NO845169L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZIMIDAZOLE DERIVATIVES - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZIMIDAZOLE DERIVATIVESInfo
- Publication number
- NO845169L NO845169L NO845169A NO845169A NO845169L NO 845169 L NO845169 L NO 845169L NO 845169 A NO845169 A NO 845169A NO 845169 A NO845169 A NO 845169A NO 845169 L NO845169 L NO 845169L
- Authority
- NO
- Norway
- Prior art keywords
- group
- general formula
- benzimidazole
- phenyl
- methoxy
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 8
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title claims description 3
- 150000001556 benzimidazoles Chemical class 0.000 title claims description 3
- 230000001225 therapeutic effect Effects 0.000 title 1
- -1 hydroxy- Chemical class 0.000 claims description 115
- 150000001875 compounds Chemical class 0.000 claims description 85
- 239000002253 acid Substances 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 7
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 3
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000021235 carbamoylation Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims description 3
- 238000006264 debenzylation reaction Methods 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- SKJMXFYDJLQRSX-UHFFFAOYSA-N 2-(2-methoxy-4-prop-2-ynoxyphenyl)-3h-benzimidazole-5-carbonitrile Chemical compound COC1=CC(OCC#C)=CC=C1C1=NC2=CC=C(C#N)C=C2N1 SKJMXFYDJLQRSX-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- HOPHVZYQZLXWGE-UHFFFAOYSA-N 2-(2-methoxy-4-methylsulfonylphenyl)-3h-benzimidazole-5-carbonitrile Chemical compound COC1=CC(S(C)(=O)=O)=CC=C1C1=NC2=CC=C(C#N)C=C2N1 HOPHVZYQZLXWGE-UHFFFAOYSA-N 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 229960000583 acetic acid Drugs 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012362 glacial acetic acid Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 15
- 229960004756 ethanol Drugs 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- 238000009835 boiling Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- RIZQKJHWYJFKAP-UHFFFAOYSA-N 2-methoxy-4-prop-2-ynoxybenzoic acid Chemical compound COC1=CC(OCC#C)=CC=C1C(O)=O RIZQKJHWYJFKAP-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000009090 positive inotropic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- JFWBWLHAYKHBFG-UHFFFAOYSA-N 2-(2-methoxy-4-methylsulfanylphenyl)-3h-benzimidazole-5-carbonitrile Chemical compound COC1=CC(SC)=CC=C1C1=NC2=CC=C(C#N)C=C2N1 JFWBWLHAYKHBFG-UHFFFAOYSA-N 0.000 description 2
- GXDJZYFPFPEPTE-UHFFFAOYSA-N 2-(2-methoxy-4-methylsulfanylphenyl)-3h-benzimidazole-5-carboxamide Chemical compound COC1=CC(SC)=CC=C1C1=NC2=CC=C(C(N)=O)C=C2N1 GXDJZYFPFPEPTE-UHFFFAOYSA-N 0.000 description 2
- HMCIMXUDLBAPBY-UHFFFAOYSA-N 2-(2-methoxy-4-methylsulfinylphenyl)-3h-benzimidazole-5-carbonitrile Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC2=CC=C(C#N)C=C2N1 HMCIMXUDLBAPBY-UHFFFAOYSA-N 0.000 description 2
- BDFDUVRCPCOICK-UHFFFAOYSA-N 2-(2-methoxy-4-prop-2-ynoxyphenyl)-3h-benzimidazole-5-carboxylic acid Chemical compound COC1=CC(OCC#C)=CC=C1C1=NC2=CC=C(C(O)=O)C=C2N1 BDFDUVRCPCOICK-UHFFFAOYSA-N 0.000 description 2
- CWMQSSZCYHTFQN-UHFFFAOYSA-N 2-(2-methoxy-4-sulfamoylphenyl)-3h-benzimidazole-5-carboxylic acid Chemical compound COC1=CC(S(N)(=O)=O)=CC=C1C1=NC2=CC=C(C(O)=O)C=C2N1 CWMQSSZCYHTFQN-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- YRTOLUBGMMPKCK-UHFFFAOYSA-N 4-(6-cyano-1h-benzimidazol-2-yl)-3-methoxybenzenesulfonamide Chemical compound COC1=CC(S(N)(=O)=O)=CC=C1C1=NC2=CC=C(C#N)C=C2N1 YRTOLUBGMMPKCK-UHFFFAOYSA-N 0.000 description 2
- GALBBJWFBVIQRH-UHFFFAOYSA-N 6-fluoro-2-(2-methoxy-4-phenylmethoxyphenyl)-1h-benzimidazole Chemical compound C=1C=C(C=2NC3=CC(F)=CC=C3N=2)C(OC)=CC=1OCC1=CC=CC=C1 GALBBJWFBVIQRH-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000005336 allyloxy group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- COJOJJDGZHELMI-UHFFFAOYSA-N methyl 2-(2-methoxy-4-sulfamoylphenyl)-3h-benzimidazole-5-carboxylate Chemical compound N1C2=CC(C(=O)OC)=CC=C2N=C1C1=CC=C(S(N)(=O)=O)C=C1OC COJOJJDGZHELMI-UHFFFAOYSA-N 0.000 description 2
- ULSKIUHUELQDBP-UHFFFAOYSA-N methyl 3,4-diaminobenzoate;dihydrochloride Chemical compound Cl.Cl.COC(=O)C1=CC=C(N)C(N)=C1 ULSKIUHUELQDBP-UHFFFAOYSA-N 0.000 description 2
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
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- MWDRCFMBSXUODJ-UHFFFAOYSA-N methyl 2-(2-methoxy-4-prop-2-ynoxyphenyl)-3h-benzimidazole-5-carboxylate Chemical compound N1C2=CC(C(=O)OC)=CC=C2N=C1C1=CC=C(OCC#C)C=C1OC MWDRCFMBSXUODJ-UHFFFAOYSA-N 0.000 description 1
- WQKSSERGHCNFIL-UHFFFAOYSA-N methyl 2-[2-methoxy-4-(methylsulfamoyl)phenyl]-3h-benzimidazole-5-carboxylate Chemical compound COC1=CC(S(=O)(=O)NC)=CC=C1C1=NC2=CC=C(C(=O)OC)C=C2N1 WQKSSERGHCNFIL-UHFFFAOYSA-N 0.000 description 1
- OQCYBPONLOWFQI-UHFFFAOYSA-N methyl 2-[4-(dimethylsulfamoyl)-2-methoxyphenyl]-3h-benzimidazole-5-carboxylate Chemical compound N1C2=CC(C(=O)OC)=CC=C2N=C1C1=CC=C(S(=O)(=O)N(C)C)C=C1OC OQCYBPONLOWFQI-UHFFFAOYSA-N 0.000 description 1
- ZUKAXVAMLWQMQN-UHFFFAOYSA-N methyl 2-[4-(dipropylsulfamoyl)-2-ethoxyphenyl]-3h-benzimidazole-5-carboxylate Chemical compound CCOC1=CC(S(=O)(=O)N(CCC)CCC)=CC=C1C1=NC2=CC=C(C(=O)OC)C=C2N1 ZUKAXVAMLWQMQN-UHFFFAOYSA-N 0.000 description 1
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000500 noncardiotoxic Toxicity 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Inorganic materials [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WJUFNBHSODTIHU-UHFFFAOYSA-N propyl 2-(2-methoxy-4-methylsulfanylphenyl)-3h-benzimidazole-5-carboxylate Chemical compound N1C2=CC(C(=O)OCCC)=CC=C2N=C1C1=CC=C(SC)C=C1OC WJUFNBHSODTIHU-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 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 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- UNHKSXOTUHOTAB-UHFFFAOYSA-N sodium;sulfane Chemical compound [Na].S UNHKSXOTUHOTAB-UHFFFAOYSA-N 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003450 sulfenic acids Chemical class 0.000 description 1
- 150000003455 sulfinic acids Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
-
- 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
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av nye benzimidazol-derivater med den generelle formel This invention relates to a process for the production of new benzimidazole derivatives with the general formula
deres tautomerer og deres syreaddisjonssalter, særlig deres fysiologisk forlikelige syreaddisjonssalter med uorganiske eller organiske syrer, som oppviser verdifulle farmakologiske egenskaper, særlig en virkning på blodtrykket og på hjertemuskelens kontraktilitet. their tautomers and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids, which exhibit valuable pharmacological properties, in particular an effect on blood pressure and on cardiac muscle contractility.
I den ovenstående generelle formel I betyrIn the above general formula I means
R1en hydroksy-, alkoksy-, fenylalkoksy-, cyanalkoksy-, alkylsulf enyl-, alkylsulfinyl-, alkylsulfonyl-, aminosulfonyl-, alkylaminosulfonyl-, dialkylaminosulfonyl-, alkylsulfoksimino-, alkenyloksy- eller alkynyloksygruppe, R1 is a hydroxy, alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfoximino, alkenyloxy or alkynyloxy group,
1*2et hydrogenatom, en hydroksy-, alkoksy-, fenylalkoksy-,;amino-, alkylamino- eller dialkylaminogruppe,;Ro et hydrogenatom eller en alkoksygruppe, og;et hydrogen- eller halogenatom, en cyan-, nitro-, amino-, karboksy-, alkoksykarbonyl-, aminokarbonyl-, alkylaminokarbonyl-, dialkylaminokarbonyl-, aminokarbonylamino-, alkylaminokarbonylamino- eller dialkylaminokarbonylaminogruppe, ;idet alkyldelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, og alkenyl- eller alkynyldelen i hvert tilfelle kan inneholde 3 til 5 karbonatomer. ;Blant de innledningsvis angitte betydninger for restene;R-^ til R^, kommer for eksempel i betraktning;for R^betydningen en hydroksy-, metoksy-, etoksy-, n-propoksy-, benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, 3-fenylpropoksy-, metylsulfenyl-, etylsulfenyl-, isopropylsulfenyl-, metylsulfinyl-, etylsulfinyl-, n-propylsulfinyl-, metylsulfonyl-, etylsulfonyl-, n-propylsulfonyl-, isopropylsulfonyl-, cyanmetoksy-, 2-cyan-etoksy-, 3-cyanpropoksy-, aminosulfonyl-, metylaminosulfonyl-, etylaminosulfonyl-, n-propylaminosulfonyl-, dimetylaminosulfonyl-, ;dietylaminosulfonyl-, diisopropylaminosulfonyl-, N-metyletyl-aminosulfonyl-, metylsulfoksimino-, etylsulfoksimino-, n-propylsulfoksimino-, allyloksy-, but-2-enyloksy-, pent-2-enyloksy-, propargyloksy-, but-2-inyloksy- eller pent-2-inyloksygruppe, ;for R~betydningen et hydrogenatom, en metoksy-, etoksy-, n-propoksy-, isopropoksy-, benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, 3-fenylpropoksy-, amino-, metylamino-, etylamino-, isopropylamino-, dimetylamino-, dietylamino-, di-n-propylamino-, diisopropylamino-, N-metyl-etylamino-, N-metyl-isopropylamino-eller N-etyl-n-propylaminogruppe, ;for R., betydningen et hydrogenatom, en metoksy-, etoksy-, n-propoksy- eller isopropoksygruppe og ;for R^betydningen et hydrogen-, fluor-, klor-, eller bromatom, en cyan-, nitro-, amino-, karboksy-, metoksykarbonyl-, etoksykarbonyl-, n-propoksykarbonyl-, aminokarbonyl-, metyl-aminokarbonyl-, etylaminokarbonyl-, n-propylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, diisopropylamino-karbonyl-, aminokarbonylamino-, metylamino-karbonylamino-, etylaminokarbonylamino-, n-propylaminokarbonylamino-, dimetyl-aminokarbonylamino-, dietylaminokarbonylamino-, di-n-propylaminokarbonylamino- eller N-metyletylaminokarbonylaminogruppe. ;Foretrukne forbindelser med den ovenstående generelle formel I er de hvor R^og R^er som innledningsvis angitt, ;R2har de for R2innledningsvis angitte betydninger med unntagelse av et hydrogenatom, og R^ betyr et hydrogenatom, spesielt de forbindelser hvor R^ står i 4-stilling og R2i 2-stilling, og R^har de for R^innledningsvis angitte betydninger med unntagelse av et hydrogenatom. ;Særlig foretrukne forbindelser er de forbindelser med;den generelle formel; ; hvor ;R-^betyr en hydroksy-, benzyloksy-, allyloksy-, propargyloksy-, alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl-, alkylsulfoksimino-eller aminosulfonylgruppe, ;R2betyr en alkoksygruppe, og;R4betyr et fluor-, klor- eller bromatom, en cyan-, karboksy-, aminokarbonyl-, alkoksykarbonyl-, nitro- eller aminogruppe, ;hvor alkyldelen i hvert tilfelle kan inneholde 1 eller 2 karbonatomer, deres tautomerer og deres syreaddisjonssalter, særlig deres fysiologisk forlikelige syreaddisjonssalter med uorganiske eller organiske syrer. ;Ifølge oppfinnelsen fremstilles de nye forbindelser ved følgende fremgangsmåter: ;a) Ringslutning av en eventuelt i reaksjonsblandingen fremstilt forbindelse med den generelle formel ; hvor ;R 4 er som innledningsvis angitt,;en av restene X eller Y er et hydrogenatom og den annen av restene X og Y eller begge restene X og Y er en gruppe med formelen ; ; hvor ;R^til R^er som innledningsvis angitt,;Zlog Z2'SOItl kan være like eller forskjellige, betyr eventuelt substituerte aminogrupper eller eventuelt med lavere alkylgrupper substituerte hydroksy- eller merkaptogrupper, eller Zlog Z2betyr sammen et oksygen- eller svovelatom, en ;eventuelt med en alkylgruppe med 1 til 3 karbonatomer substituert ;iminogruppe, en alkylendioksy- eller alkylenditiogruppe med hver 2 eller 3 karbonatomer. ;Ringslutningen utføres hensiktsmessig i et oppløsnings-middel eller en oppløsningsmiddelblanding såsom etanol, iso-propanol, iseddik, benzen, klorbenzen, toluen, xylen, glykol, glykolmonometyleter, dietylenglykoldimetyleter, sulfolan, dimetylformamid, tetralin eller i et overskudd av det for fremstillingen av forbindelsen med den generelle formel II anvendte acyleringsmiddel, for eksempel i det passende nitril, anhydrid, syrehalogenid, ester, amid eller metojodid, for eksempel ved temperaturer mellom 0 og 2 50°C, fortrinnsvis ved reaksjonsblandingens koketemperatur, eventuelt i nærvær av et kondensasjonsmiddel såsom fosforoksyklorid, tionylklorid, sulfurylklorid, svovelsyre, p-toluensulfonsyre, saltsyre, fosforsyre, polyfosforsyre, eddiksyreanhydrid eller eventuelt også i nærvær av en base såsom kaliumetylat eller kalium-tert.-butylat. Ringslutningen kan imidlertid også utføres uten oppløsningsmiddel og/eller kondensasjonsmiddel. b) For fremstilling av forbindelser med den generelle formel I hvor R^betyr en alkylsulf inyl- eller alkylsulf onylgruppe: Oksydasjon av en forbindelse med den generelle formel ; hvor ;R2til R^er som innledningsvis angitt, og;R^<1>betyr en alkylsulfenyl- eller alkylsulfinylgruppe med hver 1 til 3 karbonatomer i alkyldelen. ;Oksydasjonen foretas fortrinnsvis i et oppløsningsmiddel eller en oppløsningsmiddelblanding, for eksempel i vann, vann/pyridin, aceton, iseddik, fortynnet svovelsyre eller trifluoreddiksyre, alt efter det anvendte oksydasjonsmiddel hensiktsmessig ved temperaturer mellom -80 og 100°C. ;For fremstilling av en alkylsulfinylforbindelse med den generelle formel I foretas oksydasjonen hensiktsmessig med en ekvivalent av det anvendte oksydasjonsmiddel, for eksempel med hydrogenperoksyd i iseddik, trifluoreddiksyre eller maursyre ved 0 til 20°C eller i aceton ved 0 til 60°C, med en persyre såsom permaursyre i iseddik eller trifluoreddiksyre ved 0 til 5 0°C, eller med m-klorperbenzoesyre i metylenklorid eller kloroform ved -2 0 til 60°C, med natriummetaperjodat i vandig metanol eller etanol ved -15 til 25°C, med brom i iseddik eller vandig eddiksyre, med N-brom-suksinimid i etanol, med tert.-butyl-hypokloritt i metanol ved -80 til -3 0°C, med jod-benzodiklorid i vandig pyridin ved 0 til 50°C, med salpeter-syre i iseddik ved 0 til 20°C, med kromsyre i iseddik eller i aceton ved 0 til 2 0°C og med sulfurylklorid i metylenklorid ved -7 0°C, idet det herved oppnådde tioeter-klor-kompleks hensiktsmessig hydrolyseres med vandig etanol. ;For fremstilling av en alkylsulfonylforbindelse med den generelle formel I foretas oksydasjonen hensiktsmessig med en resp. med to eller flere ekvivalenter av det anvendte oksydasjonsmiddel, for eksempel med hydrogenperoksyd i iseddik, trifluoreddiksyre eller i maursyre ved 20 til 100°C eller i aceton ved 0 til 60°C, men en persyre såsom permaursyre eller m-klorperbenzoesyre i iseddik, trifluoreddiksyre, metylenklorid eller kloroform ved temperaturer mellom 0 og 60°C, med salpeter-syre i iseddik ved 0 til 2 0°C, med kromsyre eller kalium-permanganat i iseddik, vann/svovelsyre eller i aceton ved 0 ;til 2 0°C.;c) For fremstilling av forbindelser med den generelle formel I hvor betyr en alkoksy-, fenylalkoksy-, cyanalkoksy-, ;alkylsulfenyl-, alkenyloksy- eller alkynyloksygruppe:;Omsetning av en forbindelse med den generellle formel ; hvor ;R. er som innledningsvis angitt,;U betyr en hydroksy- eller merkaptogruppe,;R2 1 betyr en hydroksygruppe eller har de for R2innledningsvis angitte betydninger, og ;R3' betyr en hydroksygruppe eller har de for R^ innledningsvis angitte betydninger, ;med et halogenid med den generelle formel; ; hvor ;R^betyr en alkyl-, fenylalkyl-, cyanalkyl-, alkenyl- eller alkynylgruppe, hvor alkyldelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer og alkenyl- resp. alkynyldelen kan inneholde 3 til 5 karbonatomer, og ;W betyr en nukleofil utgående gruppe såsom et klor-, brom-eller jodatom. ;Omsetningen utføres hensiktsmessig i et oppløsningsmiddel såsom tetrahydrofuran, dioksan, dimetylformamid, sulfolan, dimetylsulfoksyd eller etylenglykoldimetyleter, fortrinnsvis i nærvær av et syrebindende middel såsom kaliumkarbonat, kalium-tert.-butylat eller natriumhydrid, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 2 0 ;og 50°C.;d) For fremstilling av forbindelser med den generelle formel I hvor R^ betyr en alkoksykarbonyl-, aminokarbonyl-, alkylaminokarbonyl- eller dialkylaminokarbonylgruppe: Omsetning av et benzimidazol med den generelle formel ; hvor ;R1til er som innledningsvis angitt, eller dets eventuelt i reaksjonsblandingen fremstilte reaktive derivat, med en forbindelse med den generelle formel ; ; hvor ;Rg er en alkoksy-, amino-, alkylamino- eller dialkylaminogruppe, hvor alkyIdelen i hvert tilfelle kan inneholde 1 til 3 karbonatomer, eller med et eventuelt i reaksjonsblandingen ;dannet N-aktivert amin med den generelle formel VII når en karboksylsyre med den generelle formel VI anvendes. ;Fremgangsmåten angår således acylering av en forbindelse med den generelle formel VII med en karboksylsyre med den generelle formel VI i nærvær av et syre-aktiverende eller et vanntiltrekkende middel, eller med funksjonelle derivater derav, eller ;omsetning av en karboksylsyre med den generelle formel VI med et amin med den generelle formel VII i nærvær av et aminogruppe-aktiverende middel eller med reaktive derivater derav. ;Som eventuelt i reaksjonsblandingen fremstilte funksjonelle derivater av en karboksylsyre med den generelle formel VI kommer for eksempel i betraktning dens alkyl-, aryl- eller aralkyl-estere eller -tioestere såsom metyl-, etyl-, fenyl- eller benzyl-estrene, dens imidazolid-derivater, dens syrehalogenider såsom syrekloridet eller -bromidet, dens anhydrider, dens blandede anhydrider med alifatiske eller aromatiske karboksyl-, sulfen-, sulfin- eller sulfonsyrer eller karbonsyreestere, for eksempel med eddiksyre, propionsyre, p-toluensulfonsyre eller 0-etyl-karbonsyre, dens O-trifenylfosfonium-komplekser, dens N-acyl-oksyimider, dens azider eller nitriler eller de tilsvarende amino-tiokarboksylsyre-derivater, og som eventuelt i reaksjonsblandingen fremstilte reaktive derivater av et amin med den generelle formel VI dets fosfazo-derivater. ;Som syreaktiverende og/eller vanntiltrekkende midler kommer for eksempel i betraktning en klormaursyreester såsom klormaur-syreetylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N'-dicykloheksylkarbodii:ruid, N,N'-karbonyldiimidazol, N,N<*->tionyldiimidazol, bortrifluorideterat eller trifenylfosfin/- karbontetraklorid. 1*2 a hydrogen atom, a hydroxy-, alkoxy-, phenyl-alkyl-,;amino-, alkylamino- or dialkylamino group,;Ro a hydrogen atom or an alkoxy group, and;a hydrogen or halogen atom, a cyan-, nitro-, amino-, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group, wherein the alkyl part in each case may contain 1 to 3 carbon atoms, and the alkenyl or alkynyl part in each case may contain 3 to 5 carbon atoms . ;Among the initially stated meanings for the residues;R-^ to R^, comes into consideration, for example; for the R^ meaning a hydroxy-, methoxy-, ethoxy-, n-propoxy-, benzyloxy-, 1-phenylethoxy-, 2 -phenylethoxy-, 3-phenylpropoxy-, methylsulfenyl-, ethylsulfenyl-, isopropylsulfenyl-, methylsulfinyl-, ethylsulfinyl-, n-propylsulfinyl-, methylsulfonyl-, ethylsulfonyl-, n-propylsulfonyl-, isopropylsulfonyl-, cyanomethoxy-, 2-cyano- ethoxy-, 3-cyanopropoxy-, aminosulfonyl-, methylaminosulfonyl-, ethylaminosulfonyl-, n-propylaminosulfonyl-, dimethylaminosulfonyl-, ;diethylaminosulfonyl-, diisopropylaminosulfonyl-, N-methylethylaminosulfonyl-, methylsulfoximino-, ethylsulfoximino-, n-propylsulfoximino-, allyloxy-, but-2-enyloxy-, pent-2-enyloxy-, propargyloxy-, but-2-inyloxy- or pent-2-inyloxy group, for R~ meaning a hydrogen atom, a methoxy-, ethoxy-, n- propoxy-, isopropoxy-, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-, 3-phenylpropoxy-, amino-, methylamino-, ethylamino-, isopropylamino-, di methylamino-, diethylamino-, di-n-propylamino-, diisopropylamino-, N-methyl-ethylamino-, N-methyl-isopropylamino- or N-ethyl-n-propylamino group, ; for R., the meaning of a hydrogen atom, a methoxy- , ethoxy-, n-propoxy or isopropoxy group and; for the R^ meaning a hydrogen, fluorine, chlorine, or bromine atom, a cyano-, nitro-, amino-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, n- propoxycarbonyl-, aminocarbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, n-propylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, diisopropylaminocarbonyl-, aminocarbonylamino-, methylaminocarbonylamino-, ethylaminocarbonylamino-, n-propylaminocarbonylamino-, dimethylaminocarbonylamino- , diethylaminocarbonylamino, di-n-propylaminocarbonylamino or N-methylethylaminocarbonylamino group. Preferred compounds with the above general formula I are those where R^ and R^ are as indicated at the beginning, R2 has the meanings indicated for R2 at the beginning with the exception of a hydrogen atom, and R^ means a hydrogen atom, especially those compounds where R^ stands in 4-position and R2i 2-position, and R^ has the meanings indicated for R^ at the beginning with the exception of a hydrogen atom. Particularly preferred compounds are those with the general formula; ; where ;R-^ means a hydroxy-, benzyloxy-, allyloxy-, propargyloxy-, alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl-, alkylsulfoximino- or aminosulfonyl group, ;R2 means an alkoxy group, and;R4 means a fluorine, chlorine or bromine atom, a cyan, carboxy, aminocarbonyl, alkoxycarbonyl, nitro or amino group, where the alkyl part in each case may contain 1 or 2 carbon atoms, their tautomers and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids. ;According to the invention, the new compounds are produced by the following methods: ;a) Ring closure of any compound produced in the reaction mixture with the general formula; where R 4 is, as stated at the beginning, one of the residues X or Y is a hydrogen atom and the other of the residues X and Y or both residues X and Y is a group with the formula; ; where ;R^ to R^ are as stated at the beginning,;Zlog Z2'SOItl can be the same or different, optionally substituted amino groups or optionally substituted with lower alkyl groups hydroxy or mercapto groups, or Zlog Z2 together means an oxygen or sulfur atom, a ; optionally with an alkyl group with 1 to 3 carbon atoms substituted;imino group, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms each. The ring closure is conveniently carried out in a solvent or a solvent mixture such as ethanol, iso-propanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess thereof for the preparation of the compound with the general formula II used acylating agent, for example in the appropriate nitrile, anhydride, acid halide, ester, amide or methoiodide, for example at temperatures between 0 and 250°C, preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride , thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in the presence of a base such as potassium ethylate or potassium tert-butylate. However, the cyclization can also be carried out without solvent and/or condensing agent. b) For the preparation of compounds of the general formula I where R 1 denotes an alkylsulfinyl or alkylsulfonyl group: Oxidation of a compound of the general formula ; where ;R2 to R^ are as indicated at the beginning, and;R^<1>means an alkylsulfenyl or alkylsulfinyl group with each 1 to 3 carbon atoms in the alkyl part. The oxidation is preferably carried out in a solvent or a solvent mixture, for example in water, water/pyridine, acetone, glacial acetic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used, suitably at temperatures between -80 and 100°C. For the preparation of an alkylsulfinyl compound of the general formula I, the oxidation is suitably carried out with an equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20°C or in acetone at 0 to 60°C, with a peracid such as permauric acid in glacial acetic acid or trifluoroacetic acid at 0 to 5 0°C, or with m-chloroperbenzoic acid in methylene chloride or chloroform at -2 0 to 60°C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25°C, with bromine in glacial acetic or aqueous acetic acid, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -3 0°C, with iodobenzodichloride in aqueous pyridine at 0 to 50°C, with saltpeter -acid in glacial acetic acid at 0 to 20°C, with chromic acid in glacial acetic acid or in acetone at 0 to 20°C and with sulfuryl chloride in methylene chloride at -7 0°C, the thioether-chlorine complex thus obtained being appropriately hydrolyzed with aqueous ethanol. ;For the preparation of an alkylsulfonyl compound with the general formula I, the oxidation is suitably carried out with a resp. with two or more equivalents of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20 to 100°C or in acetone at 0 to 60°C, but a peracid such as performatic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid , methylene chloride or chloroform at temperatures between 0 and 60°C, with nitric acid in glacial acetic acid at 0 to 2 0°C, with chromic acid or potassium permanganate in glacial acetic acid, water/sulfuric acid or in acetone at 0 to 2 0°C .;c) For the preparation of compounds with the general formula I where means an alkoxy-, phenyl-, cyano-, ;alkylsulfenyl-, alkenyloxy- or alkynyloxy group:; Reaction of a compound with the general formula ; where ;R. is as stated at the beginning, U means a hydroxy or mercapto group, R2 1 means a hydroxy group or has the meanings given for R2 at the beginning, and R3' means a hydroxy group or has the meanings given for R^ at the beginning, with a halide with the general formula; ; where R^means an alkyl, phenylalkyl, cyanoalkyl, alkenyl or alkynyl group, where the alkyl part in each case may contain 1 to 3 carbon atoms and alkenyl or the alkynyl moiety may contain 3 to 5 carbon atoms, and ;W means a nucleophilic leaving group such as a chlorine, bromine or iodine atom. The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, dimethylformamide, sulfolane, dimethyl sulfoxide or ethylene glycol dimethyl ether, preferably in the presence of an acid-binding agent such as potassium carbonate, potassium tert-butylate or sodium hydride, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C.;d) For the preparation of compounds of the general formula I where R^ denotes an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group: Reaction of a benzimidazole with the general formula; where ;R 1til is as indicated at the outset, or its possibly reactive derivative produced in the reaction mixture, with a compound of the general formula ; ; where Rg is an alkoxy, amino, alkylamino or dialkylamino group, where the alkyl part may in each case contain 1 to 3 carbon atoms, or with an optional N-activated amine of the general formula VII formed in the reaction mixture when a carboxylic acid with the general formula VI is used. The method thus concerns the acylation of a compound of the general formula VII with a carboxylic acid of the general formula VI in the presence of an acid-activating or a water-attracting agent, or with functional derivatives thereof, or the reaction of a carboxylic acid of the general formula VI with an amine of the general formula VII in the presence of an amino group-activating agent or with reactive derivatives thereof. As optional functional derivatives of a carboxylic acid with the general formula VI produced in the reaction mixture, for example, its alkyl, aryl or aralkyl esters or thioesters such as the methyl, ethyl, phenyl or benzyl esters, its imidazolide -derivatives, its acid halides such as the acid chloride or bromide, its anhydrides, its mixed anhydrides with aliphatic or aromatic carboxylic, sulfenic, sulfinic or sulfonic acids or carboxylic acid esters, for example with acetic acid, propionic acid, p-toluenesulfonic acid or O-ethylcarbonic acid , its O-triphenylphosphonium complexes, its N-acyl-oxyimides, its azides or nitriles or the corresponding amino-thiocarboxylic acid derivatives, and which optionally in the reaction mixture produced reactive derivatives of an amine with the general formula VI its phosphazo derivatives. As acid-activating and/or water-attracting agents, for example, a chloroformic acid ester such as chloroformic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodi:ruide, N,N'-carbonyldiimidazole, N,N<*->thionyldiimidazole comes into consideration , boron trifluoride etherate or triphenylphosphine/carbon tetrachloride.
Omsetningen utføres hensiktsmessig i et oppløsningsmiddel såsom metylenklorid, kloroform, karbontetraklorid, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt i nærvær av en uorganisk base såsom natriumkarbonat, eller en tertiær organisk base såsom trietyl-amin eller pyridin, som samtidig kan tjene som oppløsnings-middel, og eventuelt i nærvær av et syreaktiverende middel ved temperaturer mellom -25 og 250°C, fortrinnsvis ved temperaturer mellom -10 og det anvendte oppløsningsmiddels koketemperatur. Herunder trenger et eventuelt i reaksjonsblandingen dannet funksjonelt derivat av en forbindelse med den generelle formel VI eller VII ikke å bli isolert, og dessuten kan omsetningen også utføres uten oppløsningsmiddel. Videre kan vann som er dannet under omsetningen, fraskilles ved azeotropisk destilla-sjon, for eksempel ved oppvarmning med toluen i en vannutskiller, eller ved tilsetning av et tørkemiddel såsom magnesiumsulfat eller molekylsikt. e) For fremstilling av forbindelser med den generelle formel I hvor betyr en alkylsulfoksiminogruppe: Omsetning av et sulfoksyd med den generelle formel The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, which at the same time can serve as a solvent, and possibly in the presence of an acid activating agent at temperatures between -25 and 250°C, preferably at temperatures between -10 and the boiling temperature of the solvent used. Herein, any functional derivative of a compound of the general formula VI or VII formed in the reaction mixture does not need to be isolated, and moreover the reaction can also be carried out without a solvent. Furthermore, water formed during the reaction can be separated by azeotropic distillation, for example by heating with toluene in a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieves. e) For the preparation of compounds of the general formula I where an alkylsulfoximino group means: Reaction of a sulfoxide of the general formula
hvor where
R2til R^er som innledningsvis angitt, ogR2 to R^ are as indicated at the outset, and
R7betyr en alkylgruppe med 1 til 3 karbonatomer, med eventuelt i reaksjonsblandingen dannet hydrogenazid. R7 means an alkyl group with 1 to 3 carbon atoms, possibly with hydrogen azide formed in the reaction mixture.
Omsetningen utføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding såsom metylenklorid, dimetylformamid eller tetrahydrofuran, ved temperaturer mellom 0 og 40°C, fortrinnsvis ved temperaturer mellom 10 og 35°C. Særlig fordelaktig foretas omsetningen med en alkaliazid, for eksempel natriumazid, og polyfosforsyre som oppløsningsmiddel. f) For fremstilling av forbindelser med den generelle formel I hvor betyr en alkylsulfoksiminogruppe: The reaction is suitably carried out in a solvent or a solvent mixture such as methylene chloride, dimethylformamide or tetrahydrofuran, at temperatures between 0 and 40°C, preferably at temperatures between 10 and 35°C. The reaction is particularly advantageously carried out with an alkali azide, for example sodium azide, and polyphosphoric acid as solvent. f) For the preparation of compounds of the general formula I where an alkylsulfoximino group means:
Omsetning av et sulfoksyd med den generelle formelReaction of a sulfoxide with the general formula
hvor where
R2til R^ er som innledningsvis angitt, ogR 2 to R 1 are as indicated at the outset, and
R^betyr en alkylgruppe med 1 til 3 karbonatomer, med en forbindelse med den generelle formel R₁ means an alkyl group of 1 to 3 carbon atoms, with a compound of the general formula
hvor where
W betyr en karbonyl- eller sulfonylgruppe, ogW means a carbonyl or sulfonyl group, and
Rg betyr en i o-stilling disubstituert arylgruppe såsom en 2,4,6-trimetylfenyl- eller 2,4,6-triisopropylfenylgruppe. Rg means an aryl group disubstituted in the o-position such as a 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl group.
Omsetningen utføres hensiktsmessig i et oppløsnings-middel eller en oppløsningsmiddelblanding såsom metylenklorid, kloroform, dimetylformamid, tetrahydrofuran eller dioksan, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved temperaturer mellom 5 og 4 0°C, og eventuelt i nærvær av en katalyttisk mengde av en syre såsom p-toluensulfonsyre. Særlig fordelaktig utføres omsetningen ved at en forbindelse med den generelle formel IX uten forutgående isolering anvendes resp. fremstilles i reaksjonsblandingen. The reaction is conveniently carried out in a solvent or a solvent mixture such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane, at temperatures between 0 and 50°C, preferably at temperatures between 5 and 40°C, and optionally in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid. The reaction is particularly advantageously carried out by using a compound of the general formula IX without prior isolation or is produced in the reaction mixture.
Hvis man ifølge oppfinnelsen fremstiller en forbindelse med den generelle formel I hvor R^betyr en alkoksykarbonyl-, cyan-, aminokarbonyl-, alkylaminokarbonyl- eller dialkylaminokarbonylgruppe, kan denne ved hydrolyse overføres til en tilsvarende forbindelse med den generelle formel I hvor R^betyr en karboksylgruppe, og/eller If, according to the invention, a compound of the general formula I is prepared where R^ means an alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, this can be transferred by hydrolysis to a corresponding compound of the general formula I where R^ means a carboxyl group, and/or
hvis man fremstiller en forbindelse med den generelle formel I if one prepares a compound of the general formula I
hvor R4betyr en aminokarbonylgruppe, så kan denne ved dehydratisering overføres til en tilsvarende forbindelse med den generelle formel I hvor betyr en cyangruppe, where R4 means an aminocarbonyl group, then this can be transferred by dehydration to a corresponding compound with the general formula I where means a cyano group,
og/ellerand or
hvis man fremstiller en forbindelse med den generelle formel I hvor R4betyr en nitrogruppe, så kan denne ved reduksjon over-føres til den tilsvarende forbindelse med den generelle formel I hvor R^betyr en aminogruppe, og/eller if one prepares a compound with the general formula I where R 4 means a nitro group, then this can be transferred by reduction to the corresponding compound with the general formula I where R 4 means an amino group, and/or
hvis man fremstiller en forbindelse med den generelle formel I hvor R^betyr en aminogruppe, så kan denne ved karbamoylering overføres til en tilsvarende forbindelse med den generelle formel I hvor R^betyr en aminokarbonylamino-, alkylaminokarbonylamino- eller dialkylaminokarbonylaminogruppe, if one prepares a compound of the general formula I where R^ denotes an amino group, this can be transferred by carbamoylation to a corresponding compound of the general formula I where R^ denotes an aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group,
og/ellerand or
hvis man fremstiller en forbindelse med den generelle formel I hvor R^og/eller R2betyr en benzyloksygruppe, så kan denne ved debenzylering overføres til en tilsvarende forbindelse med den generelle formel I hvor R^og/eller R2betyr en hydroksygruppe. if one prepares a compound of the general formula I where R^ and/or R 2 means a benzyloxy group, then this can be transferred by debenzylation to a corresponding compound of the general formula I where R^ and/or R 2 means a hydroxy group.
Den påfølgende hydrolyse foretas hensiktsmessig enten i nærvær av en syre såsom saltsyre, svovelsyre, fosforsyre eller trikloreddiksyre, eller i nærvær av en base såsom natrium-hydroksyd eller kaliumhydroksyd, i et egnet oppløsningsmiddel såsom vann, vann/metanol, etanol, vann/etanol, vann/isopropanol eller vann/dioksan, ved temperaturer mellom -10 og 12 0°C, for eksempel ved temperaturer mellom romtemperatur og reaksjonsblandingens koketemperatur, idet den partielle hydrolyse fortrinnsvis utføres med konsentrert svovelsyre. The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 and 12 0°C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture, the partial hydrolysis preferably being carried out with concentrated sulfuric acid.
Den påfølgende dehydratisering foretas med et vanntiltrekkende middel såsom fosforpentoksyd, fosforoksyklorid, svovelsyre eller p-toluensulfonsyreklorid, eventuelt i et oppløsnings-middel såsom metylenklorid eller pyridin, ved temperaturer mellom 0 og 10 0°C, fortrinnsvis ved temperaturer mellom 2 0 og 8 0°C. The subsequent dehydration is carried out with a water-attracting agent such as phosphorus pentoxide, phosphorus oxychloride, sulfuric acid or p-toluenesulphonic acid chloride, optionally in a solvent such as methylene chloride or pyridine, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80° C.
Den påfølgende reduksjon av nitrogruppen foretas fortrinnsvis i et oppløsningsmiddel såsom vann, vann/etanol, metanol, iseddik, eddiksyreetylester eller dimetylformamid, hensiktsmessig med hydrogen i nærvær av en hydrogenerings- katalysator såsom Raney-nikkel, platina eller palladium/kull, med metaller såsom jern, tinn eller sink, i nærvær av en syre, med salter såsom jern(II)sulfat, tinn(II)klorid, natriumsulfid, natriumhydrogensulfid eller natriumditionitt, eller med hydrazin i nærvær av Raney-nikkel ved temperaturer mellom 0 The subsequent reduction of the nitro group is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, suitably with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron , tin or zinc, in the presence of an acid, with salts such as ferrous sulphate, stannous chloride, sodium sulphide, sodium hydrogen sulphide or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0
og 50°C, fortrinnsvis, ved romtemperatur.and 50°C, preferably at room temperature.
Den påfølgende karbamoylering foretas i et inert opp-løsningsmiddel såsom vann, metylenklorid, tetrahydrofuran eller dioksan, med et passende isocyanat såsom metylisocyanat eller kaliumisocyanat, i nærvær av en syre såsom eddiksyre, eller med et passende karbamoylklorid såsom dimetylamino-karbonylklorid, ved temperaturer mellom 0 og 50°C. The subsequent carbamoylation is carried out in an inert solvent such as water, methylene chloride, tetrahydrofuran or dioxane, with a suitable isocyanate such as methyl isocyanate or potassium isocyanate, in the presence of an acid such as acetic acid, or with a suitable carbamoyl chloride such as dimethylaminocarbonyl chloride, at temperatures between 0 and 50°C.
Den påfølgende debenzylering foretas hensiktsmessig iThe subsequent debenzylation is suitably carried out in
et oppløsningsmiddel såsom metanol, etanol, etylacetat eller iseddik, ved hjelp av katalyttisk aktivert hydrogen, for eksempel med hydrogen i nærvær av platina eller palladium/kull, ved temperaturer mellom 0 og 7 5°C, fortrinnsvis ved romtemperatur, og ved en hydrogentrykk på 1-5 bar. a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, using catalytically activated hydrogen, for example with hydrogen in the presence of platinum or palladium/charcoal, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1-5 bars.
Videre kan de oppnådde forbindelser ved den generelle formel I derefter eventuelt overføres til sine fysiologisk forlikelige syreaddisjonssalter med uorganiske eller organiske syrer. Som syrer kommer her for eksempel i betraktning saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, melkesyre, maleinsyre eller metansulfonsyre. Furthermore, the compounds obtained by the general formula I can then optionally be transferred to their physiologically compatible acid addition salts with inorganic or organic acids. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid come into consideration.
De som utgangsstoffer anvendte forbindelser med de generelle formler II til IX er delvis kjent fra litteraturen eller kan fremstilles ved metoder som er kjent fra litteraturen. The compounds with the general formulas II to IX used as starting materials are partly known from the literature or can be prepared by methods known from the literature.
Således oppnår man for eksempel de som utgangsstoffer anvendte forbindelser ved den generelle formel II ved acylering av en passende o-diaminoforbindelse, og forbindelsene med de generelle formler III, IV, VI og VIII ved påfølgende kondensasjon med et passende benzoesyrederivat og eventuelt påfølgende oksydasjon (se EP-A-0 022 495L. Thus, for example, the compounds of the general formula II used as starting materials are obtained by acylation of a suitable o-diamino compound, and the compounds of the general formulas III, IV, VI and VIII by subsequent condensation with a suitable benzoic acid derivative and possibly subsequent oxidation (see EP-A-0 022 495L.
Som nevnt innledningsvis oppviser de nye forbindelser med den generelle formel I, deres 1H tautomerer og deres fysiologisk forlikelige syreaddisjonssalter ved en lang virkningsvarighet overlegne farmakologiske egenskaper, særlig en blodtrykksenkende, positiv-inotrop og/eller antitrombotisk virkning. As mentioned at the outset, the new compounds of the general formula I, their 1H tautomers and their physiologically compatible acid addition salts exhibit superior pharmacological properties with a long duration of action, in particular a blood pressure lowering, positive inotropic and/or antithrombotic effect.
Som eksempler ble forbindelseneAs examples were the compounds
A = 2-(2-metoksy-4-metylsulfonyl-fenyl1-5-cyano-benzimidazolA = 2-(2-methoxy-4-methylsulfonyl-phenyl-1-5-cyano-benzimidazole).
og and
B = 2-(2-metoksy-4-propargyloksy-f enyl).-5-cyano-benzimidazolB = 2-(2-methoxy-4-propargyloxy-phenyl).-5-cyano-benzimidazole
med hensyn til sine biologiske egenskaper som følger: Bestemmelse av blodtrykkvirkningen og den positivt inotrope virkning på narkotiserte katter with regard to its biological properties as follows: Determination of the blood pressure effect and the positive inotropic effect in anesthetized cats
Undersøkelsene ble foretatt på katter som var narkoti-sert med pentobarbital-natrium (40 mg/kg i.p.). Dyrene pustet spontant. Det arterielle blodtrykk ble målt i Aorta abdominalis med en Statham-trykkomvandler (P 23 Dc). For å oppnå den positivt inotrope virkning ble trykket i det venstre hjerte-kammer målt med et katetertipmanometer (Millar PC-3 50 A). På dette grunnlag ble kontraktilitetsparameteren dp/dt maK,s bestemt ved hjelp av en analogidiffrensiator. Prøveforbindelsene ble injisert i en Vena femoralis. Som oppløsningsmiddel tjente Polydiol 2 00. Hver forbindelse ble undersøkt på minst 3 katter. The investigations were carried out on cats that were anesthetized with pentobarbital sodium (40 mg/kg i.p.). The animals breathed spontaneously. The arterial blood pressure was measured in the Aorta abdominalis with a Statham pressure transducer (P 23 Dc). To achieve the positive inotropic effect, the pressure in the left heart chamber was measured with a catheter tip manometer (Millar PC-3 50 A). On this basis, the contractility parameter dp/dt maK,s was determined using an analog differentiator. The test compounds were injected into a femoral vein. Polydiol 200 served as solvent. Each compound was tested in at least 3 cats.
Den følgende tabell inneholder de fundne middelverdier:The following table contains the average values found:
De nye forbindelser er godt forlikelige, og således kunne ved undersøkelsen ingen hjertetoksiske virkninger eller kretsløpsskader iakttaes for forbindelsene A og B. The new compounds are well compatible, and thus no cardiotoxic effects or circulatory damage could be observed for compounds A and B during the examination.
På grunn av sine farmakologiske egenskaper er de ifølge oppfinnelsen fremstilte forbindelser med den generélle formel I og deres fysiologisk forlikelige syreaddisjonssalter egnet til behandling av hjerteinsuffisienser av forskjellig opp-rinnelse, eftersom de øker hjertets kontraksjonskraft og letter tømningen av hjertet ved blodtrykksenkning. Due to their pharmacological properties, the compounds of the general formula I prepared according to the invention and their physiologically compatible acid addition salts are suitable for the treatment of heart insufficiency of various origins, since they increase the contraction force of the heart and facilitate the emptying of the heart when blood pressure is lowered.
For disse formål kan de nye forbindelser og deres fysiologisk forlikelige syreaddisjonssalter, eventuelt i kombinasjon med andre virkestoffer, innarbeides i de vanlige farmasøytiske anvendelsesformer såsom tabletter, dragéer, pulvere, stikkpiller, suspensjoner, ampuller eller dråper. Enkeltdosen utgjør 1-4 x daglig 0,3 - 2,2 mg/kg kroppsvekt, fortrinnsvis 0,7 - 1,5 mg/kg kroppsvekt. For these purposes, the new compounds and their physiologically compatible acid addition salts, possibly in combination with other active substances, can be incorporated into the usual pharmaceutical application forms such as tablets, dragees, powders, suppositories, suspensions, ampoules or drops. The single dose is 1-4 x daily 0.3 - 2.2 mg/kg body weight, preferably 0.7 - 1.5 mg/kg body weight.
De følgende eksempler illustrerer oppfinnelsen ytter-ligere: Eksempel 1 2-(2-metoksy-4-metylmerkapto-fenyl)-5-metoksykarbonyl-benzimidazol 2 3,9 g 4-metoksykarbonyl-l,2-fenylendiamin-dihydroklorid og 19,8 g 2-metoksy-4-metylmerkapto-benzoesyre oppvarmes med 7 00 ml fosforoksyklorid i 2,5 timer under tilbakeløpskjøling. Derefter avdestilleres overskudd av fosforoksyklorid i vakuum, det krystallinske residuum utrøres med isvann, tilsettes konsentrert ammoniakk til alkalisk reaksjon, og krystallene avsuges. Man krystalliserer fra 70 %-ig etylalkohol og tørker ved 7 0°C. The following examples further illustrate the invention: Example 1 2-(2-methoxy-4-methylmercapto-phenyl)-5-methoxycarbonyl-benzimidazole 2 3.9 g of 4-methoxycarbonyl-1,2-phenylenediamine dihydrochloride and 19.8 g of 2-methoxy-4-methylmercapto-benzoic acid is heated with 700 ml of phosphorus oxychloride for 2.5 hours under reflux. The excess phosphorus oxychloride is then distilled off in a vacuum, the crystalline residue is stirred with ice water, concentrated ammonia is added for an alkaline reaction, and the crystals are suctioned off. It is crystallized from 70% ethyl alcohol and dried at 70°C.
Smeltepunkt: 206-208°C,Melting point: 206-208°C,
utbytte: 23,0 g (70 % av det teoretiske).yield: 23.0 g (70% of theoretical).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etyImerkapto-fenyl)-5-metoksykarbonyl-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylImercapto-phenyl)-5-methoxycarbonyl-benzimidazole
2-(2-etoksy-4-n-propylmerkapto-fenyl)-5-metoksykarbonyl-benzimidazol 2-(2-ethoxy-4-n-propylmercapto-phenyl)-5-methoxycarbonyl-benzimidazole
2-(2-metoksy-4-metylmerkapto-fenyl)-5-propoksykarbonyl-benzimidazol 2-(2-Methoxy-4-methylmercapto-phenyl)-5-propoxycarbonyl-benzimidazole
Eksempel 2 Example 2
2-( 2- metoksy- 4- metyImerkapto- fenyl)- 5- karboksy- benzimidazol 10,2 g 2-(2-metoksy-4-metylmerkapto-fenyl)-5-metoksy- 2-(2-Methoxy-4-methylImercapto-phenyl)-5-carboxybenzimidazole 10.2 g 2-(2-Methoxy-4-methylmercapto-phenyl)-5-methoxy-
karbonyl-benzimidazol oppvarmes i 3 00 mT.2N natronlut i 2 timer til kokning under tilbakeløpskjøling. Derefter filtreres blandingen varm over kiselgur og surgjøres med 2N saltsyre. Man avsuger, vasker med vann og tørker ved 7 0°C. carbonyl-benzimidazole is heated in 3 00 mT.2N caustic soda for 2 hours to boiling under reflux. The mixture is then filtered hot over diatomaceous earth and acidified with 2N hydrochloric acid. Extract with suction, wash with water and dry at 70°C.
Smeltepunkt: 308-310°C (dekomp.}..,Melting point: 308-310°C (decomp.}..,
utbytte: 8,6 g (88 % av det teoretiskel.yield: 8.6 g (88% of the theoretical.
Analogt fremstilles følgende forbindelser: 2- (2-metoksy-4-e ty Imer kap to-f enyl).-5-karboksy-benzimidazol 2- (2-et oksy-4-n-propy Imer kapto-f enyl). -5-karboksy-benzimidazol Eksempel 3 Analogously, the following compounds are prepared: 2-(2-Methoxy-4-e ty Imer capto-phenyl).-5-carboxy-benzimidazole 2-(2-ethoxy-4-n-propyl Imer capto-phenyl). -5-carboxybenzimidazole Example 3
2-(2-metoksy-4-metylmerkapto-fenyl)-5-aminokarbonyl-benzimidazol 2-(2-Methoxy-4-methylmercapto-phenyl)-5-aminocarbonyl-benzimidazole
6,7 g 2-(2-metoksy-4-metylmerkapto-fenyl)-5-karboksy-benzimidazol, suspendert i 120 ml kloroform, blir under tilbakeløpskjøling tilsatt dråpevis 25,4 g tionylklorid under kraftig gassutvikling. Efter 2 timers oppvarmning avkjøler man til romtemperatur og avsuger det dannede syreklorid. Råproduktet innføres i 100 ml konsentrert ammoniakk. Man avsuger det oppnådde syreamid, oppløser det i kokende etanol og feller med varmt vann. Krystallene avsuges og tørkes ved 80°C. 6.7 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5-carboxy-benzimidazole, suspended in 120 ml of chloroform, 25.4 g of thionyl chloride are added dropwise under reflux cooling under strong gas evolution. After 2 hours of heating, it is cooled to room temperature and the acid chloride formed is sucked off. The raw product is introduced into 100 ml of concentrated ammonia. The acid amide obtained is filtered off with suction, dissolved in boiling ethanol and precipitated with hot water. The crystals are suctioned off and dried at 80°C.
Smeltepunkt: 138-142°C,Melting point: 138-142°C,
utbytte: 4,5 g (67,4 % av det teoretiske).yield: 4.5 g (67.4% of theory).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-metylmerkapto-fenyl)-5-metylaminokarbonyl-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylmercapto-phenyl)-5-methylaminocarbonyl-benzimidazole
2-(2-metoksy-4-metylmerkapto-fenyl)-5-etylaminokarbonyl-benzimidazol 2-(2-Methoxy-4-methylmercapto-phenyl)-5-ethylaminocarbonyl-benzimidazole
2-(2-metoksy-4-metylmerkapto-fenyl)-5-dimetylaminokarbonyl-benzimidazol 2-(2-Methoxy-4-methylmercapto-phenyl)-5-dimethylaminocarbonyl-benzimidazole
2-(2-metoksy-4-metyImerkapto-fenyl)-5-di-n-propylaminokarbonyl-benzimidazol 2-(2-Methoxy-4-methylmercapto-phenyl)-5-di-n-propylaminocarbonyl-benzimidazole
2-(2-metoksy-4-etylmerkapto-fenyl)-5-aminokarbonyl-benzimidazol 2-(2-etoksy-4-metylmerkapto-fenyl)-5-metylaminokarbonyl-benzimidazol 2-(2-Methoxy-4-ethylmercapto-phenyl)-5-aminocarbonyl-benzimidazole 2-(2-ethoxy-4-methylmercapto-phenyl)-5-methylaminocarbonyl-benzimidazole
2- (2-etoksy-4-etylmerkapto-f enyl).-5-dietylaminokarbonyl-benzimidazol 2-(2-ethoxy-4-ethylmercapto-phenyl).-5-diethylaminocarbonyl-benzimidazole
2-(2-metoksy-4-n-propylmerkapto-fenyl)-5-aminokarbonyl-benzimidazol 2-(2-Methoxy-4-n-propylmercapto-phenyl)-5-aminocarbonyl-benzimidazole
Eksempel 4 Example 4
2- ( 2- metoksy- 4- metylmer' kapto- f enyl)- 5- cyano- benzimidazol2- ( 2- methoxy- 4- methylmer' capto- phenyl)- 5- cyano- benzimidazole
3,5 g 2-(2-metoksy-4-metylmerkapto-fenyl)-5-aminokarbonyl-benzimidazol oppvarmes med 100 ml fosforoksyklorid i 2,5 timer under tilbakeløpskjøling, og derefter avdestilleres overskudd av fosforoksyklorid i vakuum. Residuet dekomponeres med is/vann, tilsettes konsentrert ammoniakk til alkalisk reaksjon og avsuges. De oppnådde krystaller tørkes ved 7 0°C. Smeltepunkt: 211-215°C, 3.5 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5-aminocarbonyl-benzimidazole is heated with 100 ml of phosphorus oxychloride for 2.5 hours under reflux, and then excess phosphorus oxychloride is distilled off in vacuo. The residue is decomposed with ice/water, concentrated ammonia is added for an alkaline reaction and suction is applied. The crystals obtained are dried at 70°C. Melting point: 211-215°C,
utbytte: 3,05 g (92,4 % av det teoretiske).yield: 3.05 g (92.4% of theory).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etylmerkapto-fenyl)-5-cyano-benzimidazol 2-(2-metoksy-4-n-propylmerkapto-fenyl)-5-cyano-benzimidazol 2-(2-etoksy-4-metylmerkapto-fenyl)-5-cyano-benzimidazol Eksempel 5 Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylmercapto-phenyl)-5-cyano-benzimidazole 2-(2-methoxy-4-n-propylmercapto-phenyl)-5-cyano-benzimidazole 2-(2- ethoxy-4-methylmercapto-phenyl)-5-cyano-benzimidazole Example 5
2-( 2- metoksy- 4- metylsulfinyl- fenyl)- 5- cyano- benzimidazol2-( 2- methoxy- 4- methylsulfinyl- phenyl)- 5- cyano- benzimidazole
2,0 g 2-(2-metoksy-4-metylmerkapto-fenyl)-5-cyano-benzimidazol oppløses i 50 ml iseddik og tilsettes 0,61 ml hydrogenperoksyd (399 mg/ml). Efter 14 timer tilsettes 50 ml vann og 3 ml av en 40 %-ig natriumbisulfitt-oppløsning, og derefter inndampes til tørrhet i vakuum. Residuet opptaes i vann, avsuges og tørkes ved 7 0°C. Dissolve 2.0 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5-cyano-benzimidazole in 50 ml of glacial acetic acid and add 0.61 ml of hydrogen peroxide (399 mg/ml). After 14 hours, 50 ml of water and 3 ml of a 40% sodium bisulphite solution are added, and then evaporated to dryness in vacuo. The residue is taken up in water, suctioned off and dried at 70°C.
Smeltepunkt: 115-116°C,Melting point: 115-116°C,
utbytte: 1,79 g (84,9 % av det teoretiske).yield: 1.79 g (84.9% of theory).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etylsulfinyl-fenyl)-5-cyano-benzimidazol 2-(2-metoksy-4-n-propylsulfinyl^fenyl)-5-cyano-benzimidazol 2- (2-etoksy-4-metyl sulfinyl-f enyl).-5^-cyano-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfinyl-phenyl)-5-cyano-benzimidazole 2-(2-methoxy-4-n-propylsulfinyl^phenyl)-5-cyano-benzimidazole 2-(2- ethoxy-4-methyl sulfinyl-phenyl).-5^-cyano-benzimidazole
Eksempel 6 Example 6
2-( 2- metok sy- 4- mety1su1fonyl- fenyl)-5-cyano-benz imidazo 12-(2-Methoxy-4-methylsulfonyl-phenyl)-5-cyano-benz imidazo 1
0,7 g 2-(2-metoksy-4-metylmerkapto-fenyl)-5-cyano-benzimidazol oppløses i 10 ml maursyre, tilsettes 0,51 ml hydrogenperoksyd (399 mg/ml) og får stå i 4 timer. Derefter fortynner man med 4 0 ml vann, avsuger de utskilte krystaller og tørker ved 6 0°C. 0.7 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5-cyano-benzimidazole is dissolved in 10 ml of formic acid, 0.51 ml of hydrogen peroxide (399 mg/ml) is added and allowed to stand for 4 hours. It is then diluted with 40 ml of water, the separated crystals are suctioned off and dried at 60°C.
Smeltepunkt: 260-261°C,Melting point: 260-261°C,
utbytte: 0,71 g (91,5 % av det teoretiske).yield: 0.71 g (91.5% of theory).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etylsulfonyl-fenyl)-5-cyano-benzimidazol 2-(2-metoksy-4-n-propylsulfonyl-fenyl)-5-cyano-benzimidazol 2-(2-etoksy-4-metylsulfonyl-fenyl)-5-cyano-benzimidazol Eksempel 7 Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfonyl-phenyl)-5-cyano-benzimidazole 2-(2-methoxy-4-n-propylsulfonyl-phenyl)-5-cyano-benzimidazole 2-(2- ethoxy-4-methylsulfonyl-phenyl)-5-cyano-benzimidazole Example 7
2-( 2- metoksy- 4- metylsulfoksimino- fenyl)- 5- cyano- benzimidazol 2-( 2- methoxy- 4- methylsulfoximino- phenyl)- 5- cyano- benzimidazole
0,623 g 2-(2-metoksy-4-metylsulfinyl-fenyl)-5-cyano-benzimidazol , oppløst i 5 ml dimetylformamid, tilsettes 1,4 3 g O-mesitylensulfonyl-acethydroksamsyreetylester og 1,71 g p-toluensulfonsyre. Efter 20 timer tilsetter man 10 ml vann og tilsetter konsentrert ammoniakk til alkalisk reaksjon. Det utkrystalliserte stoff omkrystalliseres fra etanol. Smeltepunkt: 262-263°C (dekomp.)>To 0.623 g of 2-(2-methoxy-4-methylsulfinyl-phenyl)-5-cyano-benzimidazole, dissolved in 5 ml of dimethylformamide, 1.43 g of O-mesitylenesulfonyl-acethydroxamic acid ethyl ester and 1.71 g of p-toluenesulfonic acid are added. After 20 hours, 10 ml of water is added and concentrated ammonia is added for an alkaline reaction. The crystallized substance is recrystallized from ethanol. Melting point: 262-263°C (decomp.)>
utbytte: 0,33 g (50,6 % av det teoretiske).yield: 0.33 g (50.6% of theory).
Analogt fremstilles følgende forbindelse: 2-(2-metoksy-4-etylsulfoksimino-fenyl)-5-cyano-benzimidazol Eksempel 8 Analogously, the following compound is prepared: 2-(2-methoxy-4-ethylsulfoximino-phenyl)-5-cyano-benzimidazole Example 8
2-( 2- metoksy- 4- metylsulfinyl- fenyl)- 5- karbamido- benzimidazol 2-( 2- methoxy- 4- methylsulfinyl- phenyl)- 5- carbamido- benzimidazole
Fremstilt analogt med eksempel 5 fra 2-(2-metoksy-4-metylmerkapto-fenyl)-5-karbamido-benzimidazo og hydrogenperoksyd i iseddik. Prepared analogously to example 5 from 2-(2-methoxy-4-methylmercapto-phenyl)-5-carbamido-benzimidazo and hydrogen peroxide in glacial acetic acid.
Smeltepunkt: 175-178°C,Melting point: 175-178°C,
utbytte: 53,5 % av det teoretiske.yield: 53.5% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etylsulfinyl-fenyl)-5-karbamido-benzimidazol 2-(2-metoksy-4-n-propylsulfinyl-fenyl)-5-karbamido-benzimidazol 2- (2-etoksy-4-metylsulf inyl-f enyl) -5-karbamido-benzimidazol Eksempel 9 Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfinyl-phenyl)-5-carbamido-benzimidazole 2-(2-methoxy-4-n-propylsulfinyl-phenyl)-5-carbamido-benzimidazole 2-(2- ethoxy-4-methylsulfinyl-phenyl)-5-carbamido-benzimidazole Example 9
2- ( 2- metoksy- 4- metylsulf onyl- f enyl),- 5- karbamido- behzimidazol 2- ( 2- methoxy- 4- methylsulfonyl- phenyl),- 5- carbamido- behzimidazole
Fremstilt analogt med eksempel 6 fra 2-(2-metoksy-4-metylmerkapto-fenyl)-5-karbamido-benzimidazol og hydrogenperoksyd i maursyre. Prepared analogously to example 6 from 2-(2-methoxy-4-methylmercapto-phenyl)-5-carbamido-benzimidazole and hydrogen peroxide in formic acid.
Smeltepunkt: 278-280°C,Melting point: 278-280°C,
utbytte: 41,6 % av det teoretiske.yield: 41.6% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etylsulfonyl-fenyl)-5-karbamido-benzimidazol 2-(2-metoksy-4-n-propylsulfonyl-fenyl)-5-karbamido-benzimidazol 2-(2-etoksy-4-metylsulfonyl-fenyl)-5-karbamido-benzimidazol Eksempel 10 Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfonyl-phenyl)-5-carbamido-benzimidazole 2-(2-methoxy-4-n-propylsulfonyl-phenyl)-5-carbamido-benzimidazole 2-(2- ethoxy-4-methylsulfonyl-phenyl)-5-carbamido-benzimidazole Example 10
2-(2-metoksy-4-metylsulfoksimino-fenyl)-5-karbamido-benzimidazol 2-(2-Methoxy-4-methylsulfoximino-phenyl)-5-carbamido-benzimidazole
Fremstilt analogt med eksempel 7 fra 2-(2-metoksy-4-metylsulfinyl-fenyl)-5-karbamido-benzimidazo og O-mesitylen-acet-hydroksamsyre-etylester. Prepared analogously to example 7 from 2-(2-methoxy-4-methylsulfinyl-phenyl)-5-carbamido-benzimidazo and O-mesitylene-acet-hydroxamic acid ethyl ester.
Smeltepunkt: 260-262°C,Melting point: 260-262°C,
utbytte: 41,4 % av det teoretiske.yield: 41.4% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-etylsulfoksimino-fenyl)-5-karbamido-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfoximino-phenyl)-5-carbamido-benzimidazole
2-(2-metoksy-4-n-propylsulfoksimino-fenyl)-5-karbamido-benzimidazol 2-(2-Methoxy-4-n-propylsulfoximino-phenyl)-5-carbamido-benzimidazole
2-(2-etoksy-4-metylsulfoksimino-fenyl)-5-karbamido-benzimidazol 2-(2-ethoxy-4-methylsulfoximino-phenyl)-5-carbamido-benzimidazole
Eksempel 11 Example 11
2-( 2- metoksy- 4- benzyloksy- fenyl)- 5- fluor- benzimidazol 2-( 2- methoxy- 4- benzyloxy- phenyl)- 5- fluoro- benzimidazole
Fremstilt analogt med eksempel 1 fra 2-amino-4-fluor-anilin og 2-metoksy-4-benzyloksy-benzoesyre i kokende fosforoksyklorid. Prepared analogously to example 1 from 2-amino-4-fluoroaniline and 2-methoxy-4-benzyloxy-benzoic acid in boiling phosphorus oxychloride.
Smeltepunkt: 190-191°C,Melting point: 190-191°C,
utbytte: 59,2 % av det teoretiske.yield: 59.2% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-benzyloksy-fenyl)-5-klor-benzimidazol 2-(2-metoksy-4-benzyloksy-fenyl)-5-brom-benzimidazol Eksempel 12 Analogously, the following compounds are prepared: 2-(2-methoxy-4-benzyloxy-phenyl)-5-chloro-benzimidazole 2-(2-methoxy-4-benzyloxy-phenyl)-5-bromo-benzimidazole Example 12
2-( 2- me toksy- 4- hydroksy- f enyl)- 5- f1uor- benzimidaz o12-( 2- me toxy- 4- hydroxy- phenyl)- 5- fluoro- benzimidaz o1
2,1 g 2-(2-metoksy-4-benzyloksy-fenyl)-5-fluor-benzimidazol hydrogeneres katalyttisk i 100 ml etanol med 0,2 g palladium/- kull (10 %-ig) ved 20°C og et hydrogentrykk på 4 bar. Derefter frafiltreres katalysatoren, den klare oppløsning inndampes, og residuet bringes til krystallisasjon ved utgnidning med eter. Smeltepunkt: 291-293°C, 2.1 g of 2-(2-methoxy-4-benzyloxy-phenyl)-5-fluoro-benzimidazole is catalytically hydrogenated in 100 ml of ethanol with 0.2 g of palladium/charcoal (10%) at 20°C and a hydrogen pressure of 4 bar. The catalyst is then filtered off, the clear solution is evaporated, and the residue is crystallized by trituration with ether. Melting point: 291-293°C,
utbytte: 87,7 % av det teoretiske.yield: 87.7% of the theoretical.
Eksempel 13 Example 13
2-( 2- metoksy- 4- cyanometoksy- fenyl)- 5- fluor- benzimidazol2-( 2- methoxy- 4- cyanomethoxy- phenyl)- 5- fluoro- benzimidazole
1,22 g 2-(2-metoksy-4-hydroksy-fenyl)-5-fluor-benzimidazol oppløses i 10 ml dimetylsulfoksyd, tilsettes 0,65 g vannfritt kaliumkarbonat, og derefter tilsettes dråpevis 0,37 g kloraceto-nitril, oppløst i 3 ml dimetylsulfoksyd, ved 20°C i løpet av 3 5 minutter under omrøring. Man omrører i 14 timer, innfører reaksjonsblandingen i 30 ml isvann og innstiller pH på 5 med 2N eddiksyre. Det utfelte produkt blir krystallinsk ved oppvarmning til 70°C. Man avsuger, vasker med vann og tørrer pro-duktet ved 7 0°C. For rensning kromatograferer man råproduktet over en silikagel-kolonne med en blanding av metylenklorid/etylacetat = 5:1. Dissolve 1.22 g of 2-(2-methoxy-4-hydroxy-phenyl)-5-fluoro-benzimidazole in 10 ml of dimethyl sulfoxide, add 0.65 g of anhydrous potassium carbonate, and then add dropwise 0.37 g of chloroacetonitrile, dissolved in 3 ml of dimethylsulfoxide, at 20°C over 35 minutes with stirring. The mixture is stirred for 14 hours, the reaction mixture is introduced into 30 ml of ice water and the pH is adjusted to 5 with 2N acetic acid. The precipitated product becomes crystalline when heated to 70°C. The product is extracted, washed with water and dried at 70°C. For purification, the crude product is chromatographed over a silica gel column with a mixture of methylene chloride/ethyl acetate = 5:1.
Smeltepunkt: 18 5-19 0°C,Melting point: 18 5-19 0°C,
utbytte: 0,68 g (48,7 % av det teoretiske).yield: 0.68 g (48.7% of theory).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-cyanometyltio-fenyl)-5-fluor-benzimidazol 2-(2-metoksy-4-allyloksy-fenyl)-5-fluor-benzimidazol 2-(2-etoksy-4-cyano-metoksy-fenyl)-5-fluor-benzimidazol 2-(2-etoksy-4-allyltio-fenyl)-5-klor-benzimidazol 2-(2-metoksy-4-cyanometoksy-fenyl)-5-brom-benzimidazol 2-(2-metoksy-4-buten-2-yloksy-fenyl)-5-fluor-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-cyanomethylthio-phenyl)-5-fluoro-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl)-5-fluoro-benzimidazole 2-(2-ethoxy- 4-cyano-methoxy-phenyl)-5-fluoro-benzimidazole 2-(2-ethoxy-4-allylthio-phenyl)-5-chloro-benzimidazole 2-(2-methoxy-4-cyanomethoxy-phenyl)-5-bromo -benzimidazole 2-(2-methoxy-4-buten-2-yloxy-phenyl)-5-fluoro-benzimidazole
Eksempel 14 Example 14
2-( 2- metoksy- 4-propargyloksy-fenyl)-5-nitro-benz imidazol 2-(2-Methoxy-4-propargyloxy-phenyl)-5-nitro-benzimidazole
Fremstilt analogt med eksempel 1 fra 2-amino-4-nitro-anilin og 2-metoksy-4-propargyloksy-benzoesyre i kokende fosforoksyklorid. Prepared analogously to example 1 from 2-amino-4-nitro-aniline and 2-methoxy-4-propargyloxy-benzoic acid in boiling phosphorus oxychloride.
Smeltepunkt: 243-245°C,Melting point: 243-245°C,
utbytte: 83,1 % av det teoretiske.yield: 83.1% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-butyn-2-yloksy-fenyl)-5-nitro-benzimidazol 2- (2~etoksy-4-propargyloksy-fenyl)-5-nitro-benzimidazol Eksempel 15 Analogously, the following compounds are prepared: 2-(2-methoxy-4-butyn-2-yloxy-phenyl)-5-nitro-benzimidazole 2-(2-ethoxy-4-propargyloxy-phenyl)-5-nitro-benzimidazole Example 15
2- ( 2- metoksy- 4- propargyloksy- f enyl).- 5- amino- benzimidazol2- ( 2- methoxy- 4- propargyloxy- phenyl).- 5- amino- benzimidazole
1,8 g 2-(2-metoksy-4-propargyloksy-fenyl).-5-nitro-benzimidazol suspenderes i 50 ml iseddik, oppvarmes til 90°C og tilsettes i løpet av 15 minutter en oppløsning av 9,4 g natriumditionitt i 5 0 ml vann. Den dannede lysebrune oppløsning inndampes i vakuum på en rotasjonsinndamper. Residuet utrøres med 50 ml vann, tilsettes natriumkarbonat til alkalisk reaksjon og ekstraheres tre ganger med en kloroform-metanol-blanding = 4:1. Den samlede ekstrakt tørkes over magnesiumsulfat, inndampes, og det skumaktige residuum tørkes i en eksikator. Utbytte: 0,40 g (4,4 % av det teoretiske), 1.8 g of 2-(2-methoxy-4-propargyloxy-phenyl).-5-nitro-benzimidazole is suspended in 50 ml of glacial acetic acid, heated to 90°C and a solution of 9.4 g of sodium dithionite is added over the course of 15 minutes in 50 ml of water. The light brown solution formed is evaporated in vacuum on a rotary evaporator. The residue is stirred with 50 ml of water, sodium carbonate is added to give an alkaline reaction and extracted three times with a chloroform-methanol mixture = 4:1. The combined extract is dried over magnesium sulfate, evaporated, and the foamy residue is dried in a desiccator. Yield: 0.40 g (4.4% of theoretical),
R^-verdi: 0,2 5 (silikagel, utviklingsmiddel: etylenklorid/- etanol = 9:1). R^ value: 0.25 (silica gel, developer: ethylene chloride/ethanol = 9:1).
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-butyn-2-yloksy-fenyl)-5-amino-benzimidazol 2-(2-etoksy-4-propargyloksy-fenyl)-5-amino-benzimidazol Eksempel 16 Analogously, the following compounds are prepared: 2-(2-methoxy-4-butyn-2-yloxy-phenyl)-5-amino-benzimidazole 2-(2-ethoxy-4-propargyloxy-phenyl)-5-amino-benzimidazole Example 16
2-(2-metoksy-4-propargyloksy-fenyl)-5-metylaminokarbonylamino-benzimidazol 2-(2-Methoxy-4-propargyloxy-phenyl)-5-methylaminocarbonylamino-benzimidazole
0,36 g 2-(2-metoksy-4-propargyloksy-fenyl)-5-amino-benzimidazol oppløses i 5 ml tetrahydrofuran, tilsettes 0,14 g metylisocyanat og oppvarmes i 2 timer ved 60°C. Derefter foretas inndampning i vakuum. Residuet renses ved kolonnekromatografi over silikagel med etylenklorid/etanol = 10:1. 0.36 g of 2-(2-methoxy-4-propargyloxy-phenyl)-5-amino-benzimidazole is dissolved in 5 ml of tetrahydrofuran, 0.14 g of methyl isocyanate is added and heated for 2 hours at 60°C. Evaporation is then carried out in a vacuum. The residue is purified by column chromatography over silica gel with ethylene chloride/ethanol = 10:1.
Smeltepunkt: 2 03-204°C,Melting point: 2 03-204°C,
utbytte: 0,34 g (78,9 % av det teoretiske)..yield: 0.34 g (78.9% of the theoretical)..
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-butyn-2-yloksy-fenyl)-5-metylaminokarbonyl-amino-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-butyn-2-yloxy-phenyl)-5-methylaminocarbonyl-amino-benzimidazole
2-(2-etoksy-4-propargyloksy-fenyl)-5-metylaminokarbonyl-amino-benzimidazol 2-(2-ethoxy-4-propargyloxy-phenyl)-5-methylaminocarbonyl-amino-benzimidazole
2- (2 -etoksy-4 --propargyloksy-f enyl 1-5-etylaminokarbony 1-amino-benzimidazol 2-(2-ethoxy-4-propargyloxy-phenyl 1-5-ethylaminocarbonyl 1-amino-benzimidazole
Eksempel 17 Example 17
2-(2-metoksy-4-propargyloksy-fenylI-5-metoksykarbonyl-benzimidazol 2-(2-Methoxy-4-propargyloxy-phenyl1-5-methoxycarbonyl-benzimidazole
Fremstilt analogt med eksempel 1 fra 3,4-diamino-benzoe-syre-metylester-dihydroklorid og 2-metoksy-4-propargyloksy-benzoesyre i kokende fosforoksyklorid. Prepared analogously to example 1 from 3,4-diamino-benzoic acid methyl ester dihydrochloride and 2-methoxy-4-propargyloxy-benzoic acid in boiling phosphorus oxychloride.
Smeltepunkt: 116-120°C,Melting point: 116-120°C,
utbytte: 59,5 % av det teoretiske.yield: 59.5% of the theoretical.
Analogt fremstilles følgende forbindelse: 2-(2-etoksy-4-propargyloksy-fenyl)-5-metoksykarbonyl-benzimidazol Analogously, the following compound is prepared: 2-(2-ethoxy-4-propargyloxy-phenyl)-5-methoxycarbonyl-benzimidazole
Eksempel 18 Example 18
2-( 2- metoksy- 4- propargyloksy- fenyl)- 5- karboksy- benzimidazol 2-( 2- methoxy- 4- propargyloxy- phenyl)- 5- carboxy- benzimidazole
Fremstilt analogt med eksempel 2 fra 2-(2-metoksy-4-propargyloksy-fenyl)-5-metoksykarbonyl-benzimidazol og 2N natronlut. Prepared analogously to example 2 from 2-(2-methoxy-4-propargyloxy-phenyl)-5-methoxycarbonyl-benzimidazole and 2N caustic soda.
Smeltepunkt: 235-240°C,Melting point: 235-240°C,
utbytte: 9 2,8 % av det teoretiske.yield: 9 2.8% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-etoksy-4-propargyloksy-fenyl)-5-karboksy-benzimidazol 2-(2-metoksy-4-allyloksy-fenyl)-5-karboksy-benzimidazol Eksempel 19 Analogously, the following compounds are prepared: 2-(2-ethoxy-4-propargyloxy-phenyl)-5-carboxy-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl)-5-carboxy-benzimidazole Example 19
2 -(2-metoksy-4-propargyloksy-fenyl1-5-aminokarbonyl-benzimidazol 2-(2-methoxy-4-propargyloxy-phenyl1-5-aminocarbonyl-benzimidazole
Fremstilt ifølge eksempel 3 fra 2-(2-metoksy-4-propargyloksy-fenyl)-5-karboksy-benzimidazol og tionylklorid og på- følgende omsetning av det dannede 2-(2-metoksy-4-propargyloksy-fenyl)-5-klorkarbonyl-benzimidazol med konsentrert ammoniakk. Råproduktet renses ved kolonnekromatografi over silikagel med etylenklorid/etanol = 9:1. Prepared according to example 3 from 2-(2-methoxy-4-propargyloxy-phenyl)-5-carboxy-benzimidazole and thionyl chloride and subsequent reaction of the formed 2-(2-methoxy-4-propargyloxy-phenyl)-5- chlorocarbonyl-benzimidazole with concentrated ammonia. The crude product is purified by column chromatography over silica gel with ethylene chloride/ethanol = 9:1.
Smeltepunkt: 150-152°C,Melting point: 150-152°C,
utbytte: 35,0 % av det teoretiske.yield: 35.0% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-propargyloksy-fenyl)-5-metylaminokarbonyl-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-propargyloxy-phenyl)-5-methylaminocarbonyl-benzimidazole
2- (2-etoksy-4-propargyloksy-fenyl)-5-aminokarbonyl-benzimidazol 2- (2-metoksy-4-allyloksy-fenyl)-5-aminokarbonyl-benzimidazol 2-(2-metoksy-4-allyloksy-fenyl)-5-n-propylamino-karbonyl-benzimidazol 2-(2-ethoxy-4-propargyloxy-phenyl)-5-aminocarbonyl-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl)-5-aminocarbonyl-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl) )-5-n-propylamino-carbonyl-benzimidazole
Eksempel 2 0 Example 2 0
2-( 2- metoksy- 4- propargyloksy- fenyl)- 5- cyano- benzimidazol 2-( 2- methoxy- 4- propargyloxy- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eksempel 1 fra 2-amino-4-cyano-anilin og 2-metoksy-4-propargyloksy-benzoesyre i kokende fosforoksyklorid. Prepared analogously to example 1 from 2-amino-4-cyano-aniline and 2-methoxy-4-propargyloxy-benzoic acid in boiling phosphorus oxychloride.
Smeltepunkt: 243-245°C,Melting point: 243-245°C,
utbytte: 85,0 % av det teoretiske.yield: 85.0% of the theoretical.
Analogt fremstilles følgende forbindelse: 2-(2-etoksy-4-propargyloksy-fenyl)-5-cyano-benzimidazol Eksempel 21 Analogously, the following compound is prepared: 2-(2-ethoxy-4-propargyloxy-phenyl)-5-cyano-benzimidazole Example 21
2-( 2- metoksy- 4- aminosulfonyl- fenyl)- 5- cyano- benzimidazol2-( 2- methoxy- 4- aminosulfonyl- phenyl)- 5- cyano- benzimidazole
a) 1,47 g 2-nitro-4-cyano-anilin og 1,96 g 2-metoksy-4-aminosulfonyl-benzoylklorid oppvarmes i 50 ml tørr klorbenzen a) 1.47 g of 2-nitro-4-cyano-aniline and 1.96 g of 2-methoxy-4-aminosulfonyl-benzoyl chloride are heated in 50 ml of dry chlorobenzene
i 5 timer til kokning under tilbakeløpskjøling. Fra den opp-rinnelig klare oppløsning utskilles i løpet av denne tid krystaller av (2-metoksy-4-aminosulfonyl)-benz-(2-nitro-4-cyano)-anilid. Man avsuger dem i varm tilstand, vasker dem med kald klorbenzen og derefter med etylacetat og tørker ved 6 0°C. for 5 hours until boiling under reflux. During this time crystals of (2-methoxy-4-aminosulfonyl)-benz-(2-nitro-4-cyano)-anilide are separated from the initially clear solution. They are sucked off while hot, washed with cold chlorobenzene and then with ethyl acetate and dried at 60°C.
Smeltepunkt: 270-274°C,Melting point: 270-274°C,
utbytte: 2,47 g (72,9 % av det teoretiske).yield: 2.47 g (72.9% of theory).
b) 2,40 g av det ifølge eksempel a) oppnådde stoff opp-slemmes i 2 50 ml iseddik, tilsettes 20 g jernpulver og oppvarmes 1,5 timer til kokning under tilbakeløpskjøling. Man frafiltrerer jernresiduet, avdestillerer etylacetat i vakuum og utrører residuet med vann. De utskilte krystaller avsuges og kromatograferes på en silikagelkolonne med metylenklorid/- etylacetat = 1:1. Man får hvite krystaller av 2-(2-metoksy-4-aminosulfonyl-fenyl)-5-cyano-benzimidazol. b) 2.40 g of the substance obtained according to example a) is slurried in 2 50 ml of glacial acetic acid, 20 g of iron powder is added and heated for 1.5 hours to boiling under reflux cooling. The iron residue is filtered off, ethyl acetate is distilled off in a vacuum and the residue is stirred with water. The separated crystals are filtered off and chromatographed on a silica gel column with methylene chloride/ethyl acetate = 1:1. White crystals of 2-(2-methoxy-4-aminosulfonyl-phenyl)-5-cyano-benzimidazole are obtained.
Smeltepunkt: 284-286°C,Melting point: 284-286°C,
utbytte: 0,455 g (21,7 % av det teoretiske). yield: 0.455 g (21.7% of theory).
Analogt fremstilles følgende forbindelser: 2- (2-metoksy-4-me ty laminosulf onyl-f enyl). -5-cyano-benzimidazol 2- (2-metoksy-4-dimety laminosulf onyl-f enyl5-cyano-benzimidazol 2-(2-etoksy-4-aminosulfonyl-fenyl)-5-cyano-benzimidazol 2-(2-etoksy-4-metylaminosulfonyl-fenyl)-5-cyano-benzimidazol 2- (2-etoksy-4-dimety laminosulf onyl-f enyl). -5-cyano-benzimidazol 2-(2-metoksy-4-n-propylaminosulfonyl-fenyl)-5-cyano-benzimidazol 2- (2-metoksy-4-di-n-propylaminosulfonyl-fenyl)-5-cyano-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylaminosulfonyl-phenyl). -5-cyano-benzimidazole 2-(2-methoxy-4-dimethylaminosulfonyl-phenyl5-cyano-benzimidazole 2-(2-ethoxy-4-aminosulfonyl-phenyl)-5-cyano-benzimidazole 2-(2-ethoxy -4-methylaminosulfonyl-phenyl)-5-cyano-benzimidazole 2-(2-ethoxy-4-dimethylaminosulfonyl-phenyl).-5-cyano-benzimidazole 2-(2-methoxy-4-n-propylaminosulfonyl-phenyl) )-5-cyano-benzimidazole 2-(2-methoxy-4-di-n-propylaminosulfonyl-phenyl)-5-cyano-benzimidazole
Eksempel 2 2 Example 2 2
2-(2-metoksy-4-aminosulfonyl-fenyl)-5-metoksykarbonyl-benzimidazol 2-(2-Methoxy-4-aminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole
Fremstilt analogt med eksempel 1 fra 2-metoksy-4-aminosulfonyl-benzoesyre og 3,4-diamino-benzoesyremetylester i kokende fosforoksyklorid. Prepared analogously to example 1 from 2-methoxy-4-aminosulfonyl-benzoic acid and 3,4-diamino-benzoic acid methyl ester in boiling phosphorus oxychloride.
Smeltepunkt: 284-28 6°C,Melting point: 284-28 6°C,
utbytte: 48,4 % av det teoretiske.yield: 48.4% of the theoretical.
Analogt fremstilles følgende forbindelser: 2- (2-metoksy-4-mety laminosulf onyl-f enyl )_-5-metoksykarbonyl-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylaminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole
2-(2-metoksy-4-dimetylaminosulfonyl-fenyl)-5~metoksykarbonyl-benzimidazol 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole
2-(2-etoksy-4-di-n-propylaminosulfonyl-fenyl)-5-metoksykarbonyl-benzimidazol 2-(2-ethoxy-4-di-n-propylaminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole
Eksempel 2 3 Example 2 3
2-( 2- metoksy- 4- aminosulfonyl- fenyl)- 5- karboksy- benzimidazol 2-( 2- methoxy- 4- aminosulfonyl- phenyl)- 5- carboxy- benzimidazole
Fremstilt analogt med eksempel 2 fra 2-(2-metoksy-4-aminosulfonyl-fenyl)-5-metoksykarbonyl-benzimidazol med 2N natronlut. Prepared analogously to example 2 from 2-(2-methoxy-4-aminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole with 2N caustic soda.
Smeltepunkt: 321-323°C,Melting point: 321-323°C,
utbytte: 61,5 % av det teoretiske.yield: 61.5% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-metylaminosulfonyl-fenyl)-5-karboksy-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylaminosulfonyl-phenyl)-5-carboxy-benzimidazole
2- (2-metoksy-4-dimetylaminosulfonyl-fenyl)-5-karboksy-benzimidazol 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-5-carboxy-benzimidazole
Eksempel 2 4 Example 2 4
2-(2-metoksy-4-aminosulfonyl-fenyl)-5-aminokarbonyl-benzimidazol 2-(2-Methoxy-4-aminosulfonyl-phenyl)-5-aminocarbonyl-benzimidazole
Fremstilt analogt med eksempel 3 fra 2-(2-metoksy-4-aminosulfonyl-fenyl)-5-karboksy-benzimidazol ved omsetning med tionylklorid og derefter med konsentrert ammoniakk. Smeltepunkt: 311-313°C, Prepared analogously to example 3 from 2-(2-methoxy-4-aminosulfonyl-phenyl)-5-carboxy-benzimidazole by reaction with thionyl chloride and then with concentrated ammonia. Melting point: 311-313°C,
utbytte: 7 6,0 % av det teoretiske.yield: 7 6.0% of the theoretical.
Analogt fremstilles følgende forbindelser: 2-(2-metoksy-4-aminosulfonyl-fenyl)-5-metylaminokarbonyl-benzimidazol Analogously, the following compounds are prepared: 2-(2-methoxy-4-aminosulfonyl-phenyl)-5-methylaminocarbonyl-benzimidazole
2-(2-metoksy-4-metylaminosulfonyl-fenyl)-5-amino-karbonyl-benzimidazol 2-(2-Methoxy-4-methylaminosulfonyl-phenyl)-5-amino-carbonyl-benzimidazole
2-(2-metoksy-4-dimetylaminosulfonyl-fenyl)-5-aminokarbonyl-benzimidazol 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-5-aminocarbonyl-benzimidazole
2-(2-metoksy-4-di-n-propylaminosulfonyl-fenyl)-5-aminokarbonyl-benz imidazol 2-(2-Methoxy-4-di-n-propylaminosulfonyl-phenyl)-5-aminocarbonyl-benzimidazole
2-(2-metoksy-4-aminosulfonyl-fenyl)-5-di-n-propylaminokarbonyl-benzimidazol 2-(2-Methoxy-4-aminosulfonyl-phenyl)-5-di-n-propylaminocarbonyl-benzimidazole
Eksempel 2 5 Example 2 5
2- ( 2- metoksy- 4- aminosulf onyl- f enyl),- 5- aminokarbonyl- benz imidazol 2- ( 2- methoxy- 4- aminosulfonyl- phenyl),- 5- aminocarbonyl- benzimidazole
0,657 g 2-(2-metoksy-4-aminosulfonyl-fenyl).-5-cyano-benzimidazol innføres porsjonsvis i 2 ml konsentrert svovelsyre 0.657 g of 2-(2-methoxy-4-aminosulfonyl-phenyl).-5-cyano-benzimidazole is introduced portionwise into 2 ml of concentrated sulfuric acid
og får stå ved 3 0°C i 2 4 timer. Derefter dekomponerer man med is, avsuger de utskilte krystaller og vasker dem syrefrie. Smeltepunkt: 311,5-313,5°C, and allowed to stand at 30°C for 24 hours. Then decompose with ice, suck off the separated crystals and wash them acid-free. Melting point: 311.5-313.5°C,
utbytte: 6 0,0 % av det teoretiske. yield: 6 0.0% of the theoretical.
Claims (3)
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DE3346575A DE3346575A1 (en) | 1983-12-23 | 1983-12-23 | NEW BENZIMIDAZOLES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
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JP (1) | JPS60156676A (en) |
KR (1) | KR850004467A (en) |
AU (1) | AU3704284A (en) |
DD (1) | DD232697A5 (en) |
DE (1) | DE3346575A1 (en) |
DK (1) | DK597484A (en) |
ES (5) | ES8601913A1 (en) |
FI (1) | FI845084L (en) |
HU (1) | HU193073B (en) |
IL (1) | IL73897A0 (en) |
NO (1) | NO845169L (en) |
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LU85544A1 (en) * | 1984-09-19 | 1986-04-03 | Cird | AROMATIC HETEROCYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE THERAPEUTIC AND COSMETIC FIELDS |
DE3522230A1 (en) * | 1985-06-21 | 1987-01-02 | Thomae Gmbh Dr K | NEW 2-ARYLIMIDAZOLES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, AND METHOD FOR THE PRODUCTION THEREOF |
FR2677020B1 (en) * | 1991-05-31 | 1993-08-27 | Cird Galderma | COMPOUNDS DERIVED FROM BENZIMIDAZOLE, THEIR PREPARATION PROCESS AND THEIR USE IN THE THERAPEUTIC AND COSMETIC FIELDS. |
US5821258A (en) * | 1994-12-27 | 1998-10-13 | Mitsui Chemicals, Inc. | Phenylbenzimidazole derivatives |
EA000999B1 (en) | 1995-08-02 | 2000-08-28 | Ньюкастл Юниверсити Венчерз Лимитед | Benzimidazole compounds |
US5942532A (en) * | 1997-09-05 | 1999-08-24 | Ortho Pharmaceutical Corporation | 2-substituted phenyl-benzimidazole antibacterial agents |
JP4637481B2 (en) | 2001-10-19 | 2011-02-23 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | 2-phenylbenzimidazole and imidazo- [4,5] -pyridine as CDS1 / CHK2 inhibitors and adjuvants for chemotherapy or radiotherapy in cancer treatment |
JP2006513159A (en) * | 2002-11-01 | 2006-04-20 | メルク エンド カムパニー インコーポレーテッド | Carbonylamino-benzimidazole derivatives as androgen receptor modulators |
DE602004006852D1 (en) | 2003-04-17 | 2007-07-19 | Janssen Pharmaceutica Nv | 2-PHENYL-BENZIMIDAZOLE AND 2-PHENYL-IMIDAZO-4,5'-PYRIDINE DERIVATIVES AS CHECKPOINT-KINASE-CDS1 (CHK2) INHIBITOR FOR THE TREATMENT OF CANCER |
US7250427B2 (en) | 2004-06-30 | 2007-07-31 | Janssen Pharmaceutica, N.V. | Aryl-substituted benzimidazole and imidazopyridine ethers |
BR112013016022B1 (en) | 2010-12-24 | 2019-05-07 | Sumitomo Chemical Company, Limited | Fused heterocyclic compound and use for same control. |
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CH350763A (en) * | 1958-10-14 | 1960-12-15 | Ciba Geigy | Use of azole compounds as a protective agent against ultraviolet radiation |
DE1447733B2 (en) * | 1963-12-23 | 1977-04-21 | Hoechst Ag, 6000 Frankfurt | 2- (3,5-DIHYDROXYPHENYL) BENZIMIDAZOLE DERIVATIVES |
IL23847A (en) * | 1964-08-07 | 1969-02-27 | Merck & Co Inc | Benzimidazoles useful as antifungals |
FR1569337A (en) * | 1968-06-18 | 1969-05-30 | ||
DE2742093A1 (en) * | 1977-09-19 | 1979-03-29 | Cassella Ag | PROCESS FOR THE PREPARATION OF 2- (3'- OR 4'-AMINOPHENYL) -5 (OR 6) -AMINOBENZIMIDAZOLES |
DE2927987A1 (en) * | 1979-07-11 | 1981-02-05 | Thomae Gmbh Dr K | NEW 2-ALKOXYPHENYL-IMIDAZO ANGLE CLAMP ON 4.5-B ANGLE CLAMP ON PYRIDINE, THEIR PRODUCTION AND THE USE THEREOF AS MEDICINAL PRODUCTS |
DE3224512A1 (en) * | 1982-07-01 | 1984-01-05 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW IMIDAZOLE DERIVATIVES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
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1983
- 1983-12-23 DE DE3346575A patent/DE3346575A1/en not_active Withdrawn
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1984
- 1984-12-08 EP EP84114999A patent/EP0148431A1/en not_active Withdrawn
- 1984-12-13 DK DK597484A patent/DK597484A/en not_active Application Discontinuation
- 1984-12-20 JP JP59269563A patent/JPS60156676A/en active Pending
- 1984-12-20 PT PT79718A patent/PT79718B/en unknown
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- 1984-12-21 FI FI845084A patent/FI845084L/en not_active Application Discontinuation
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- 1984-12-21 IL IL73897A patent/IL73897A0/en unknown
- 1984-12-21 ES ES538929A patent/ES8601913A1/en not_active Expired
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- 1984-12-21 ZA ZA849972A patent/ZA849972B/en unknown
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1985
- 1985-06-13 ES ES544117A patent/ES8604163A1/en not_active Expired
- 1985-06-13 ES ES544119A patent/ES8604165A1/en not_active Expired
- 1985-06-13 ES ES544116A patent/ES8604162A1/en not_active Expired
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ES8604165A1 (en) | 1986-01-16 |
ES544117A0 (en) | 1986-01-16 |
JPS60156676A (en) | 1985-08-16 |
IL73897A0 (en) | 1985-03-31 |
ES544116A0 (en) | 1986-01-16 |
ES538929A0 (en) | 1985-11-16 |
FI845084L (en) | 1985-06-24 |
ES8604163A1 (en) | 1986-01-16 |
ZA849972B (en) | 1986-08-27 |
ES8604164A1 (en) | 1986-01-16 |
DE3346575A1 (en) | 1985-07-04 |
DD232697A5 (en) | 1986-02-05 |
ES8604162A1 (en) | 1986-01-16 |
FI845084A0 (en) | 1984-12-21 |
ES544119A0 (en) | 1986-01-16 |
DK597484D0 (en) | 1984-12-13 |
PT79718B (en) | 1986-12-30 |
AU3704284A (en) | 1985-07-04 |
PT79718A (en) | 1985-01-01 |
HU193073B (en) | 1987-08-28 |
EP0148431A1 (en) | 1985-07-17 |
ES8601913A1 (en) | 1985-11-16 |
DK597484A (en) | 1985-06-24 |
ES544118A0 (en) | 1986-01-16 |
KR850004467A (en) | 1985-07-15 |
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