemperatur. Raney-nikkel ble brukt som katalysator.
N-(5-klor-2-hydroksyfenyl)-2-amino-4-dimetylsul-famoylanilin, sm.p. 207-209 °C. Raney-nikkel ble brukt som katalysator.
N-(2-metoksyfenyl)-2-amino-4-dimetylsulfamoylanilin, sm.p. 162-164 °C. 5 % Pd/C ble brukt som katalysator.
N-(2-metoksyfenyl)-2-amino-4-trifluormetyl-5-klor-anilin, sm.p. 188-190 °C. Raney-nikkel ble brukt som katalysator.
N-(2-metoksyfenyl)-2-amino-4, 5-dikloranilin, hydroklorid, sm.p. 176-178 °C. Raney-nikkel ble brukt som katalysator.
N-(3-hydroksy-2-naftyl)-2-amino-4-trifluormetyl-anilin, sm.p. 280 °C (dekomp.). 5 % Pd/C ble brukt som katalysator .
N-(2-hydroksy-l-naftyl)-2-amino-4-trifluormetyl- anilin, sm.p. 154-157 °C. 5 % Pd/C ble brukt som katalysator.
2-amino-N-(5-klor-2-hydroksyfenyl)-4-fluoranilin-hydroklorid. Raney-nikkel ble brukt som katalysator. Produktet ble brukt uten ytterligere rensing.
2-amino-N-(5-fenyl-2-metoksyfenyl)-4-trifluormetyl-anilin. 5 % Pd/C ble brukt som katalysator. Produktet ble brukt uten ytterligere rensing.
2-amino-N- ( 5-f enyl-2-metoksyf enyl )-5-klor-4-trif luor-metylanilin. Raney-nikkel ble brukt som katalysator. Produktet ble brukt uten ytterligere rensing.
2-amino-N-(3,5-diklor-2-metoksyfenyl)-anilin, hydroklorid. Raney-nikkel ble brukt som katalysator. Grå krystaller, sm.p. 191-192 °C.
2-amino-N- ( 5-klor-2-hydroksyf enyl )-4-benzoylanilin. Raney-nikkel ble brukt som katalysator. Produktet ble brukt uten ytterligere rensing.
Eksempel 5
1. 3- dihvdro- l-( 2- hydroksyfenyl)- 2H- benzimidazol- 2- on
2-amino-N-(2-hydroksyfenyl)-anilin (1 g, 4,2 mmol) og 2,1 ml (15 mmol) trietylamin ble oppløst i tørt tetrahydrofuran (50 ml). Så ble 2,5 ml (5 mM i toluen) fosgen dråpevis tilsatt, hvoretter blandingen ble kokt under tilbakeløps-kjøling i 2 timer. Den resulterende blanding ble inndampet under vakuum, og resten ble fordelt mellom vann og etylacetat. Den organiske fase ble ekstrahert med en 1 N natriumhydroksid-oppløsning (20 ml). Vannfasen ble nøytralisert, hvoretter det urene produkt ble isolert ved filtrering. Produktet ble rekrystallisert fra 15 ml isopropanol. Utbytte: 0,5 g av tittelforbindelsen, sm.p. 216-217 mg.
På en lignende måte ble de følgende forbindelser syntetisert.
5-trif luormetyl-1,3-dihydro-l- (2-hydroksyfenyl)-2H-benzimidazol-2-on, sm.p. 154-155 °C.
l-(5-klor-2-hydroksyfenyl)-5-trifluormetyl-1,3-dihydro-2H-benzimidazol-2-on, sm.p. 223-224 °C.
1,3-dihydro-l-(3-hydroksyf enyl )-2H-benzimidazol-2-on, sm.p. 248-250 °C.
1,3-dihydro-l- (2-metoksyf enyl) -2H-benzimidazol-2-on, sm.p. 184-186 °C.
1-(5-klor-2-metoksyfenyl)-5-trifluormetyl-1,3-dihydro-2H-benzimidazol-2-on, sm.p. 135-138 °C. 1- ( 5-klor-2-metoksyf enyl) -1,3-dihydro-2H-benzimidazol-2-on, sm.p. 168-170 °C. l-(5-klor-2-metoksyfenyl)-5, 7-diklor-l,3-dihydro-2H-benzimidazol-2-on, sm.p. 218-220 °C.
1,3-dihydro-l - (2-metoksyf enyl) - 5-trif luormetyl-2H-benzimidazol-2-on, sm.p. 223-226 °C.
1- ( 5-acetamino-2-hydroksyfenyl )-l, 3-dihydro-5-tri-fluormetyl-2H-benzimidazol-2-on, sm.p. 180-185 °C.
1,3-dihydro-l- (2-merkaptof enyl )-2H-benzimidazol-2-on, sm.p. 190-195 °C.
1,3-dihydro-l- (2-metoksy-5-f enylf enyl) -2H-benzimidazol-2-on, sm.p.: omordnes ved 115 °C, smelter ved 185 °C.
5, 6-diklor-l, 3-dihydro-l - (2-hydroksyfenyl) -2H-benzimidazol-2-on, sm.p. 282-285 °C.
1,3-dihydro-( 5-klor-2-metoksyf enyl )-5-metoksy-2H-benzimidazol-2-on, sm.p. 199-202 °C.
1,3-dihydro-l - (5-klor-2-hydroksyf enyl) -5-dimetyl-sulfamoyl-2H-benzimidazol-2-on, sm.p. 100-105 °C (dekomp.).
1,3-dihydro-l-(2-metoksyf enyl )-5-dimetylsulf amoyl-2H-benzimidazol-2-on, sm.p. 200-203 °C.
1,3-dihydro-l- (2-metoksyf enyl) -5-trif luormetyl-6-klor-2H-benzimidazol-2-on, sm.p. 289-291 °C.
1,3-dihydro-l-(2-metoksyf enyl)-5, 6-diklor-2H-benzimidazol-2-on, sm.p. 262-264 °C.
1,3-dihydro-l-(3-hydroksy-2-naf tyl)-5-trif luormetyl-2H-benzimidazol-2-on, sm.p. 290-293 °C.
1,3-dihydro-l- (2-hydroksy-l-naf tyl) -5-trif luormetyl-2H-imidazol-2-on, sm.p. 223-228 °C.
Eksempel 6
1. 3- dihydro- l-( 5- klor- 2- hydroksyfenyl)- 5- trifluormetvl- 2H-benzimidazol- 2- tion
2- amino-N-( 5-klor-2-hydroksyf enyl )-4-trif luormetyl-anilin (0,51 g, 1,5 mmol), trietylamin (0,28 ml, 2 mmol) og tiokarbonyldiimidazol (0,36 g, 2 mmol) ble oppløst i tørt
tetrahydrofuran (15 ml), og blandingen ble omrørt i 30 minutter. Reaksjonsblandingen ble inndampet under vakuum. Resten ble på nytt oppløst i etanol og ble tilsatt vann og lett-bensin. Utfellingen ble isolert og renset ved kolonnekromato-grafi på silikagel med eter/lettbensin (2:1) som elueringsmiddel. Utbyttet av tittelforbindelsen var 200 mg, sm.p. 248-250 °C.
De følgende forbindelser ble fremstilt på en lignende måte.
1,3-dihydro-l-(5-klor-2-metoksyfenyl)-5-trifluor-metyl-2H-benzimidazol-2-tion, sm.p. 168-170 °C.
1,3-dihydro-l-(3-hydroksy-2-naftyl)-5-trifluormetyl-2H-benzimidazol-2-tion, sm.p. 216-220 °C.
Eksempel 7
1. 3- dihydro- l-( 5- klor- 2- hydroksyfenyl)- 5- fluor- 2H- benzimidazol- 2- on
En blanding av 2-amino-N-(5-klor-2-hydroksyfenyl)-5-fluoranilin-hydroklorid (14 mmol) og urea (1,2 g, 20 mmol) i 50 ml absolutt dimetyletylenglykol ble omrørt ved 170 °C i
4 timer. Blandingen ble etter avkjøling til omgivelsestempera-tur helt over i 200 ml isvann, og et krystallinsk produkt ble isolert ved filtrering. Det urene produkt ble behandlet med aktivkull i etanol og rekrystallisert fra toluen, hvorved man fikk tittelforbindelsen som hvite krystaller, sm.p. 256-
260 °C.
De følgende forbindelser ble fremstilt på en lignende måte.
1,3-dihydro-l-(5-fenyl-2-metoksyfenyl)-5-trifluor-metyl-2H-benzimidazol-2-on, hvite krystaller etter kolonne-kromatografi under anvendelse av metylenklorid:metanol (9:1) som elueringsmiddel, sm.p. 258-259 °C.
1,3-dihydro-l-(5-fenyl-2-metoksyfenyl)-5-trifluor-metyl-6-klor-2H-benzimidazol-2-on, hvite krystaller, sm.p. 295-298 °C.
1, 3-dihydro-l- ( 5-klor-2-hydroksyfenyl) -5-benzoyl-2H-benzimidazol-2-on, hvite krystaller, sm.p. 279-280 °C.
Eksempel 8
2- etoksvkarbonylamino- N- ( 3, 5- diklor- 2- metoksyf enyl) - anilin
En blanding av 2-amino-N-(3,5-diklor-2-metoksyfenyl)-anilin (2,23 g, 6,3 mmol) og trietylamin (1,74 ml, 12,5 mmol) i absolutt metylenklorid (40 ml) ble ved værelsestemperatur
tilsatt etylklorformiat (1,2 ml, 13,8 mmol), og blandingen ble kokt under tilbakeløpskjøling over natten. Reaksjonsblandingen fikk nå værelsestemperatur og ble fortynnet med 40 ml vann, og vannfasen ble ekstrahert to ganger med dietyleter. De kombi-nerte organiske faser ble tørket og oppkonsentrert under vakuum, hvorved man fikk en rødbrun olje som ble brukt uten ytterligere rensing.
Den følgende forbindelse ble fremstilt på en lignende måte.
2-etoksykarbonylamino-N-( 5-klor-2-hydroksyfenyl )-4-nitroanilin, brune krystaller. Produktet ble brukt uten ytterligere rensing.
Eksempel 9
a) N. N'- di-( 2- metoksyfenyl)- urea
En oppløsning av o-anisidin (12,3 g, 100 mmol) og
trietylamin (11 ml, 80 mmol) i absolutt toluen (100 ml) ble under omrøring på et isbad tilsatt fosgen (20,7 ml, 1,93 M sol i toluen, 40 mmol), og blandingen ble omrørt ved 90 °C i 3 timer. Reaksjonsblandingen ble etter avkjøling til omgivel-sestemperatur helt over i vann (100 ml), og tittelforbindelsen ble samlet opp ved filtrering og brukt uten ytterligere rensing.
b) 1. 3- dihydro- l- ( 2- metoksyf enyl) - 4- metoksy- 2H- benzimidazol- 2- on
En blanding av N,N'-di-(2-metoksyfenyl)-urea (6,81 g, 25 mmol) og tetra-n-butyl-ammoniumbromid (0,4 g, 1,3 mmol) i metylenklorid i metanol (1:1, 200 ml) ble ved værelsestemperatur under kraftig omrøring tilsatt en oppløsning av natrium-hydroksid (2 g i 10 ml vann), etterfulgt av en oppløsning av natriumhypokloritt (55 ml, Aldrich). Blandingen ble omrørt i 4 timer, og 30 ml vann ble tilsatt. Den organiske fase ble vasket med 10 ml 1 M hydrogenkloridoppløsning, tørket og opp konsentrert under vakuum. Etter triturering med dietyleter utskiltes mørkegrå krystaller. Det urene produkt ble rekrystallisert to ganger, først fra etanol og så fra etylacetat, hvorved man fikk tittelforbindelsen som hvite krystaller, sm.p. 246-247 °C.
Claims (4)
1. Analogifremgangsmåte for fremstilling av en terapeutisk aktiv forbindelse med den generelle formel I
hvor
R <1> er hydrogen, NH2 eller C^ -alkyl som kan være for
grenet ,
X er 0 eller S,
Y er 0 eller S,
R<4> ,R<5> ,R<6> ogR<7> er uavhengig av hverandre hydrogen, halogen,
CF3 , N02 , NH2 , OH, C^ -alkoksy, C(=0)-fenyl eller S02 -NR <1> R <11> , hvor R <1> og R <11> uavhengig av hverandre er hydrogen eller C^ -alkyl,
R 11 er hydrogen, halogen, N02 eller S02 NR'R'', hvor R' og R'' uavhengig av hverandre er hydrogen eller C^-alkyl,
R 13 er hydrogen, halogen, f enyl, CF3 eller N02 ,
R<12> er hydrogen eller danner sammen med R <13> en C4 _7 - <k> arbo-
syklisk ring som kan være aromatisk eller delvis mettet,
R<14> er hydrogen eller danner sammen med R <13> en C4 .7 - <k> arbo-
syklisk ring som kan være aromatisk eller delvis mettet,
karakterisert ved at
a) for fremstilling av en forbindelse med formel (I)
hvor X = 0, omsettes en forbindelse med formel
hvorR<1> ,R 4,R 5,R<6> ,R<7> , Y, R <1> 1,R1 2,R 13 og R <14> har de ovenfor angitte betydninger, med fosgen eller urea, og b) for fremstilling av en forbindelse med formel (I)
hvor X = S, omsettes en forbindelse med formel
hvorR<1> ,R 4,R 5, R <6> , R <7> , Y, R <1> 1,R 12,R 13 og R <14> har de ovenfor angitte betydninger, med tiokarbonyldiimidazol.
2. Fremgangsmåte ifølge krav 1 for fremstilling av 5-trifluormetyl-2,3-dihydro-l-( 5-klor-2-hydroksyfenyl)-1H-2- okso-benzimidazol,
karakterisert ved at det anvendes til-svarende utgangsforbindelser.
3. Fremgangsmåte ifølge krav 1 for fremstilling av 5-trifluormetyl-2,3-dihydro-l-(5-fenyl-2-hydroksyfenyl)-lH-2-okso-benzimidazol,
karakterisert ved at det anvendes til-svarende utgangsforbindelser.
4. Fremgangsmåte ifølge krav 1 for fremstilling av 5-trifluormetyl-6-nitro-2,3-dihydro-l-(3-nitro-5-klor-2-hydroksyfenyl)-lH-2-okso-benzimidazol,
karakterisert ved at det anvendes til-svarende utgangs forbindelser.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58690090A | 1990-09-24 | 1990-09-24 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO913728D0 NO913728D0 (no) | 1991-09-23 |
| NO913728L NO913728L (no) | 1992-03-25 |
| NO180795B true NO180795B (no) | 1997-03-17 |
| NO180795C NO180795C (no) | 1997-06-25 |
Family
ID=24347548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO913728A NO180795C (no) | 1990-09-24 | 1991-09-23 | Analogifremgangsmåte for fremstilling av terapeutisk aktive benzimidazolderivater |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0477819B1 (no) |
| JP (1) | JP3203017B2 (no) |
| KR (1) | KR100195770B1 (no) |
| AT (1) | ATE119887T1 (no) |
| AU (1) | AU635440B2 (no) |
| CA (1) | CA2052041C (no) |
| DE (1) | DE69108156T2 (no) |
| DK (1) | DK0477819T3 (no) |
| ES (1) | ES2072504T3 (no) |
| FI (1) | FI103408B (no) |
| IE (1) | IE67133B1 (no) |
| NO (1) | NO180795C (no) |
| NZ (1) | NZ239540A (no) |
| PT (1) | PT99032B (no) |
| ZA (1) | ZA916805B (no) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0520200T3 (da) * | 1991-06-24 | 1998-09-23 | Neurosearch As | Imadazol-forbindelser, deres fremstilling og anvendelse |
| US5158969A (en) * | 1991-08-21 | 1992-10-27 | Neurosearch A/S | Indole derivatives as potassium channel blockers |
| US5232899A (en) * | 1992-06-08 | 1993-08-03 | Imperial Chemical Industries Plc | Benzoxazolinones and their use as herbicides |
| AU5433594A (en) * | 1992-11-19 | 1994-06-08 | Dainippon Pharmaceutical Co. Ltd. | 3,4-dihydro-1-(2-hydroxyphenyl)-2(1h)-quinoxalinone derivative and related compound |
| DK154092D0 (da) * | 1992-12-23 | 1992-12-23 | Neurosearch As | Imidazolforbindelser, deres fremstilling og anvendelse |
| DK28893D0 (da) * | 1993-03-15 | 1993-03-15 | Neurosearch As | Benzimidazole derivater, deres fremstilling og anvendelse |
| DK41193D0 (da) * | 1993-04-07 | 1993-04-07 | Neurosearch As | Ionkanalaabnere |
| US5637470A (en) * | 1994-05-13 | 1997-06-10 | Merck & Co., Inc. | Screening array using cells expressing recombinant α and β subunits of the mammalian large-conductance (maxi-K) potassium channel |
| FR2722190B1 (fr) * | 1994-07-05 | 1996-10-04 | Sanofi Sa | Derives de 1-benzyl-1,3-dihydro-2h-benzimidazol-2-one, leur preparation, les compositions pharmaceutique en contenant |
| US5565483A (en) * | 1995-06-07 | 1996-10-15 | Bristol-Myers Squibb Company | 3-substituted oxindole derivatives as potassium channel modulators |
| TW504504B (en) * | 1996-11-26 | 2002-10-01 | Bristol Myers Squibb Co | 4-aryl-3-hydroxyquinolin-2-one derivatives as ion channel modulators |
| US5893085A (en) * | 1997-06-10 | 1999-04-06 | Phillips; Ronald W. | Dynamic fuzzy logic process for identifying objects in three-dimensional data |
| CA2301549A1 (en) * | 1997-08-28 | 1999-03-04 | Piyasena Hewawasam | 4-aryl-3-aminoquinoline-2-one derivatives as potassium channel modulators |
| EP1144387A1 (en) * | 1998-12-04 | 2001-10-17 | Neurosearch A/S | New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents |
| PT1133474E (pt) * | 1998-12-04 | 2007-04-30 | Bristol Myers Squibb Co | Derivados da 4-arilquinolin-2-ona substituidos em 3 posições utilizados como moduladores do canal de potássio. |
| EP1519923A1 (en) * | 2002-06-26 | 2005-04-06 | Poseidon Pharmaceuticals A/S | Novel benzimidazol-2-one derivatives and their use |
| WO2004064835A1 (en) * | 2003-01-17 | 2004-08-05 | Neurosearch A/S | Use of ion channel modulating agents for treating pain |
| ES2222831B2 (es) * | 2003-07-30 | 2006-02-16 | Laboratorios Del Dr. Esteve, S.A. | Combinacion de principio activo que comprende un compuesto 2,5-dihidroxibencenosulfonico y un modulador de los canales de k+. |
| PE20060572A1 (es) * | 2004-07-27 | 2006-06-27 | Novartis Ag | Compuestos de benzoimidazolona como inhibidores de hsp90 |
| CA2680769C (en) * | 2007-04-18 | 2015-10-13 | Kissei Pharmaceutical Co., Ltd. | Nitrogenated fused ring derivative, pharmaceutical composition comprising the same, and use of the same for medical purposes |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH460028A (de) * | 1965-01-22 | 1968-07-31 | Wander Ag Dr A | Verfahren zur Herstellung von Benzimidazolonderivaten |
| FR1561830A (no) * | 1968-05-08 | 1969-03-28 | ||
| GB1408408A (en) * | 1971-11-24 | 1975-10-01 | Beecham Group Ltd | Benzimidazole derivatives |
| GB1476949A (en) * | 1974-11-20 | 1977-06-16 | Wyeth John & Brother Ltd | Imidazo-1,2-a-benzimidazole and pyrimido-1,2-a-benzimidazole derivatives their preparation and their pharmaceutical compositions |
| CH622009A5 (no) * | 1976-06-11 | 1981-03-13 | Ciba Geigy Ag | |
| DE3042481A1 (de) * | 1980-11-11 | 1982-06-16 | A. Nattermann & Cie GmbH, 5000 Köln | (omega)-(2-oxo-benzazolinyl)-alkansaeure-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
| EG17993A (en) * | 1986-02-03 | 1991-08-30 | Janssen Pharmaceutica Nv | Anti-histaminic compositions containing n-heterocyclyl-4-piperidinanines |
-
1991
- 1991-08-26 NZ NZ239540A patent/NZ239540A/en not_active IP Right Cessation
- 1991-08-28 AU AU82767/91A patent/AU635440B2/en not_active Ceased
- 1991-08-28 ZA ZA916805A patent/ZA916805B/xx unknown
- 1991-09-11 FI FI914275A patent/FI103408B/fi not_active IP Right Cessation
- 1991-09-11 IE IE319791A patent/IE67133B1/en not_active IP Right Cessation
- 1991-09-20 JP JP24194691A patent/JP3203017B2/ja not_active Expired - Fee Related
- 1991-09-20 KR KR1019910016522A patent/KR100195770B1/ko not_active IP Right Cessation
- 1991-09-23 CA CA002052041A patent/CA2052041C/en not_active Expired - Fee Related
- 1991-09-23 DE DE69108156T patent/DE69108156T2/de not_active Expired - Fee Related
- 1991-09-23 AT AT91116148T patent/ATE119887T1/de not_active IP Right Cessation
- 1991-09-23 NO NO913728A patent/NO180795C/no unknown
- 1991-09-23 EP EP91116148A patent/EP0477819B1/en not_active Expired - Lifetime
- 1991-09-23 ES ES91116148T patent/ES2072504T3/es not_active Expired - Lifetime
- 1991-09-23 DK DK91116148.7T patent/DK0477819T3/da active
- 1991-09-24 PT PT99032A patent/PT99032B/pt not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES2072504T3 (es) | 1995-07-16 |
| EP0477819A3 (en) | 1992-05-20 |
| EP0477819B1 (en) | 1995-03-15 |
| EP0477819A2 (en) | 1992-04-01 |
| IE913197A1 (en) | 1992-02-25 |
| FI914275A (fi) | 1992-03-25 |
| FI914275A0 (fi) | 1991-09-11 |
| JPH04305568A (ja) | 1992-10-28 |
| NZ239540A (en) | 1993-11-25 |
| NO913728D0 (no) | 1991-09-23 |
| PT99032A (pt) | 1993-11-30 |
| JP3203017B2 (ja) | 2001-08-27 |
| ZA916805B (en) | 1992-05-27 |
| IE67133B1 (en) | 1996-03-06 |
| AU8276791A (en) | 1992-03-26 |
| KR920006327A (ko) | 1992-04-27 |
| NO913728L (no) | 1992-03-25 |
| FI103408B1 (fi) | 1999-06-30 |
| KR100195770B1 (ko) | 1999-06-15 |
| DE69108156T2 (de) | 1995-07-06 |
| CA2052041C (en) | 2002-08-20 |
| FI103408B (fi) | 1999-06-30 |
| AU635440B2 (en) | 1993-03-18 |
| ATE119887T1 (de) | 1995-04-15 |
| CA2052041A1 (en) | 1992-03-25 |
| DE69108156D1 (de) | 1995-04-20 |
| PT99032B (pt) | 1999-02-26 |
| DK0477819T3 (da) | 1995-07-17 |
| NO180795C (no) | 1997-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO180795B (no) | Analogifremgangsmåte for fremstilling av terapeutisk aktive benzimidazolderivater | |
| US5200422A (en) | Benzimidazole derivatives, their preparation and use | |
| US5166170A (en) | 2-(aminoaryl) indoles and indolines as topical antiinflammatory agents for the treatment of skin disorders | |
| US5162318A (en) | Benzimidazolinone derivatives | |
| US6958357B2 (en) | Substituted benzimidazoles, processes for their preparation, their use as medicaments, and medicaments comprising them | |
| EP0260817A1 (en) | Quinazolinediones and pyridopyrimidinediones | |
| AU2006278504A1 (en) | Imidazopyridine derivatives as sirtuin modulating agents | |
| US7943781B2 (en) | Process for preparing telmisartan | |
| IE58566B1 (en) | 1-Substituted oxindole-3-carboxamides as antiinflammatory and analgesic agents | |
| EP0545845B1 (en) | Imidazole compounds, their preparation and use as calcium channel blockers | |
| US3401171A (en) | 2-amidobenzimidazoles | |
| JPH09510706A (ja) | ドパミン作動性活性を有するベンゾイミダゾール誘導体 | |
| US5214059A (en) | 2-(aminoaryl) indoles and indolines as topical antiinflammatory agents for the treatment of skin disorders | |
| EP0204215A1 (en) | 2-[(1H-benzimidazol-2-ylsulfinyl)methyl]-benzenamines | |
| Kumar et al. | Syntheses and anthelmintic activity of alkyl 5 (6)-(substituted carbamoyl)-and 5 (6)-(disubstituted carbamoyl) benzimidazole-2-carbamates and related compounds | |
| US3847934A (en) | 7-(imidazolinyl-(2)-amino)-indazoles | |
| Heymann et al. | Derivatives of p, p'-Diaminodiphenyl Sulfone1a | |
| US3405136A (en) | 1-phenylsulfonyl-2-benzimidazo-linones and 1-phenylsulfonyl-2-benzimidazolinethiones | |
| US4581349A (en) | Certain benzodiimidazoles and their use as radiation sensitizers | |
| US4316021A (en) | Substituted 1-sulfonylbenzimidazoles | |
| US4499269A (en) | Fused 1,3,5-triazines | |
| DE3911603A1 (de) | Benzimidazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung | |
| PL150093B1 (pl) | SPOSÓB WYTWARZANIA n o w y c h a n i l i d ó w KWASU - / P-CHLOROBENZOILO / - AKRYLOWEGO |