NO862477L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-ARYLIMIDAZOLE DERIVATIVES. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-ARYLIMIDAZOLE DERIVATIVES.Info
- Publication number
- NO862477L NO862477L NO862477A NO862477A NO862477L NO 862477 L NO862477 L NO 862477L NO 862477 A NO862477 A NO 862477A NO 862477 A NO862477 A NO 862477A NO 862477 L NO862477 L NO 862477L
- Authority
- NO
- Norway
- Prior art keywords
- group
- methoxy
- phenyl
- benzimidazole
- ethoxy
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 18
- 238000000034 method Methods 0.000 title claims description 10
- 230000001225 therapeutic effect Effects 0.000 title 1
- -1 benzoyl- Chemical group 0.000 claims description 140
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 45
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 31
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 28
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000001589 carboacyl group Chemical group 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- KTBKDODCGZHQFD-UHFFFAOYSA-N 1-[2-(2-methoxy-4-methylsulfonylphenyl)-3h-benzimidazol-5-yl]ethanone Chemical compound COC1=CC(S(C)(=O)=O)=CC=C1C1=NC2=CC=C(C(C)=O)C=C2N1 KTBKDODCGZHQFD-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- NUFRHEGIXIIJHO-UHFFFAOYSA-N n-[4-(6-cyano-1h-benzimidazol-2-yl)-3-methoxyphenyl]methanesulfonamide Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1C1=NC2=CC=C(C#N)C=C2N1 NUFRHEGIXIIJHO-UHFFFAOYSA-N 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 238000006264 debenzylation reaction Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 3
- AJPCBKGVRQPTTJ-UHFFFAOYSA-N 2-(2-methoxy-4-methylsulfanylphenyl)-1h-imidazo[4,5-b]pyridine-6-carbonitrile Chemical compound COC1=CC(SC)=CC=C1C1=NC2=NC=C(C#N)C=C2N1 AJPCBKGVRQPTTJ-UHFFFAOYSA-N 0.000 claims description 2
- HTGDHZCTDYDXSP-UHFFFAOYSA-N 8-(2-methoxy-4-methylsulfinylphenyl)-7h-purin-2-amine Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC2=NC(N)=NC=C2N1 HTGDHZCTDYDXSP-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 claims description 2
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- LHFPAFLSIKBZTL-UHFFFAOYSA-N methyl n-[4-(3h-imidazo[4,5-c]pyridin-2-yl)-3-methoxyphenyl]carbamate Chemical compound COC1=CC(NC(=O)OC)=CC=C1C1=NC2=CC=NC=C2N1 LHFPAFLSIKBZTL-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 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
- YPOUEFHWVLMHLQ-UHFFFAOYSA-N [4-(6-acetyl-1h-benzimidazol-2-yl)-3-methoxyphenyl] methanesulfonate Chemical compound COC1=CC(OS(C)(=O)=O)=CC=C1C1=NC2=CC=C(C(C)=O)C=C2N1 YPOUEFHWVLMHLQ-UHFFFAOYSA-N 0.000 claims 1
- XGKUIGRGDCUUBI-UHFFFAOYSA-N [4-(6-carbamoyl-1h-benzimidazol-2-yl)-3-methoxyphenyl] methanesulfonate Chemical compound COC1=CC(OS(C)(=O)=O)=CC=C1C1=NC2=CC=C(C(N)=O)C=C2N1 XGKUIGRGDCUUBI-UHFFFAOYSA-N 0.000 claims 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
- 231100000241 scar Toxicity 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 229960000583 acetic acid Drugs 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
- 239000012362 glacial acetic acid Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000009835 boiling Methods 0.000 description 12
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-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
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 239000011877 solvent mixture Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
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- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 5
- UOPCPHJGGRTYNC-UHFFFAOYSA-N 2-methoxy-4-methylsulfanylbenzoic acid Chemical compound COC1=CC(SC)=CC=C1C(O)=O UOPCPHJGGRTYNC-UHFFFAOYSA-N 0.000 description 4
- AKHVPZOYHZAQQC-UHFFFAOYSA-N 4-(methanesulfonamido)-2-methoxybenzoic acid Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1C(O)=O AKHVPZOYHZAQQC-UHFFFAOYSA-N 0.000 description 4
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- 108010035532 Collagen Proteins 0.000 description 4
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- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000005242 cardiac chamber Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- UFXOKLHIOIYFDE-UHFFFAOYSA-N methyl 2-(4-hydroxy-2-methoxyphenyl)-1H-benzimidazole-4-carboxylate Chemical compound COC(=O)C1=CC=CC=2N=C(NC=21)C1=C(C=C(C=C1)O)OC UFXOKLHIOIYFDE-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- FYHMFHYIEVJDOG-UHFFFAOYSA-N n-[4-(6-benzoyl-1h-benzimidazol-2-yl)-3-methoxyphenyl]methanesulfonamide Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1C1=NC2=CC=C(C(=O)C=3C=CC=CC=3)C=C2N1 FYHMFHYIEVJDOG-UHFFFAOYSA-N 0.000 description 1
- XTBLDMQMUSHDEN-UHFFFAOYSA-N naphthalene-2,3-diamine Chemical compound C1=CC=C2C=C(N)C(N)=CC2=C1 XTBLDMQMUSHDEN-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000500 noncardiotoxic Toxicity 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 101150032584 oxy-4 gene Proteins 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BTGIZHQAAYLQJR-UHFFFAOYSA-N pyridin-1-ium;2,4,6-trimethylbenzenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC(C)=C(S([O-])(=O)=O)C(C)=C1 BTGIZHQAAYLQJR-UHFFFAOYSA-N 0.000 description 1
- CSNFMBGHUOSBFU-UHFFFAOYSA-N pyrimidine-2,4,5-triamine Chemical compound NC1=NC=C(N)C(N)=N1 CSNFMBGHUOSBFU-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- XMFCOYRWYYXZMY-UHFFFAOYSA-N sulmazole Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC2=NC=CC=C2N1 XMFCOYRWYYXZMY-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av nye 2-arylimidazoler med den generelle formel This invention relates to a process for the preparation of new 2-arylimidazoles with the general formula
og tautomerer derav når R betyr et hydrogenatom, samt forbindel- and tautomers thereof when R means a hydrogen atom, as well as connecting
sene tendon
5-cyano-2-(4<1->metansulfonylamino-2'metoksy-fenyl)-benz-5-cyano-2-(4<1->methanesulfonylamino-2'methoxy-phenyl)-benz-
imidazol ,imidazole,
4-metyl-2-(4<1->metansulfonyloksy-2-metoksy-fenyl)-benz-4-methyl-2-(4<1->methanesulfonyloxy-2-methoxy-phenyl)-benz-
imidazol ,imidazole,
4-cyano-2-(4'-metansulfonyloksy-2'-metoksy-fenyl)-benz-4-cyano-2-(4'-methanesulfonyloxy-2'-methoxy-phenyl)-benz-
imidazol ,imidazole,
4-aminokarbonyl-2-(4<1->metansulfonyloksy-2'-metoksy-fenyl-4-aminocarbonyl-2-(4<1->methanesulfonyloxy-2'-methoxy-phenyl-
benzimidazol og benzimidazole and
4-metoksykarbonyl-2-(4'-metansulfonyloksy-2<1->metoksy-fenyl)-benzimidazol 4-Methoxycarbonyl-2-(4'-methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole
og deres syreaddisjonssalter, særlig deres fysiologisk forlike-and their acid addition salts, especially their physiological
lige syreaddisjonssalter med uorganiske og organiske syrer.equal acid addition salts with inorganic and organic acids.
De nye forbindelser og deres fysiologisk forlikelige syreaddisjonssalter oppviser verdifulle farmakologiske egen- The new compounds and their physiologically compatible acid addition salts exhibit valuable pharmacological properties
skaper, særlig en virkning på blodtrykket og på hjertemuskelens kontraktilitet samt antitrombotiske virkninger. Forbindelsene fremstilt ifølge oppfinnelsen kan anvendes i legemidler som er egnet til behandling av hjerteinsuffisienser av forskjellig opprinnelse, til behandling og til forebyggelse av trombo- creates, in particular, an effect on blood pressure and on the contractility of the heart muscle as well as antithrombotic effects. The compounds produced according to the invention can be used in medicines which are suitable for the treatment of heart insufficiency of various origins, for the treatment and for the prevention of thrombo-
emboliske lidelser, til forebyggelse av arteriosklerose og til metastase-forebyggelse. embolic disorders, for the prevention of arteriosclerosis and for metastasis prevention.
I den ovenstående generelle formel I betyrIn the above general formula I means
R en hydrogenatom eller en alkylgruppe,R a hydrogen atom or an alkyl group,
Ar en gruppe med formelenAr is a group with the formula
A og B sammen med de to mellomliggende karbonatomer en gruppe med formelen A and B together with the two intermediate carbon atoms form a group with the formula
hvor where
betyr en alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl-means an alkylsulfenyl, alkylsulfinyl, alkylsulfonyl
eller alkylsulfoksiminogruppe, en på nitrogenatomet med en alkanoyl-, alkylsulfonyl- eller hydroksykarbonyl-alkylenkarbonylgruppe substituert alkylsulfoksiminogruppe, en etoksy-eller n-propoksygruppe, som i endestilling er substituert med en alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl- eller alkylsulf oksiminogruppe , en alkoksykarbonylamino- eller N-alkylaminokarbonylaminogruppe eller også i 4-stilling en hydroksy-, fenylalkoksy-, aminosulfonyl-, alkylsulfonyloksy- eller alkylsulfonylaminogruppe, når or alkylsulfoximino group, an alkylsulfoximino group substituted on the nitrogen atom with an alkanoyl, alkylsulfonyl or hydroxycarbonylalkylenecarbonyl group, an ethoxy or n-propoxy group, which is substituted in the terminal position with an alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or alkylsulfoximino group, an alkoxycarbonylamino- or N-alkylaminocarbonylamino group or also in the 4-position a hydroxy, phenylalkoxy, aminosulfonyl, alkylsulfonyloxy or alkylsulfonylamino group, when
a) A og B sammen med de 2 mellomliggende karbonatomer er en a) A and B together with the 2 intermediate carbon atoms are one
b) R4er en alkyl-, alkanoyl-, N-alkanoyl-aminometyl-, benzoyl-, fenyl-metoksymetyl-, aminosulfonyl-, N-etylaminokarbonyl-amino-, N-n-propylaminokarbonyl-amino-, N-isopropylaminokarbonylamino- eller N-alkyl-N-alkylaminokarbonylaminogruppe eller c) R,b, er en aminogruppe, idet minst én av restene må ha de under a), b) og c) angitte betydninger, b) R 4 is an alkyl-, alkanoyl-, N-alkanoyl-aminomethyl-, benzoyl-, phenyl-methoxymethyl-, aminosulfonyl-, N-ethylaminocarbonyl-amino-, N-n-propylaminocarbonyl-amino-, N-isopropylaminocarbonylamino- or N-alkyl -N-alkylaminocarbonylamino group or c) R,b, is an amino group, as at least one of the residues must have the meanings specified under a), b) and c),
R2betyr et hydrogenatom eller en alkoksygruppe,R2 means a hydrogen atom or an alkoxy group,
R3betyr en etoksy- eller n-propoksygruppe, som hver i endestilling er substituert med en alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl- eller alkylsulfoksiminogruppe, betyr en alkyl-, alkoksykarbonyl-, alkanoyl-, N-alkanoyl-aminometyl-, benzoyl-, fenylmetoksymetyl-, aminokarbonyl-, cyano-, trifluormetyl-, aminosulfonyl-, N-alkylaminokarbonylamino- eller N-alkyl-N-alkylaminokarbonylaminogruppe, R3 means an ethoxy or n-propoxy group, each of which is substituted in the terminal position with an alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or alkylsulfoximino group, means an alkyl, alkoxycarbonyl, alkanoyl, N-alkanoyl-aminomethyl, benzoyl, phenylmethoxymethyl -, aminocarbonyl, cyano, trifluoromethyl, aminosulfonyl, N-alkylaminocarbonylamino or N-alkyl-N-alkylaminocarbonylamino group,
R,- betyr et hydrogen- eller halogenatom, en alkyl- eller cyanogruppe, og R,- means a hydrogen or halogen atom, an alkyl or cyano group, and
Rg betyr et hydrogenatom eller en aminogruppe, under forut-setning at a) R^betyr ikke en alkylmerkaptogruppe i 4-stilling når Rg betyr et hydrogenatom eller R^i 5-stilling en metoksykarbonyl-, aminokarbonyl- eller cyanogruppe og samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, Rg means a hydrogen atom or an amino group, provided that a) R^ does not mean an alkyl mercapto group in the 4-position when Rg means a hydrogen atom or R^ in the 5-position a methoxycarbonyl, aminocarbonyl or cyano group and at the same time R2 in 2- position a methoxy or ethoxy group and R a hydrogen atom,
b) R^betyr ikke en alkylsulfinylgruppe i 4-stilling, når Rg betyr et hydrogenatom eller R^i 5-stilling en cyano- eller b) R^ does not mean an alkylsulfinyl group in the 4-position, when Rg means a hydrogen atom or R^ in the 5-position a cyano- or
aminokarbonylgruppe og samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, aminocarbonyl group and at the same time R2 in 2-position a methoxy or ethoxy group and R a hydrogen atom,
c) R^betyr ikke en alkylsulfonylgruppe i 4-stilling, når Rg betyr et hydrogenatom eller R^i 5-stilling en cyano- eller c) R^ does not mean an alkylsulfonyl group in the 4-position, when Rg means a hydrogen atom or R^ in the 5-position a cyano- or
aminokarbonylgruppe og samtidig R2i 2-stilling en metoksy-aminocarbonyl group and at the same time R2i 2 position a methoxy
eller etoksygruppe og R et hydrogenatom,or ethoxy group and R a hydrogen atom,
d) R^betyr ikke en alkylsulfoksiminogruppe i 4-stilling,d) R^ does not mean an alkylsulfoximino group in the 4-position,
når R^ i 5-stilling betyr en cyano- eller karbamidogruppe og when R^ in the 5-position means a cyano or carbamido group and
samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, eller at the same time R 2 in 2 position a methoxy or ethoxy group and R a hydrogen atom, or
e) R-^i 4-stilling betyr ikke en hydroksy- eller fenyl-alkoksygruppe, når Rg betyr et hydrogenatom eller R^i 5-stilling e) R-^in 4-position does not mean a hydroxy or phenyl-alkoxy group, when Rg means a hydrogen atom or R^in 5-position
en metoksykarbonyl-, aminokarbonyl- eller cyanogruppe og samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, a methoxycarbonyl, aminocarbonyl or cyano group and at the same time R2i 2-position a methoxy or ethoxy group and R a hydrogen atom,
idet de ovennevnte alkyl-, alkylen-, alkoksy- og alkanoyldeler i hvert tilfelle kan inneholde 1-3 karbonatomer. in that the above-mentioned alkyl, alkylene, alkoxy and alkanoyl parts can in each case contain 1-3 carbon atoms.
For de ved definisjonen av restene R og R-^til Rg innledningsvis angitte betydninger kommer f.eks. i betraktning for R betydningen et hydrogenatom, en metyl-, etyl-, n-propyl-eller isopropylgruppe, For the definitions of the residues R and R-^ to Rg given at the beginning, e.g. whereas for R the meaning is a hydrogen atom, a methyl, ethyl, n-propyl or isopropyl group,
for R^ betydningen en metylmerkapto-, etylmerkapto-, n-propyl-merkapto-, metylsulfinyl-, etylsulfinyl-, isopropylsulfinyl-, metylsulfonyl-, etylsulfonyl-, n-propylsulfonyl-, metylsulfoksimino-, etylsulf oksimino-, isopropylsulfoksimi.no-, N-acetyl- for R^ the meaning of a methylmercapto-, ethylmercapto-, n-propyl-mercapto-, methylsulfinyl-, ethylsulfinyl-, isopropylsulfinyl-, methylsulfonyl-, ethylsulfonyl-, n-propylsulfonyl-, methylsulfoximino-, ethylsulfoximino-, isopropylsulfoximino-, N-acetyl-
metylsulfoksimino-, N-propionyl-metylsulfoksimino-, N-metansulfonyl-metylsulfoksimino-, N-etansulfonyl-metylsulfoksimino-, N-hydroksykarbonylmetylenkarbonyl-metylsulfoksimino-, N-(2-hydroksykarbonyl-etylenkarbonyl)-metylsulfoksimino-, N-(3-hydroksykarbony 1-propylenkarbonyl) -metylsulfoksimi.no- , N-acetyl-etylsulfoksimi.no- , N-metansulf onyl-etylsulf oksimino- , N-acetyl-n-propylsulfoksimino-, 2-metylmerkaptoetoksy-, 2-i.sopropyl-merkaptoetoksy-, 2-metylsulfinyletoksy-, 2-metylsulfonyletoksy-, 2-metylsulfoksiminoetoksy-, 3-metylmerkapto-n-propoksy-,3-metylsulfinyl-n-propoksy-, 3-metylsulfonyl-n-propoksy-, 3-metylsulf oksimino-n-propoksy- , metoksykarbonylami.no-, etoksykarbonyl-ami.no- , n-propoksykarbonylami.no-, N-metylami nokarbonylamino-, N-etylaminokarbonylami.no- , N-isopropylaminokarbonyl- , hydroksy- , benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, 3-fenylpropoksy-, aminosulfonyl-, metylsulfonyloksy-, etylsulfonyloksy-, n-propylsulf onyloksy-, metansulfonylami.no-, etansulfonylami.no- eller propansulfonylaminogruppe, methylsulfoximino-, N-propionyl-methylsulfoximino-, N-methanesulfonyl-methylsulfoximino-, N-ethanesulfonyl-methylsulfoximino-, N-hydroxycarbonylmethylenecarbonyl-methylsulfoximino-, N-(2-hydroxycarbonyl-ethylenecarbonyl)-methylsulfoximino-, N-(3-hydroxycarbonyl) 1-propylenecarbonyl)-methylsulfoximino-, N-acetyl-ethylsulfoximino-, N-methanesulfonyl-ethylsulfoximino-, N-acetyl-n-propylsulfoximino-, 2-methylmercaptoethoxy-, 2-isopropyl-mercaptoethoxy- , 2-methylsulfinylethoxy-, 2-methylsulfonylethoxy-, 2-methylsulfoximinoethoxy-, 3-methylmercapto-n-propoxy-,3-methylsulfinyl-n-propoxy-, 3-methylsulfonyl-n-propoxy-, 3-methylsulfoximino-n- propoxy-, methoxycarbonylamino-, ethoxycarbonyl-amino-, n-propoxycarbonylamino-, N-methylaminocarbonylamino-, N-ethylaminocarbonylamino-, N-isopropylaminocarbonyl-, hydroxy-, benzyloxy-, 1-phenylethoxy- , 2-phenylethoxy-, 3-phenylpropoxy-, aminosulfonyl-, methylsulfonyloxy-, ethylsulfonyloxy-, n-propylsulfonyloxy-, methanesulfonylami.no-, ethanesulfonyl ami.no- or propanesulfonylamino group,
for R_ betydningen et hydrogenatom, en metoksy-, etoksy-, n-propoksy- eller isopropoksygruppe, for R_ meaning a hydrogen atom, a methoxy, ethoxy, n-propoxy or isopropoxy group,
for R^betydningen en 2-metylmerkaptoetoksy-, 2-etylmerkapto-etoksy-, 2-n-propylmerkaptoetoksy-, 2-metylsulfinyletoksy-, 2- i.sopropylsulf inyletoksy- , 2-metylsulf onyletoksy-, 2-etyl-sulfonyletoksy-, 2-metylsulfoksiminoetoksy-, 2-etylsulfoksimino-etoksy- , 2-n-propylsulfoksiminoetoksy-, 3-metylmerkaptopropoksy-, 3- etylmerkaptopropoksy-, 3-n-propylmerkaptopropoksy-, 3-metylsulf i.nylpropoksy- , 3-isopropylsulfinylpropoksy-, 3-metylsulfonyl-propoksy-, 3-etylsulfonylpropoksy-, 3-metylsulfoksiminopropoksy-, 3-etylsulfoksiminopropoksy- eller 3-n-propylsulfoksiminopropoksy-gruppe, for the R meaning a 2-methylmercaptoethoxy-, 2-ethylmercaptoethoxy-, 2-n-propylmercaptoethoxy-, 2-methylsulfinylethoxy-, 2-isopropylsulfinylethoxy-, 2-methylsulfonylethoxy-, 2-ethylsulfonylethoxy-, 2-methylsulfoximinoethoxy-, 2-ethylsulfoximinoethoxy-, 2-n-propylsulfoximinoethoxy-, 3-methylmercaptopropoxy-, 3- ethylmercaptopropoxy-, 3-n-propylmercaptopropoxy-, 3-methylsulf i.nylpropoxy-, 3-isopropylsulfinylpropoxy-, 3 -methylsulfonylpropoxy, 3-ethylsulfonylpropoxy, 3-methylsulfoximinopropoxy, 3-ethylsulfoximinopropoxy or 3-n-propylsulfoximinopropoxy group,
for R4betydningen en metyl-, etyl-, n-propyl-, metoksykarbonyl-, etoksykarbonyl-, i.sopropoksykarbonyl-, acetyl-, propionyl-, benzoyl-, N-acetyl-aminometyl-, N-propionyl-aminometyl-, fenyl-metoksymetyl-, aminokarbonyl-, cyano-, trifluormetyl-, amino-sulf onyl-, N-metylaminokarbonyl-amino-, N-etylaminokarbonyl-amino-, N-n-propylaminokarbonyl-amino-, N-isopropylaminokarbonyl-amino- , N-metyl-N-metylaminokarbonyl-amino- , N-etyl-N-etylami.no-karbonyl-amino-, eller N-metyl-N-etylaminokarbonyl-aminogruppe, for R^betydningen et hydrogen-, fluor-, klor- eller brom-atom, en cyano-, metyl-, etyl-, n-propyl- eller isopropylgruppe, og for the R4 meaning a methyl-, ethyl-, n-propyl-, methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl-, acetyl-, propionyl-, benzoyl-, N-acetyl-aminomethyl-, N-propionyl-aminomethyl-, phenyl- methoxymethyl-, aminocarbonyl-, cyano-, trifluoromethyl-, amino-sulfonyl-, N-methylaminocarbonyl-amino-, N-ethylaminocarbonyl-amino-, N-n-propylaminocarbonyl-amino-, N-isopropylaminocarbonyl-amino-, N-methyl- N-methylaminocarbonyl-amino-, N-ethyl-N-ethylamino.no-carbonyl-amino-, or N-methyl-N-ethylaminocarbonyl-amino group, for R^ meaning a hydrogen, fluorine, chlorine or bromine atom , a cyano, methyl, ethyl, n-propyl or isopropyl group, and
for Rg betydningen et hydrogenatom eller en aminogruppe. for Rg meaning a hydrogen atom or an amino group.
Foretrukne forbindelser med den ovenstående generelle formel I er de hvor Preferred compounds of the above general formula I are those wherein
R betyr et hydrogenatom eller en metylgruppe,R means a hydrogen atom or a methyl group,
R1betyr en metylsulfenyl-, etylsulfenyl-, metylsulfinyl-, etylsulfinyl-, metylsulfonyl-, etylsulfonyl-, metylsulfoksimino-, etylsulfoksimi.no- eller n-propylsulf oksimi nogruppe, en på nitrogenatomet med en acetyl-, metansulfonyl- eller hydroksykarbonyl-etylenkarbonylgruppe substituert metylsulfoksiminogruppe , en i endestiIling med en metylsulfoksiminogruppe substituert etoksygruppe, en metoksykarbonylami.no- eller N-metylami.no-karbonylaminogruppe eller også i. 4-stilling en hydroksy-, benzyloksy-, aminosulfonyl-, metansulfonyloksy- eller metansulf onylaminogruppe , når R1 denotes a methylsulfenyl, ethylsulfenyl, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, methylsulfoximino, ethylsulfoximino or n-propylsulfoximino group, a methylsulfoximino group substituted on the nitrogen atom with an acetyl-, methanesulfonyl- or hydroxycarbonyl-ethylenecarbonyl group , an ethoxy group substituted at the end with a methylsulfoximino group, a methoxycarbonylamino- or N-methylamino-carbonylamino group or also in the 4-position a hydroxy-, benzyloxy-, aminosulfonyl, methanesulfonyloxy or methanesulfonylamino group, when
a) A og B sammen med de to mellomliggende karbonatomer betyr en a) A and B together with the two intervening carbon atoms means one
b) R4betyr en metyl-, acetyl-, N-acetyl-aminometyl-, benzoyl-, fenylmetoksymetyl-, aminosulfonyl-, N-etylami.nokarbonylami.no-, N-i.sopropylami.nokarbonylamino- eller N-metyl-N-metylaminokarbonyl-aminogruppe, eller b) R4 represents a methyl-, acetyl-, N-acetyl-aminomethyl-, benzoyl-, phenylmethoxymethyl-, aminosulfonyl-, N-ethylaminocarbonylamino-, N-isopropylaminocarbonylamino- or N-methyl-N-methylaminocarbonyl- amino group, or
c) Rg betyr en aminogruppe,c) Rg means an amino group,
idet minst én av restene må ha de under a), b) og c) as at least one of the residues must have those under a), b) and c)
angitte betydninger,stated meanings,
R2betyr et hydrogenatom, en metoksy- eller en etoksygruppe, R3betyr en etoksygruppe som i. endesti Iling er substi tuert med en metylsulfenyl-, metylsulfinyl-, metylsulfonyl- eller metylsulf oksiminogruppe , R2 means a hydrogen atom, a methoxy or an ethoxy group, R3 means an ethoxy group which is ultimately substituted with a methylsulfenyl, methylsulfinyl, methylsulfonyl or methylsulfoximino group,
R4betyr en metyl-, metoksykarbonyl-, acetyl-, N-acetylamino-metyl-, benzoyl-, fenylmetoksymetyl-, aminokarbonyl-, cyano-, trifluormetyl-, aminosulfonyl-, N-etylaminokarbonyl-amino-, N-isopropylaminokarbonyl-amino- eller N-metyl-N-metylaminokarbonyl-aminogruppe, R4 means a methyl-, methoxycarbonyl-, acetyl-, N-acetylamino-methyl-, benzoyl-, phenylmethoxymethyl-, aminocarbonyl-, cyano-, trifluoromethyl-, aminosulfonyl-, N-ethylaminocarbonyl-amino-, N-isopropylaminocarbonyl-amino- or N-methyl-N-methylaminocarbonyl-amino group,
R,- betyr et hydrogen- eller kloratom, en metyl- eller cyanogruppe og R,- means a hydrogen or chlorine atom, a methyl or cyano group and
Rg betyr et hydrogenatom eller en aminogruppe, under den forut-setning at Rg means a hydrogen atom or an amino group, provided that
a) R^betyr ikke en metyl- eller etylmerkaptogruppe i 4-stilling når Rg betyr et hydrogenatom eller R^i 5-stilling en a) R^ does not mean a methyl or ethyl mercapto group in the 4-position when Rg means a hydrogen atom or R^ in the 5-position a
metoksykarbonyl-, aminokarbonyl- eller cyanogruppe og samtidig R2 i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, methoxycarbonyl, aminocarbonyl or cyano group and at the same time R2 in the 2-position a methoxy or ethoxy group and R a hydrogen atom,
b) R^betyr ikke en metyl- eller etylsulfinylgruppe i 4-stilling når Rg betyr et hydrogenatom eller R^i 5-stilling b) R^ does not mean a methyl or ethylsulfinyl group in the 4-position when Rg means a hydrogen atom or R^ in the 5-position
en cyano- eller aminokarbonylgruppe og samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, a cyano or aminocarbonyl group and at the same time R 2 in 2 position a methoxy or ethoxy group and R a hydrogen atom,
c) R^betyr ikke en metyl- eller etylsulfonylgruppe i 4-stilling når Rg betyr et hydrogenatom eller R^i 5-stilling en c) R^ does not mean a methyl or ethylsulfonyl group in the 4-position when Rg means a hydrogen atom or R^ in the 5-position a
cyano- eller aminokarbonylgruppe og samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, d) R^betyr ikke en metyl- eller etylsulfoksiminogruppe i 4-stilling når R4i 5-stilling betyr en cyano- eller karbamidogruppe og samtidig R2i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, eller e) R-^i 4-stilling betyr ikke en hydroksy- eller benzyloksygruppe når Rg betyr et hydrogenatom eller R^i 5-stilling en cyano or aminocarbonyl group and at the same time R2i 2 position a methoxy or ethoxy group and R a hydrogen atom, d) R^ does not mean a methyl or ethylsulfoximino group in the 4-position when R4i 5-position means a cyano or carbamido group and at the same time R2i 2 -position a methoxy or ethoxy group and R a hydrogen atom, or e) R-^i 4-position does not mean a hydroxy or benzyloxy group when Rg means a hydrogen atom or R^i 5-position a
metoksykarbonyl-, aminokarbonyl- eller cyanogruppe og samtidig R2 i 2-stilling en metoksy- eller etoksygruppe og R et hydrogenatom, samt forbindelsene methoxycarbonyl, aminocarbonyl or cyano group and at the same time R2 in the 2-position a methoxy or ethoxy group and R a hydrogen atom, as well as the compounds
5-cyano-2-(4'-metansulfonylami no-2'-metoksy-fenyl)-benzimidazol , 5-cyano-2-(4'-methanesulfonylamino-2'-methoxy-phenyl)-benzimidazole,
4-metyl-2-(4'-metansulfonyloksy-2<1->metoksy-fenyl)-benzimidazol , 4-methyl-2-(4'-methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole,
4-cyano-2-(4'-metansulfonyloksy-2'-metoksy-fenyl)-benzimidazol , 4-cyano-2-(4'-methanesulfonyloxy-2'-methoxy-phenyl)-benzimidazole,
4-aminokarbonyl-2-(4<1->metansulfonyloksy-2<1->metoksy-fenyl)-benzimidazol og 4-aminocarbonyl-2-(4<1->methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole and
4-metoksykarbonyl-2-(4<1->metansulfonyloksy-2<1->metoksy-fenyl)-benzimidazol, 4-methoxycarbonyl-2-(4<1->methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole,
deres tautomerer og deres syreaddisjonssalter, særlig deres fysiologisk forlikelige syreaddisjonssalter. their tautomers and their acid addition salts, especially their physiologically compatible acid addition salts.
Særlig foretrukne forbindelser med den generelle formelParticularly preferred compounds of the general formula
I er 2-[2'-metoksy-4'-(N-acetyl-metylsulfoksimino-fenyl)]-5-cyano-benzimidazol I is 2-[2'-methoxy-4'-(N-acetyl-methylsulfoximino-phenyl)]-5-cyano-benzimidazole
2-(2'-metoksy-4'-metylsulfinyl-fenyl)-5-acetyl-benzimidazol, 2-(2'-metoksy-4'-metylsulfonyl-fenyl)-5-acetyl-benzimidazol, 5- cyano-2-(4'-metansulfonylamino-2'-metoksyfenyl)-benzimidazol, 2-(2<1->metoksy-4'-metoksykarbonylamino-fenyl)-imidazo[4,5-c]-pyridin, 2-(2'-Methoxy-4'-methylsulfonyl-phenyl)-5-acetyl-benzimidazole, 2-(2'-Methoxy-4'-methylsulfonyl-phenyl)-5-acetyl-benzimidazole, 5- cyano-2- (4'-methanesulfonylamino-2'-methoxyphenyl)-benzimidazole, 2-(2<1->methoxy-4'-methoxycarbonylamino-phenyl)-imidazo[4,5-c]-pyridine,
6- cyano-2-(2'-metoksy-4-metylmerkapto-fenyl)-imidazo[4,5-b]-pyridin, 6- cyano-2-(2'-methoxy-4-methylmercapto-phenyl)-imidazo[4,5-b]-pyridine,
2-amino-8-(2'-metoksy-4<1->metylsulfinyl-fenyl)-purin, 2-(2'-metoksy-4'-metylsulfoksimino-fenyl)-lH-imidazo[4,5-c]-pyridin, 2-amino-8-(2'-methoxy-4<1->methylsulfinyl-phenyl)-purine, 2-(2'-methoxy-4'-methylsulfoximino-phenyl)-1H-imidazo[4,5-c] -pyridine,
5-aminokarbonyl-2-(4'-metansulfonyloksy-2<1->metoksy-fenyl)-benzimidazol og 5-aminocarbonyl-2-(4'-methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole and
5-acetyl-2-(4<1->metansulfonyloksy-2'-metoksy-fenyl)-benzimidazol, deres tautomerer og deres syreaddisjonssalter, særlig deres fysiologisk forlikelige syreaddisjonssalter. 5-Acetyl-2-(4<1->methanesulfonyloxy-2'-methoxy-phenyl)-benzimidazole, their tautomers and their acid addition salts, especially their physiologically compatible acid addition salts.
Ifølge oppfinnelsen fremstilles de nye forbindelser ved følgende fremgangsmåter: a) ringslutning av en eventuelt i reaksjonsblandingen fremstilt forbindelse med den generelle formel According to the invention, the new compounds are produced by the following methods: a) ring closure of a compound with the general formula possibly produced in the reaction mixture
hvor where
A, B og R er som innledningsvis angitt,A, B and R are, as indicated at the outset,
én av restene X eller Y betyr et hydrogenatom og den annen av restene X og Y eller begge restene X og Y betyr en gruppe med formelen one of the residues X or Y means a hydrogen atom and the other of the residues X and Y or both residues X and Y means a group with the formula
Ar er som innledningsvis angitt, Ar is, as stated at the outset,
Z^og Z2, som kan være like eller forskjellige, betyr eventuelt substituerte aminogrupper eller eventuelt med lavere alkyl-grupper substituerte hydroksy- eller merkaptogrupper, eller og Z2betyr sammen et oksygen- eller svovelatom, en eventuelt med en alkylgruppe med 1-3 karbonatomer substituert iminogruppe, en alkylendioksy- eller alkylenditiogruppe med hver 2 eller 3 karbonatomer. Z^ and Z 2 , which may be the same or different, mean optionally substituted amino groups or optionally substituted with lower alkyl groups hydroxy or mercapto groups, or and Z 2 together mean an oxygen or sulfur atom, one optionally substituted with an alkyl group with 1-3 carbon atoms imino group, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms.
Ringslutningen foretas hensiktsmessig i et oppløsning-middel eller en oppløsningsmiddel-blanding såsom etanol, iso-propanol, iseddik, benzen, klorbenzen, toluen, xylen, glykol, glykolmonometyleter, dietylenglykoldimetyleter, sulfolan, dimetylformamid, tetralin eller i et overskudd av det for fremstilling av forbindelsen med den generelle formel II anvendte acyleringsmiddel, f.eks. i det passende nitril, anhydrid, syre-halogenid, ester, amid eller metojodid, f.eks. ved temperaturer mellom 0 og 250°C, fortrinnsvis ved reaksjonsblandingens koketemperatur, eventuelt i nærvær av et kondensasjonsmiddel såsom fosforoksyklorid, tionylklorid, sulfurylklorid, svovelsyre, p-toluensulfonsyre, metansulfonsyre, saltsyre, fosforsyre, polyfosforsyre, eddiksyreanhydrid eller eventuelt også i nærvær av en base såsom kaliumetylat eller kalium-tert.-butylat. Ringslutningen kan også utføres uten oppløsningsmiddel og/eller kondensasjonsmiddel. b) For fremstilling av forbindelser med den generelle formel I hvor R^betyr en alkylsulfinyl-, alkylsulfonyl- eller alkylsulf oksiminogruppe , en på nitrogenatomet med en alkanoyl-, alkylsulfonyl- eller hydroksykarbonyl-alkylenkarbonylgruppe substituert alkylsulfoksimonogruppe, en etoksy- eller n-propoksygruppe, som i endestilling er substituert med en alkylsulf inyl-, alkylsulfonyl- eller alkylsulfoksiminogruppe, eller R^ en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulfinyl-, alkylsulfonyl- eller alkylsulf oksiminogruppe : oksydasjon av en forbindelse med den generelle formel The cyclization 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 production of the compound with the general formula II used acylating agent, e.g. in the appropriate nitrile, anhydride, acid halide, ester, amide or methoiodide, e.g. 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, methanesulfonic 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. The cyclization can also be carried out without solvent and/or condensing agent. b) For the preparation of compounds with the general formula I where R^ denotes an alkylsulfonyl, alkylsulfonyl or alkylsulfoximino group, an alkylsulfoxy monogroup substituted on the nitrogen atom with an alkanoyl, alkylsulfonyl or hydroxycarbonylalkylenecarbonyl group, an ethoxy or n-propoxy group, which is substituted in the terminal position with an alkylsulfinyl, alkylsulfonyl or alkylsulfoximino group, or R^ an ethoxy or n-propoxy group which is substituted in the terminal position with an alkylsulfinyl, alkylsulfonyl or alkylsulfoximino group: oxidation of a compound of the general formula
hvor K where K
A, B og R er som innledningsvis angitt, ogA, B and R are as stated at the outset, and
Ar-^har de for Ar innledningsvis angitte betydninger, idet imidlertid R^betyr en alkylsulfenyl-, alkylsulfinyl- eller alkylsulfiminogruppe, en på nitrogenatomet med en alkanoyl-, alkylsulfonyl- eller hydroksykarbonylalkylenkarbonylgruppe substituert alkylsulfiminogruppe, en etoksy- eller n-propoksygruppe, som i endestilling er substituert med en alkylsulfenyl-, alkylsulfinyl- eller alkylsulfiminogruppe, eller R., en etoksy-eller n-propoksygruppe, som i endestilling er substituert med en alkylsulfenyl-, alkylsulfinyl- eller alkylsulfiminogruppe. Ar-^ has the meanings given for Ar at the beginning, with R^, however, meaning an alkylsulfinyl, alkylsulfinyl or alkylsulfimino group, an alkylsulfimino group substituted on the nitrogen atom with an alkanoyl, alkylsulfonyl or hydroxycarbonylalkylenecarbonyl group, an ethoxy or n-propoxy group, as in end position is substituted with an alkylsulfenyl, alkylsulfinyl or alkylsulfimino group, or R., an ethoxy or n-propoxy group, which is substituted at the end position with an alkylsulfenyl, alkylsulfinyl or alkylsulfimino group.
Oksydasjonen foretas fortrinnsvis i et oppløsningsmiddel eller en oppløsningsmiddel-blanding, f.eks. i vann, vann/pyridin, aceton, iseddik, fortynnet svovelsyre eller trifluoreddiksyre, alt efter det anvendte oksydasjonsmiddel hensiktsmessig ved temperaturer mellom -80 og 100°C. The oxidation is preferably carried out in a solvent or a solvent mixture, e.g. 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 fremstilling av en alkylsulf inyl- eller sulfoksi.mi.no-forbi.ndelse med den generelle formel I fortas oksydasjonen hensiktsmessig med en ekvivalent av det anvendte oksydasjonsmiddel, f. eks. med hydrogenperoksyd i. iseddik, trif luoreddiksyre eller maursyre ved 0-20°C eller i aceton ved 0-60°C, med en persyre såsom permaursyre i iseddik eller trufluoreddiksyre ved 0-50°C, eller med m-klorperbenzosyre i metylenklorid eller kloroform ved -20-60°C, med natrium-metaperjodat i vandig metanol eller etanol ved -15-25°C, med brom i iseddik eller vandig eddiksyre, med N-bromsuksini.mid i etanol, med tert.butyl-hypokloritt i. metanol ved -80 til -30°C, med jodbenzodiklorid i vandig pyridin ved 0-50°C, med salpetersyre i iseddik ved 0-20°C, med kromsyre i iseddik eller i. aceton ved 0-20°C og med sulfurylklorid i metylenklorid ved -70°C, idet det herved oppnådde tioeter-klor-kompleks hensiktsmessig hydrolyseres med vandig etanol. For the preparation of an alkylsulfinyl or sulfoxymino compound with the general formula I, the oxidation is suitably carried out with an equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0-20°C or in acetone at 0-60°C, with a peracid such as permauric acid in glacial acetic acid or trifluoroacetic acid at 0-50°C, or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20-60°C, with sodium metaperiodate in aqueous methanol or ethanol at -15-25°C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in . methanol at -80 to -30°C, with iodobenzodichloride in aqueous pyridine at 0-50°C, with nitric acid in glacial acetic acid at 0-20°C, with chromic acid in glacial acetic acid or in. acetone at 0-20°C and with sulfuryl chloride in methylene chloride at -70°C, the thioether-chlorine complex thus obtained being suitably hydrolysed with aqueous ethanol.
For fremstilling av en alkylsulfonylforbindelse med den generelle formel I foretas oksydasjonen hensiktsmessig med én resp. med to eller flere ekvivalenter av det anvendte oksydasjonsmiddel, f. eks. med hydrogenperoksyd i. iseddik, trif luoreddiksyre eller i maursyre ved 20-100°C eller i. aceton ved 0-60°C, med en persyre såsom permaursyre eller m-klorperbenzosyre i iseddik, trifluoreddi.ksye, metylenklorid eller kloroform ved temperaturer mellom 0 og 60°C, med salpetersyre i iseddik ved 0-20°C, med kromsyre eller kaliumpermanganat i. iseddik, vann/svovelsyre eller i. aceton ved 0-20°C. For the preparation of an alkylsulfonyl compound of the general formula I, the oxidation is suitably carried out with one resp. with two or more equivalents of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20-100°C or in acetone at 0-60°C, with a peracid such as performic 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 0-20°C, with chromic acid or potassium permanganate in glacial acetic acid, water/sulfuric acid or in. acetone at 0-20°C.
c) For fremstilling av forbindelser med den generelle formel I, hvor R^betyr en alkylsulfoksiminogruppe, en etoksy- eller c) For the preparation of compounds of the general formula I, where R^ denotes an alkylsulfoximino group, an ethoxy- or
n-propoksygruppe, som i endestilling er substituert med en alkylsulfoksiminogruppe, eller R^en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulfoksiminogruppe : n-propoxy group, which is substituted in the terminal position with an alkylsulfoximino group, or R^an ethoxy or n-propoxy group which is substituted in the terminal position with an alkylsulfoximino group:
omsetning av et sulfoksyd med den generelle formelreaction of a sulfoxide with the general formula
hvor where
A, B og R er som innledningsvis angitt, ogA, B and R are as stated at the outset, and
Ar2har de for Ar innledningsvis angitte betydninger,Ar2 has the meanings given for Ar at the beginning,
idet imidlertid R^er en alkylsulfinylgruppe, en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulf inylgruppe, eller R^en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulfinylgruppe, med eventuelt i reaksjonsblandingen dannet hydrogenazid. where, however, R^ is an alkylsulfinyl group, an ethoxy or n-propoxy group which is substituted in the end position with an alkylsulfinyl group, or R^ an ethoxy or n-propoxy group which is substituted in the end position with an alkylsulfinyl group, possibly with hydrogen azide formed in the reaction mixture .
Omsetningen foretas hensiktsmessig i. et oppløsningsmiddel eller en oppløsningsmiddel-blanding 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 et alkaliazid, f.eks. natriumazid, og polyfosforsyre som oppløsningsmiddel. The reaction is conveniently 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. It is particularly advantageous to carry out the reaction with an alkali azide, e.g. sodium azide, and polyphosphoric acid as solvent.
d) For fremstilling av forbindelser med den generelle formel I hvor R^betyr en alkylsulfoksiminogruppe, en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulf oksiminogruppe , eller R^en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulfoksiminogruppe: omsetning av et sulfoksyd med den generelle formel d) For the preparation of compounds with the general formula I where R^ means an alkylsulfoximino group, an ethoxy or n-propoxy group which is substituted in the end position with an alkylsulfoximino group, or R^ an ethoxy or n-propoxy group which is substituted in the end position with an alkylsulfoximino group: reaction of a sulfoxide of the general formula
hvor where
A, B og R er som innledningsvis angitt, ogA, B and R are as stated at the outset, and
Ar2her de for Ar innledningsvis angitte betydninger,Ar2here the meanings given for Ar at the beginning,
idet imidlertid R^betyr en alkylsulfinylgruppe, en etoksy-eller n-propoksygruppe som i endestilling er substituert med en alkylsulfinylgruppe, eller R^ en etoksy- eller n-propoksygruppe som i endestilling er substituert med en alkylsulfinylgruppe , med en eventuelt i reaksjonsblandingen fremstilt forbindelse med den generelle formel where, however, R^ means an alkylsulfinyl group, an ethoxy or n-propoxy group which is substituted in the end position with an alkylsulfinyl group, or R^ an ethoxy or n-propoxy group which is substituted in the end position with an alkylsulfinyl group, with a compound possibly produced in the reaction mixture with the general formula
hvor where
U betyr en karbonyl- eller sulfonylgruppe ogU means a carbonyl or sulfonyl group and
R.^ en i o-stilling disubstituert arylgruppe såsom en 2,4,6-trimetylfenyl- eller 2,4,6-triisopropylfenylgruppe. R.^ 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 oppløsningsmiddel eller en oppløsningsmiddel-blanding såsom metylenklorid, kloroform, dimetylformamid, tetrahydrofuran eller dioksan, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved temperaturer mellom 5 og 40°C, og eventuelt i nærvær av en katalytisk mengde av en syre såsom p-toluensulfonsyre. Særlig fordelaktig foretas imidlertid omsetningen ved at en forbindelse med den generelle formel V anvendes uten forutgående isolering resp. fremstilles i reaksjonsblandingen. e) For fremstilling av en forbindelse med den generelle formel I, hvor R^betyr en på nitrogenatomet med en alkanoyl-, alkylsulfonyl- eller hydroksykarbonyl-alkylenkarbonylgruppe substituert alkylsulfoksiminogruppe: The reaction is suitably 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. However, the conversion is particularly advantageous by using a compound of the general formula V without prior isolation or is produced in the reaction mixture. e) For the preparation of a compound of the general formula I, where R^ denotes an alkylsulfoximino group substituted on the nitrogen atom with an alkanoyl, alkylsulfonyl or hydroxycarbonylalkylenecarbonyl group:
acylering av en forbindelse med den generelle formelacylation of a compound of the general formula
hvor where
A, B og R er som innledningsvis angitt, ogA, B and R are as stated at the outset, and
Ar^har de for Ar innledningsvis angitte betydninger,Ar^ have the meanings indicated for Ar at the beginning,
idet imidlertid R-^betyr en alkylsulf oksiminogruppe, med en however, R-^ means an alkylsulfoximino group, with a
forbindelse med den generelle formel connection with the general formula
hvor where
Rg betyr en alkanoyl-, alkylsulfonyl- eller hydroksykarbonyl-alkylenkarbonylgruppe og Rg means an alkanoyl, alkylsulfonyl or hydroxycarbonyl-alkylenecarbonyl group and
V en nukleofug utgående gruppe såsom et halogenatom eller en alkanoyloksygruppe, eller dens estere og anhydrider. V is a nucleofuge leaving group such as a halogen atom or an alkanoyloxy group, or its esters and anhydrides.
Omsetningen utføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddel-blanding såsom vann, metylenklorid, kloroform, eter, tetrahydrofuran, dioksan eller dimetylformamid, med en passende forbindelse i nærvær av et syre-aktiverende eller vanntiltrekkende middel såsom tionylklorid, med anhydrider såsom eddiksyreanhydrid, med estere såsom eddiksyreetylester, med halogenider såsom acetylklorid eller metansulfonylklorid, eventuelt i. nærvær av en uorganisk eller tertiær organisk base såsom natriumhydroksyd, kaliumkarbonat, trietylamin eller pyridin, idet de to sistnevnte samtidig også kan tjene som oppløsnings-middel, ved temperaturer mellom -25 og 100°C, fortrinnsvis ved temperaturer mellom -10 og 80°C. f) For fremstilling av forbindelser med den generelle formel I hvor R^betyr en alkylsulf onyloksy-, alkylsulfonylami.no-, alkoksykarbonylamino- eller N-alkylaminokarbonyl-aminogruppe eller R^en alkanoylami.nometyl-, N-etylami nokarbonylamino-, N-n-propylaminokarbonylamino-, N-i.sopropylami.nokarbonylami.no-eller N-alkyl-N-alkylaminokarbon<y>1-ami.nogruppe: The reaction is suitably carried out in a solvent or solvent mixture such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide, with a suitable compound in the presence of an acid-activating or water-attracting agent such as thionyl chloride, with anhydrides such as acetic anhydride, with esters such as acetic acid ethyl ester, with halides such as acetyl chloride or methanesulfonyl chloride, optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, the two latter at the same time also serving as a solvent, at temperatures between -25 and 100 °C, preferably at temperatures between -10 and 80°C. f) For the preparation of compounds of the general formula I where R^ means an alkylsulfonyloxy-, alkylsulfonylamino-, alkoxycarbonylamino- or N-alkylaminocarbonyl-amino group or R^ an alkanoylaminomethyl-, N-ethylaminocarbonylamino-, N-n- propylaminocarbonylamino, N-isopropylaminocarbonylamino or N-alkyl-N-alkylaminocarbon<y>1-amino group:
acylering av en forbindelse med den generelle formelacylation of a compound of the general formula
hvor where
A, B og R er som innledningsvis angitt, og Ar^har de for Ar innledningsvis angitte betydninger, idet imidlertid R^betyr en hydroksy- eller aminogruppe eller R. en aminometyl- eller aminogruppe, med en forbindelse med den generelle formel A, B and R are as indicated at the beginning, and Ar^ has the meanings indicated for Ar at the beginning, with R^ meaning a hydroxy or amino group or R. an aminomethyl or amino group, with a compound of the general formula
hvor where
Rg betyr en alkylgruppe med 1-3 karbonatomer ogRg means an alkyl group with 1-3 carbon atoms and
W en 0=N=C- eller halogensulfonylgruppe såsom en klor- eller bromsulfonylgruppe, eller W an O=N=C- or halosulfonyl group such as a chloro or bromosulfonyl group, or
Rg betyr en metyl- eller etylgruppe ogRg means a methyl or ethyl group and
W en -CO-V-gruppe, hvor V betyr en nukleofug utgående gruppeW a -CO-V group, where V means a nucleofuge leaving group
såsom et halogenatom eller en alkanoyloksygruppe.such as a halogen atom or an alkanoyloxy group.
Omsetningen utføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddel-blanding såsom metylenklorid, kloroform, karbontetraklorid, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt også i nærvær av et syre-aktiverende middel eller et vanntiltrekkende middel, f.eks. i nærvær av klormaursyreetylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N<1->dicykloheksylkarbodiimid, N,N<1->dicykloheksylkarbodiimid/N-N-hydroksysuksinimid, N,N<1->karbonyl-diimidazol eller N,N<1->tionyldiimidazol, og eventuelt i nærvær av en uorganisk base såsom natriumkarbonat eller en tertiær organisk base såsom trietylamin eller pyridin, idet begge de sistnevnte også kan tjene som oppløsningsmiddel, ved temperaturer mellom -25 og 250°C, fortrinnsvis ved temperaturer mellom -10°C The reaction is conveniently carried out in a solvent or a solvent mixture such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally also in the presence of an acid-activating agent or a water-attracting agent, e.g. . in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N<1->dicyclohexylcarbodiimide, N,N<1->dicyclohexylcarbodiimide/N-N-hydroxysuccinimide, N,N<1->carbonyldiimidazole or N,N<1- >thionyldiimidazole, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, the latter both of which can also serve as a solvent, at temperatures between -25 and 250°C, preferably at temperatures between -10° C
og det anvendte oppløsningsmiddels koketemperatur.and the boiling point of the solvent used.
g) For fremstilling av forbindelser med den generelle formel I hvor R betyr en alkylgruppe: g) For the preparation of compounds of the general formula I where R means an alkyl group:
alkylering av en forbindelse med den generelle formelalkylation of a compound of the general formula
hvor where
A, B og Ar er som inneldningsvis angitt.A, B and Ar are as initially indicated.
Omsetningen foretas med et passende alkyleringsmiddel såsom metyljodid, etyljodid, dietylsulfat, dimetylsulfat eller n-propylbromid, hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddel-blanding såom metylenklorid, eter, tetrahydrofuran, dioksan, vann eller benzen, eventuelt i nærvær av et syre-bindende middel såsom natriumkarbonat, natriumhydroksyd, trietyl amin eller pyridin, idet de to sistnevnte samtidig også kan anvendes som oppløsningsmiddel, fortrinnsvis ved temperaturer mellom 0 og 100°C, f.eks. mellom romtemperatur og 50°C. The reaction is carried out with a suitable alkylating agent such as methyl iodide, ethyl iodide, diethyl sulphate, dimethyl sulphate or n-propyl bromide, suitably in a solvent or a solvent mixture such as methylene chloride, ether, tetrahydrofuran, dioxane, water or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, sodium hydroxide, triethyl amine or pyridine, the two latter can also be used as a solvent at the same time, preferably at temperatures between 0 and 100°C, e.g. between room temperature and 50°C.
Hvis man ifølge oppfinnelsen oppnår en forbindelse med den generelle formel I hvor R, betyr en benzyloksygruppe, kan denne ved debenzylering overføres til den tilsvarende hydroksyforbindelse, og/eller If, according to the invention, a compound with the general formula I is obtained where R means a benzyloxy group, this can be transferred by debenzylation to the corresponding hydroxy compound, and/or
en fremstilt forbindelse med den generelle formel I hvor R^ betyr en cyangruppe, kan ved hydrolyse overføres til den tilsvarende aminokarbonylforbindelse. a prepared compound of the general formula I where R 1 means a cyano group can be transferred by hydrolysis to the corresponding aminocarbonyl compound.
Den påfølgende debenzylering foretas fortrinnsvis i et oppløsningsmiddel såsom vann, vann/etanol, metanol, iseddik, eddiksyreetylester eller dimetylformamid, hensiktsmessig med hydrogen i nærvær av en hydrogeneringskatalysator såsom Raney-nikkel, platina eller palladium/kull, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. The subsequent debenzylation 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, at temperatures between 0 and 50°C , preferably at room temperature.
Den påfølgende hydrolyse utføres i nærvær av en uorganisk base med hydrogenperoksyd, f.eks. med 2N natronlut eller kalilut/hydrogenperoksyd, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. The subsequent hydrolysis is carried out in the presence of an inorganic base with hydrogen peroxide, e.g. with 2N caustic soda or caustic soda/hydrogen peroxide, at temperatures between 0 and 50°C, preferably at room temperature.
De ifølge oppfinnelsen fremstilte nye forbindelser kan derefter eventuelt overføres til sine syreaddisjonssalter. De således oppnådde forbindelser kan dessuten for farmasøytisk anvendelse overføres til sine fysiologisk forelikelige syreaddis jonssalter . Som syrer kommer her f.eks. i betraktning saltsyre, bromhydrogensyre, svovelseyre, fosforsyre, fumarsyre, ravsyre, vinsyre, sitronsyre, melkesyre, maleinsyre eller metansulf onsyre. The new compounds produced according to the invention can then optionally be transferred to their acid addition salts. The compounds thus obtained can also be transferred for pharmaceutical use to their physiologically compatible acid addition salts. As acids, e.g. considering hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
De som utgangsstoffer anvendte forbindelser med de generelle formler II til X er delvis kjent fra litteraturen eller kan fremstilles ved i og for seg kjente fremgangsmåter. Således oppnår man f.eks. de som utgangsstoffer anvendte forbindelser med den generelle formel II ved acylering av de tilsvarende o-diami.no-forbindelser resp. ved reduksjon av de tilsvarende acylami.no-nitro-forbindelser, samt forbindelsene med de generelle formler III, IV, VI, VII eller X ved ri.ngslutni.ng av en tilsvarende o-acylamino-aminoforbindelse (se BE-PS 810.545 og EP-A-0.024.290) og eventuelt påfølgende debenzylering. The compounds with the general formulas II to X used as starting materials are partly known from the literature or can be prepared by methods known per se. Thus one achieves e.g. the compounds with the general formula II used as starting materials by acylation of the corresponding o-diami.no compounds resp. by reduction of the corresponding acylamino-nitro compounds, as well as the compounds with the general formulas III, IV, VI, VII or X by addition of a corresponding o-acylamino-amino compound (see BE-PS 810.545 and EP -A-0.024.290) and possibly subsequent debenzylation.
Som nevnt innledningsvis oppviser de nye forbindelser med den generelle formel I, deres 1H tautomerer ogderesfysiologi.sk forli.kelige syreaddis jonssalter langvarige, 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 long-lasting, superior pharmacological properties, 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'-(N-acetyl-sulfoksimino-fenyl)]-5-cyano-beivzimidazol, A = 2-[2'-methoxy-4'-(N-acetyl-sulfoximino-phenyl)]-5-cyano-beivzimidazole,
B = 2-(2'-metoksy-4<1->metylsulfinyl-fenyl)-5-acetyl-benzimidazol , B = 2-(2'-methoxy-4<1->methylsulfinyl-phenyl)-5-acetyl-benzimidazole,
C = 2-(2'-metoksy-4<1->metylsulfonyl-fenyl)-5-acetyl-benzimidazol , C = 2-(2'-methoxy-4<1->methylsulfonyl-phenyl)-5-acetyl-benzimidazole,
D = 5-cyano-2-(4<1->metansulfonylamino-2<1->metoksy-fenyl)-benzimidazol og D = 5-cyano-2-(4<1->methanesulfonylamino-2<1->methoxy-phenyl)-benzimidazole and
E = 2-(2'-metoksy-4'-metoksykarbonylamino-fenyl)-imidazo-[4,5-c]pyridin E = 2-(2'-methoxy-4'-methoxycarbonylamino-phenyl)-imidazo-[4,5-c]pyridine
undersøkt med hensyn til sine biologiske egenskaper som følger: 1. Bestemmelse av blodtrykkvirkningen og positiv inotrop virkning på narkotiserte katter examined with regard to its biological properties as follows: 1. Determination of the blood pressure effect and positive inotropic effect on anesthetized cats
Undersøkelsene ble foretatt på katter som var narkotisert 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 bestemme den positiv-inotrope virkning ble trykket i. det venstre hjertekammer målt med et katetertippmanometer (Millar PC-350 A) . På dette grunnlag ble kontraktilitetsparameteren ^P/^t^^g funnet ved hjelp av en analogdifferensiator. Prøveforbindelsen ble injisert i en Vena femoralis. Som oppløsningsmiddel ble anvendt Polydiol 200. Hver forbindelse ble undersøkt på minst 2 katter. The investigations were carried out on cats 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 determine the positive inotropic effect, the pressure in the left heart chamber was measured with a catheter tip manometer (Millar PC-350 A). On this basis, the contractility parameter ^P/^t^^g was found using an analog differentiator. The test compound was injected into a femoral vein. Polydiol 200 was used as solvent. Each compound was tested on at least 2 cats.
Den følgende tabell inneholder de fundne middelverdier: The following table contains the average values found:
2. Antitrombotisk virkning 2. Antithrombotic effect
MetodikkMethodology
Trombocytt-aggregasjonen ble målt ved metoden ifølge Born og Cross (J. Physiol. 170, 397 (1964) i blodplaterikt plasma fra friske forsøkspersoner. For å hemme koagulasjonen ble blodet tilsatt natriumcitrat 3,14% i volumforhold 1:10. Platelet aggregation was measured by the method according to Born and Cross (J. Physiol. 170, 397 (1964) in platelet-rich plasma from healthy subjects. To inhibit coagulation, sodium citrate 3.14% was added to the blood in a volume ratio of 1:10.
Kollagen- fremkalt aggregasjonCollagen-induced aggregation
Forløpet av reduksjonen i den optiske tetthet i blodplate-suspensjonen ble efter tilsetning av det aggregasjons-utløsende stoff målt fotometrisk og registrert. På grunnlag av tetthets-kurvens helningsvinkel bestemmes aggregasjonshastigheten. Det punkt på kurven hvor den største lysgjennomtrengning foreligger, tjener til beregning av optisk tetthet. The course of the reduction in the optical density in the platelet suspension was measured photometrically and recorded after the addition of the aggregation-triggering substance. On the basis of the angle of inclination of the density curve, the rate of aggregation is determined. The point on the curve where the greatest light penetration exists is used to calculate optical density.
Kollagen - mengden velges så lav som mulig, men imidlertid slik at man får en irreversibelt forløpende reaksjonskurve. Det anvendes handelsvanlig kollagen fra firma Hormonchemie, Munchen. Collagen - the amount is chosen as low as possible, but in such a way that an irreversibly continuous reaction curve is obtained. Commercial collagen from the company Hormonchemie, Munich, is used.
Før kollagen-tilsetningen inkuberes plasmaet i hvert tilfelle i 10 minutter med prøveforbindelsen. Before the collagen addition, the plasma is incubated in each case for 10 minutes with the test compound.
På grunnlag av de oppnådde måletall beregnes grafisk en EC^q, som representerer en 50% endring av den optiske tetthet som uttrykk for aggregasjonshemning. On the basis of the obtained measurement figures, an EC^q is graphically calculated, which represents a 50% change in the optical density as an expression of aggregation inhibition.
Den følgende tabell inneholder de oppnådde resultater:The following table contains the results obtained:
De nye forbindelser er godt forlikelige, og således kunne ved undersøkelse av forbindelsene ingen hjertetoksiske virkninger eller kretsløpsskader iakttas. The new compounds are well compatible, and thus no cardiotoxic effects or circulatory damage could be observed when examining the compounds.
På grunn av sine farmakologiske egenskaper er forbindelsene fremstilt ifølge oppfinnelsen og deres fysiologisk forlikelige syreaddisjonssalter egnet til behandling av hjerteinsuffisienser av forskjellig opprinnelse, da de øker hjertets sammentreknings-kraft og ved blodtrykksenkning letter tømningen av hjertet, for behandling og til forebyggelse av trombo-emboliske lidelser såsom koronarinfarkt, cerebralinfarkt, såkalte forbigående ischemiske anfall, Amaurosis fugax, til forebyggelse av arteriosklerose og til metastase-forebyggelse. Due to their pharmacological properties, the compounds produced according to the invention and their physiologically compatible acid addition salts are suitable for the treatment of heart insufficiency of various origins, as they increase the contraction force of the heart and, by lowering blood pressure, facilitate the emptying of the heart, for the treatment and prevention of thromboembolic disorders such as coronary infarction, cerebral infarction, so-called transient ischemic attacks, Amaurosis fugax, for the prevention of arteriosclerosis and for metastasis prevention.
Den dosering som er nødvendig for å oppnå en passende virkning, utgjør hensiktsmessig 2-4 ganger daglig 0,3 til 4 mg/kg kroppsvekt, fortrinnsvis 0,3 til 2 mg/kg kroppsvekt. The dosage necessary to achieve an appropriate effect is suitably 0.3 to 4 mg/kg body weight, preferably 0.3 to 2 mg/kg body weight, 2-4 times a day.
For dette formål kan forbindelsene fremstilt ifølge oppfinnelsen, eventuelt i kombinasjon med andre virkestoffer, sammen med ett eller flere inerte vanlige bærermidler og/eller fortynnings-midler, f.eks. med maisstivelse, melkesukker, rørsukker, mikro-krystallinsk cellulose, magnesiumstearat, plolyvinylpyrrolidon, citronsyre, vinsyre, vann, vann/etanol, vann/glycerol, vann/sorbi-tol, vann/polyetylenglykol, propylenglykol, cetylstearylalkohol, karboksymetylcellulose eller fettholdige stoffer såsom hardt fett eller egnede blandinger derav, innarbeides i vanlige galeniske preparater såsom tabletter, dragéer, kapsler, pulvere, suspen-sjoner eller stikkpiller. For this purpose, the compounds produced according to the invention, possibly in combination with other active substances, together with one or more inert common carriers and/or diluents, e.g. with corn starch, milk sugar, cane sugar, micro-crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, are incorporated into usual galenic preparations such as tablets, dragées, capsules, powders, suspensions or suppositories.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
Eksempel 1 Example 1
1(3)-metyl-2-(2'-metoksy-4'-metylmerkapto-fenyl)-5-cyano-benzimidazol 1(3)-methyl-2-(2'-methoxy-4'-methylmercapto-phenyl)-5-cyano-benzimidazole
1,0 g (0,003386 mol) 2-(2'-metoksy-4'-metylmerkapto-fenyl)-5-cyano-benzimidazol, oppløst i 15 ml dimetylformamid, tilsettes 1,90 g (5 x 0,003386 mol) kalium-tert.-butylat og derefter under omrøring 1,6 ml (5 x 0,003386 mol) dimetylsulfat. Efter 30 1.0 g (0.003386 mol) of 2-(2'-methoxy-4'-methylmercapto-phenyl)-5-cyano-benzimidazole, dissolved in 15 ml of dimethylformamide, add 1.90 g (5 x 0.003386 mol ) potassium tert.-butylate and then, with stirring, 1.6 ml (5 x 0.003386 mol) of dimethyl sulfate. After 30
minutters omrøring fordeler man 4 ganger mellom 20 ml vann og 20 ml etylacetat hver gang. De samlede etylacetatekstrakter minute stirring is distributed 4 times between 20 ml of water and 20 ml of ethyl acetate each time. The combined ethyl acetate extracts
tørres med 20 ml mettet koksaltoppløsning over magnesiumsulfat etter risting og inndampes til tørrhet. Man får en olje som delvis krystalliserer. dry with 20 ml saturated sodium chloride solution over magnesium sulphate after shaking and evaporate to dryness. You get an oil that partially crystallizes.
Utbytte: 1,05 g (60% av det teoretiske), Yield: 1.05 g (60% of the theoretical),
tynnsjiktkromatogrammet (silikagel; metylenklorod/etylaceat = 1:1) viser en isomer ved Rf= 0,45 og en isomer ved R^= 0,40. Ved kolonnekromatografi på silikagel med metylenklorid/etylacetat fraskilles isomeren med R^= 0,45 i ren form. the thin-layer chromatogram (silica gel; methylene chloride/ethyl acetate = 1:1) shows an isomer at Rf= 0.45 and an isomer at R^= 0.40. By column chromatography on silica gel with methylene chloride/ethyl acetate, the isomer with R^= 0.45 is separated in pure form.
Smp.: 212-214°C. M.p.: 212-214°C.
Eksempel 2 Example 2
1(3)-metyl-2-(2'-metoksy-4'-metylsulfonyl-fenyl)-5-cyano-benzimidazol 1(3)-methyl-2-(2'-methoxy-4'-methylsulfonyl-phenyl)-5-cyano-benzimidazole
Fremstilt ved oksydasjon av 1(3)-metyl-2-(2'-metoksy-4'-metylmerkapto-fenyl)-5-cyano-benzimidazol i maursyre med den 3-dobbelte molare mengde av hydrogenperoksyd. Man oppnår hvite krystaller i et utbytte på 80% av det teoretiske, som smelter i et intervall fra 194 til 220°C (isomerblanding). Prepared by oxidation of 1(3)-methyl-2-(2'-methoxy-4'-methylmercapto-phenyl)-5-cyano-benzimidazole in formic acid with the 3-fold molar amount of hydrogen peroxide. White crystals are obtained in a yield of 80% of the theoretical, which melt in an interval from 194 to 220°C (isomer mixture).
Eksempel 3 Example 3
1(3)-metyl-2-(2'-metoksy-4'-metylsulfinyl-fenyl)-5-cyano-benzimidazol 1(3)-methyl-2-(2'-methoxy-4'-methylsulfinyl-phenyl)-5-cyano-benzimidazole
485 mg (0,001568 mol) 1(3)-metyl-2-(2'-metoksy-4'-metylmerkapto-f enyl)-5-cyano-benzimidazol får stå ved romtemperatur i 65 timer i 5 ml iseddik med 0,12 ml hydrogenperoksyd (399 mg/ml; 485 mg (0.001568 mol) 1(3)-methyl-2-(2'-methoxy-4'-methylmercapto-phenyl)-5-cyano-benzimidazole is allowed to stand at room temperature for 65 hours in 5 ml of glacial acetic acid with 0 .12 ml of hydrogen peroxide (399 mg/ml;
svarende til 0,9 x 0,001568 mol). Man får hvite krystaller. Smelteintervall: 168-175°C (isomerblanding). corresponding to 0.9 x 0.001568 mol). You get white crystals. Melting range: 168-175°C (mixture of isomers).
Utbytte: 330 mg (64,7% av det teoretiske).Yield: 330 mg (64.7% of the theoretical).
Eksempel 4 Example 4
1(3)-metyl-2-(2<1->metoksy-4<1->metylsulfoksimino-fenyl)-5-cyano-benzimidazol 1(3)-methyl-2-(2<1->methoxy-4<1->methylsulfoximino-phenyl)-5-cyano-benzimidazole
1,048 g (0,00322 mol) 1(3)-metyl-2-(2<1->metoksy-4'-metylsulf inyl-f enyl ) -5-cyano-benzimidazol oppløses i 7 ml dimetylformamid sammen med 2,3 g (2,5 x 0,00 322 mol) O-mesitylensulfonyl-acethydroksamsyre-etylester og 2,87 g (4,5 x 0,00322 mol) 4- toluensulfonsyrehydrat under omrøring og får stå i 48 timer ved romtemperatur. Man gjør blandingen alkalisk med 2N natronlut under avkjøling og ekstraherer uttømmende med en blanding av kloroform og etanol = 9:1. Efter avdampning av oppløsningsmiddel-blandingen kromatograferer man på en silikagelkolonne med etylenklorid/etanol = 4:1. Man oppnår hvite krystaller. Smelteintervall: 207-218°C. 1.048 g (0.00322 mol) of 1(3)-methyl-2-(2<1->methoxy-4'-methylsulfinyl-phenyl)-5-cyano-benzimidazole is dissolved in 7 ml of dimethylformamide together with 2.3 g (2.5 x 0.00 322 mol) O-mesitylenesulfonyl-acethydroxamic acid ethyl ester and 2.87 g (4.5 x 0.00322 mol) 4-toluenesulfonic acid hydrate under stirring and allowed to stand for 48 hours at room temperature. The mixture is made alkaline with 2N caustic soda while cooling and extracted exhaustively with a mixture of chloroform and ethanol = 9:1. After evaporating the solvent mixture, the mixture is chromatographed on a silica gel column with ethylene chloride/ethanol = 4:1. White crystals are obtained. Melting range: 207-218°C.
Utbytte: 0,450 g (41% av det teoretiske).Yield: 0.450 g (41% of the theoretical).
Eksempel 5 Example 5
2-[2'-metoksy-4'-(N-metansulfonyl-metylsulfoksimino)-fenyl]-5- cyano- benzimidazol 2-[2'-methoxy-4'-(N-methanesulfonyl-methylsulfoximino)-phenyl]-5-cyano- benzimidazole
Fremstilt fra 2-(2'-metoksy-4'-metylsulfoksimino-fenyl)-5-cyano-benzimidazol og metansulfonylklorid i pyridin. Prepared from 2-(2'-methoxy-4'-methylsulfoximino-phenyl)-5-cyano-benzimidazole and methanesulfonyl chloride in pyridine.
Smp.: 270-273°C. M.p.: 270-273°C.
Utbytte: 62% av det teoretiske.Yield: 62% of the theoretical.
Eksempel 6 Example 6
2-[2'-metoksy-4'-(N-acetyl-metylsulfoksimino)-fenyl]-5-cyano-benzimidazol 2-[2'-methoxy-4'-(N-acetyl-methylsulfoximino)-phenyl]-5-cyano-benzimidazole
Fremstilt fra 2-(2'-metoksy-4<1->metylsulfoksimino-fenyl)-5-cyano-benzimidazol og eddiksyreanhydrid. Prepared from 2-(2'-methoxy-4<1->methylsulfoximino-phenyl)-5-cyano-benzimidazole and acetic anhydride.
Smp.: 212,5-214°C. M.p.: 212.5-214°C.
Utbytte: 89,6% av det teoretiske.Yield: 89.6% of the theoretical.
Eksempel 7Example 7
2-(2'-metoksy-4'-metylmerkapto-fenyl)-5-trifluormetyl-benzimidazol 2-(2'-methoxy-4'-methylmercapto-phenyl)-5-trifluoromethyl-benzimidazole
5,0 g (0,02 mol) 2-ami.no-4'-trifluormetylanilin og 4,0 g (0,02 mol) 2-metoksy-4-metylmerkapto-benzosyre oppvarmes i 90 ml fosforoksyklorid i 2 timer til kokning. Overskudd av fosforoksyklorid fjernes i vakuum på en rotasjonsinndamper, residuet tilsettes isvann og nøytraliseres med natriumhydrogenkarbonat. 5.0 g (0.02 mol) of 2-amino.no-4'-trifluoromethylaniline and 4.0 g (0.02 mol) of 2-methoxy-4-methylmercapto-benzoic acid are heated in 90 ml of phosphorus oxychloride for 2 hours until boiling . Excess phosphorus oxychloride is removed in vacuum on a rotary evaporator, the residue is added to ice water and neutralized with sodium bicarbonate.
Det utfelte reaksjonsprodukt avsuges og omkrystalliseres fra etanol. The precipitated reaction product is suctioned off and recrystallized from ethanol.
Smp.: 144-147°C. M.p.: 144-147°C.
Utbytte: 4,78 g (70,4% av det teoretiske).Yield: 4.78 g (70.4% of the theoretical).
Eksempel 8 Example 8
2-(2'-metoksy-4<1->metylsulfinyl-fenyl)-5-trifluormetyl-benzimidazol 2-(2'-Methoxy-4<1->methylsulfinyl-phenyl)-5-trifluoromethyl-benzimidazole
Fremstilt analogt med eks. 3 fra 2-(2<1->metoksy-4<1->metylmerkapto-f enyl )-5-trifluormetyl-benzimidazol og hydrogenperoksyd. Smp.: 65°C (sintring), Manufactured analogously to e.g. 3 from 2-(2<1->methoxy-4<1->methylmercapto-phenyl)-5-trifluoromethyl-benzimidazole and hydrogen peroxide. Melting point: 65°C (sintering),
dekomp. ved 120°C.decomp. at 120°C.
Utbytte: 99,1% av det teoretiske.Yield: 99.1% of the theoretical.
Eksempel 9 Example 9
2-(2<1->metoksy-4<1->metylsulfonyl-fenyl)-5-trifluormetyl-benzimidazol 2-(2<1->methoxy-4<1->methylsulfonyl-phenyl)-5-trifluoromethyl-benzimidazole
Fremstilt analogt med eks. 2 fra 2-(2'-metoksy-4<1->metylmerkapto-f enyl )-5-trifluormetyl-benzimidazol og hydrogenperoksyd. Smp.: 217-220°C. Manufactured analogously to e.g. 2 from 2-(2'-methoxy-4<1->methylmercapto-phenyl)-5-trifluoromethyl-benzimidazole and hydrogen peroxide. M.p.: 217-220°C.
Utbytte: 84% av det teoretiske.Yield: 84% of the theoretical.
Eksempel 10 Example 10
2-(2'-metoksy-4'-metylsulfoksimino-fenyl)-5-trifluormetyl-benzimidazol 2-(2'-Methoxy-4'-methylsulfoximino-phenyl)-5-trifluoromethyl-benzimidazole
Fremstilt analogt med eks. 4 fra 2-(2'-metoksy-4'-metylsulfinyl-fenyl)-5-trifluormetyl-benzimidazol og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2'-methoxy-4'-methylsulfinyl-phenyl)-5-trifluoromethyl-benzimidazole and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 154°C.M.p.: 154°C.
Utbytte: 63% av det teoretiske.Yield: 63% of the theoretical.
Eksempel 11 Example 11
2- ( 4'- metylmerkapto- fenyl)- 5- trifluormetyl- benzimidazol 2-(4'-methylmercapto-phenyl)-5-trifluoromethyl-benzimidazole
Fremstilt analogt med eks. 7 fra 2-amino-4-trifluormetyl-anilin og 4-metylmerkapto-benzosyre. Manufactured analogously to e.g. 7 from 2-amino-4-trifluoromethyl-aniline and 4-methylmercapto-benzoic acid.
Smp.: 162-164°C. M.p.: 162-164°C.
Utbytte: 69% av det teoretiske.Yield: 69% of the theoretical.
Eksempel 12 Example 12
2-( 4'- metylsulfinyl- fenyl)- 5- trifluormetyl- benzimidazol2-(4'-methylsulfinyl-phenyl)-5-trifluoromethyl-benzimidazole
Fremstilt analogt med eks. 3 fra 2-(4'-metylmerkapto-fenyl)-5-trifluormetyl-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 3 from 2-(4'-methylmercapto-phenyl)-5-trifluoromethyl-benzimidazole and hydrogen peroxide.
Smp.: 216-219°C. M.p.: 216-219°C.
Utbytte: 51% av det teoretiske.Yield: 51% of the theoretical.
Eksempel 13 Example 13
2-( 4'- metylsulfoksimino- fenyl)- 5- trifluormetyl- benzimidazol 2-(4'-methylsulfoximino-phenyl)-5-trifluoromethyl-benzimidazole
Fremstilt analogt med eks. 4 fra 2-(4'-metylsulfinyl-fenyl)-5-trifluormetyl-benzimidazol og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(4'-methylsulfinyl-phenyl)-5-trifluoromethyl-benzimidazole and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 112-117°C. M.p.: 112-117°C.
Utbytte: 56% av det teoretiske.Yield: 56% of the theoretical.
Eksempel 14 Example 14
2- (2'-metoksy-4'-metylsulfinyl-fenyl)-5-metoksykarbonyl-benzimidazol 2-(2'-Methoxy-4'-methylsulfinyl-phenyl)-5-methoxycarbonyl-benzimidazole
Fremstilt analogt med eks. 3 fra 2-(2'-metoksy-4'-metylmerkapto-f enyl) -5-metoksykarbonyl-benzimidazol og hydrogenperoksyd. Smp.: 199-200°C. Manufactured analogously to e.g. 3 from 2-(2'-methoxy-4'-methylmercapto-phenyl)-5-methoxycarbonyl-benzimidazole and hydrogen peroxide. Melting point: 199-200°C.
Utbytte: 88% av det teoretiske.Yield: 88% of the theoretical.
Eksempel 15 Example 15
2- (2 1 -metoksy-4'-metylsulfonyl-fenyl)-5-metoksykarbonyl-benzimidazbl 2-(2 1 -Methoxy-4'-methylsulfonyl-phenyl)-5-methoxycarbonyl-benzimidazbl
Fremstilt analogt med eks. 2 fra 2-(2'-metoksy-4'-metylmerkapto-f enyl)-5-metoksykarbonyl-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 2 from 2-(2'-methoxy-4'-methylmercapto-phenyl)-5-methoxycarbonyl-benzimidazole and hydrogen peroxide.
Smp.: 135°C.M.p.: 135°C.
Utbytte: 87% av det teoretiske.Yield: 87% of the theoretical.
Eksempel 16 Example 16
2-(2'-metoksy-4'-metylsulfoksimino-fenyl)-5-metoksykarbonyl-benzimidazol 2-(2'-Methoxy-4'-methylsulfoximino-phenyl)-5-methoxycarbonyl-benzimidazole
Fremstilt analogt med eks. 4 fra 2-(2'-metoksy-4'-metylsulf inyl-f enyl) -5-metoksykarbonyl-benzimidazol og O-mesitylen-sulf onyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2'-methoxy-4'-methylsulfinyl-phenyl)-5-methoxycarbonyl-benzimidazole and O-mesitylene-sulfonyl-acethydroxamic acid ethyl ester.
Smp.: 214-216°C. M.p.: 214-216°C.
Utbytte: 64% av det teoretiske.Yield: 64% of the theoretical.
Eksempel 17Example 17
2- ( 4'- metylmerkapto- fenyl)- 5- cyano- benzimidazol2-(4'-methylmercapto-phenyl)-5-cyano-benzimidazole
Fremstilt analogt med eks. 7 fra 3,4-diamino-benzonitril og 4-metylmerkapto-benzosyre. Manufactured analogously to e.g. 7 from 3,4-diamino-benzonitrile and 4-methylmercapto-benzoic acid.
Smp.: 213-215°C. M.p.: 213-215°C.
Utbytte: 40% av det teoretiske.Yield: 40% of the theoretical.
Eksempel 18Example 18
2-( 4'- metylsulfinyl- fenyl)- 5- cyano- benzimidazol2-(4'-methylsulfinyl-phenyl)-5-cyano-benzimidazole
Fremstilt analogt med eks. 3 fra 2-(4'-metylmerkapto-fenyl)-5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 3 from 2-(4'-methylmercapto-phenyl)-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 266-268°C. M.p.: 266-268°C.
Utbytte: 98% av det teoretiske.Yield: 98% of the theoretical.
Eksempel 19Example 19
2- ( 4'- metylsulfonyl- fenyl)- 5- cyano- benzimidazol2-(4'-methylsulfonyl-phenyl)-5-cyano-benzimidazole
Fremstilt analogt med eks. 2 fra 2-(4<1->metylmerkapto-fenyl)-5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 2 from 2-(4<1->methylmercapto-phenyl)-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 271-273°C. M.p.: 271-273°C.
Utbytte: 55% av det teoretiske.Yield: 55% of the theoretical.
Eksempel 20 Example 20
2-( 4'- metylsulfoksimino- fenyl)- 5- cyano- benzimidazol 2-(4'-methylsulfoximino-phenyl)-5-cyano-benzimidazole
Fremstilt analogt med eks. 4 fra 2-(4'-metylsulfinyl-fenyl)-5-cyano-benzimidazol og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(4'-methylsulfinyl-phenyl)-5-cyano-benzimidazole and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 272-274°C. M.p.: 272-274°C.
Utbytte: 78% av det teoretiske.Yield: 78% of the theoretical.
Eksempel 21 Example 21
2-[2'-metoksy-4'-(N-3-karboksypropionyl-metylsulfoksimino)]-5- cyano- ben z imida zo1 2-[2'-methoxy-4'-(N-3-carboxypropionyl-methylsulfoximino)]-5- cyano-benz imida zo1
Fremstilt fra 2-(2'-metoksy-4'-metylsulfoksimino-fenyl)-5-cyano-benzimidazol og ravsyreanhydrid i kokende pyridin. Smp.: 265-268°C. Prepared from 2-(2'-methoxy-4'-methylsulfoximino-phenyl)-5-cyano-benzimidazole and succinic anhydride in boiling pyridine. M.p.: 265-268°C.
Utbytte: 92% av det teoretiske.Yield: 92% of the theoretical.
Eksempel 22 Example 22
2-( 2'- metoksy- 5'- metylmerkapto- fenyl)- 5- cyano- benzimidazol2-( 2'- methoxy- 5'- methylmercapto- phenyl)- 5- cyano- benzimidazole
a) 6,52 g (2-metoksy-5-metylmerkapto)-benz-(2-nitro-4-cyano)-anilid (fremstilt fra 2-nitro-5-cyano-anilin og 2-metoksy-5-metylmerkapto-benzoylklorid) suspenderes i 70 ml etanol, tilsettes en oppløsning av 16,5 natriumditionitt i 70 ml vann og oppvarmes på dampbad i 30 minutter. Efter inndampning i vakuum utgnies det oppnådde residuum med litt vann og avsuges. Det oppnådde 2-(2'-metoksy-5-metylmerkapto-fenyl)-benz-(2-amino-4-cyano)-anilid anvendes i fuktig tilstand i den påfølgende reaksjon. b) Det under a) oppnådde produkt oppvarmes i 15 ml iseddik i 2 timer til kokning. Man avdestillerer iseddiken i vakuum og a) 6.52 g of (2-methoxy-5-methylmercapto)-benz-(2-nitro-4-cyano)-anilide (prepared from 2-nitro-5-cyano-aniline and 2-methoxy-5-methylmercapto- benzoyl chloride) is suspended in 70 ml of ethanol, a solution of 16.5 sodium dithionite in 70 ml of water is added and heated on a steam bath for 30 minutes. After evaporation in a vacuum, the obtained residue is rubbed with a little water and suctioned off. The obtained 2-(2'-methoxy-5-methylmercapto-phenyl)-benz-(2-amino-4-cyano)-anilide is used in a moist state in the subsequent reaction. b) The product obtained under a) is heated in 15 ml of glacial acetic acid for 2 hours until boiling. The glacial acetic acid is distilled off in a vacuum and
fordeler residuet mellom etylacetat og kald sodaoppløsning. Etylacetatfasen tørres over magnesiumsulfat og inndampes, hvorved man får lysegule krystaller. distribute the residue between ethyl acetate and cold soda solution. The ethyl acetate phase is dried over magnesium sulphate and evaporated, whereby pale yellow crystals are obtained.
Smp.: 171-173°C. M.p.: 171-173°C.
Utbytte: 3,04 g (54% av det teoretiske).Yield: 3.04 g (54% of theoretical).
Eksempel 23 Example 23
2-( 2'- metoksy- 51- metylsulfinyl- fenyl)- 5- cyano- benzimidazol 2-(2'- methoxy- 51- methylsulfinyl- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 3 fra 2-(2'-metoksy-5<1->metyl-markapto-fenyl)-5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 3 from 2-(2'-methoxy-5<1->methyl-markapto-phenyl)-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 215-217°C. M.p.: 215-217°C.
Utbytte: 75% av det teoretiske.Yield: 75% of the theoretical.
Eksempel 24 Example 24
2-( 2'- metoksy- 5'- metylsulfonyl- fenyl)- 5- cyano- benzimidazol 2-( 2'- methoxy- 5'- methylsulfonyl- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 2 fra 2-(2<1->metoksy-5<1->metylmerkapto-f enyl ) -5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 2 from 2-(2<1->methoxy-5<1->methylmercapto-phenyl)-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 276-278°C. M.p.: 276-278°C.
Utbytte: 88% av det teoretiske.Yield: 88% of the theoretical.
Eksempel 25 Example 25
2-( 2'- metoksy- 5'- metylsulfoksimino- fenyl)- 5- cyano- benzimidazol 2-( 2'- methoxy- 5'- methylsulfoximino- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 4 fra 2-(2<1->metoksy-5<1->metylsulf inyl-f enyl) -5-cyano-benzimidazol og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2<1->methoxy-5<1->methylsulfinyl-phenyl)-5-cyano-benzimidazole and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 284-285°C. M.p.: 284-285°C.
Utbytte: 84% av det teoretiske.Yield: 84% of the theoretical.
Eksempel 26 Example 26
2-( 2'- metoksy- 4'- etylmerkapto- fenyl)- 5- cyano- benzimidazol 2-( 2'- methoxy- 4'- ethyl mercapto- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 22 fra 2-(2'-metoksy-4'-etylmerkapto)-benz-(2-nitro-4-cyano)-anilid ved reduksjon med natriumditionitt og etterfølgende ringslutning. Manufactured analogously to e.g. 22 from 2-(2'-methoxy-4'-ethylmercapto)-benz-(2-nitro-4-cyano)-anilide by reduction with sodium dithionite and subsequent ring closure.
Smp.: 161-163°C. M.p.: 161-163°C.
Utbytte: 85% av det teoretiske.Yield: 85% of the theoretical.
Eksempel 27 Example 27
2-( 2'- metoksy- 4'- etylsulfinyl- fenyl)- 5- cyano- benzimidazol 2-( 2'- methoxy- 4'- ethylsulfinyl- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 3 fra 2-(2'-metoksy-4'-etylmerkapto-f enyl)-5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 3 from 2-(2'-methoxy-4'-ethylmercapto-phenyl)-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 234-236°C. M.p.: 234-236°C.
Utbytte: 98% av det teoretiske.Yield: 98% of the theoretical.
Eksempel 28 Example 28
2-( 2'- metoksy- 4'- etylsulfonyl- fenyl)- 5- cyano- benzimidazol 2-( 2'- methoxy- 4'- ethylsulfonyl- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 2 fra 2-(2'-metoksy-4'-etyl-markapto-fenyl)-5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 2 from 2-(2'-methoxy-4'-ethyl-markapto-phenyl)-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 208-209°C. M.p.: 208-209°C.
Utbytte: 85% av det teoretiske.Yield: 85% of the theoretical.
Eksempel 29 Example 29
2-( 2'- metoksy- 4'- etylsulfoksimino- fenyl)- 5- cyano- benzimidazol 2-( 2'- methoxy- 4'- ethylsulfoximino- phenyl)- 5- cyano- benzimidazole
Fremstilt analogt med eks. 4 fra 2-(2'-metoksy-4'-etylsulf inyl-f enyl) -5-cyano-benzimidazol og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2'-methoxy-4'-ethylsulfinyl-phenyl)-5-cyano-benzimidazole and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 252-254°C. M.p.: 252-254°C.
Utbytte: 85% av det teoretiske.Yield: 85% of the theoretical.
Eksempel 30 Example 30
2-[ 2'-( 2- metylmerkapto- etoksy)- naftyl- 3-]- 5- cyano- benzimidazol 2-[ 2'-( 2- methylmercapto- ethoxy)- naphthyl- 3-]- 5- cyano- benzimidazole
Fremstilt analogt med eks. 7 fra 2-amino-4-cyanoanilin og 2-(2-metylmerkapto-etoksy)-3-naftosyre ved kokning i fosforoksyklorid. Manufactured analogously to e.g. 7 from 2-amino-4-cyanoaniline and 2-(2-methylmercapto-ethoxy)-3-naphthoic acid by boiling in phosphorus oxychloride.
Smp.: 186-188°C. M.p.: 186-188°C.
Utbytte: 65% av det teoretiske.Yield: 65% of the theoretical.
Eksempel 31 Example 31
2-[ 2'-( 2- metylsulfinyl- etoksy)- naftyl- 3]- 5- cyano- benzimidazol 2-[ 2'-( 2- methylsulfinyl- ethoxy)- naphthyl- 3]- 5- cyano- benzimidazole
Fremstilt analogt med eks. 3 fra 2-[2<1->(2-metylmerkaptoetoksy )-naftyl-3]-5-cyano-benzimidazol og hydrogenperoksyd. Manufactured analogously to e.g. 3 from 2-[2<1->(2-methylmercaptoethoxy)-naphthyl-3]-5-cyano-benzimidazole and hydrogen peroxide.
Smp.: 207-208°C. M.p.: 207-208°C.
Utbytte: 58% av det teoretiske.Yield: 58% of the theoretical.
Eksempel 32 Example 32
2-[ 2- ( 2- metylsulfonyl- etoksy)- naftyl- 3-]- 5- cyano- benzimidazol 2-[ 2-( 2- methylsulfonyl- ethoxy)- naphthyl- 3-]- 5- cyano- benzimidazole
Fremstilt analogt med eks. 2 fra 2-[2'-(2-metylmerkaptoetoksy ) -naftyl-3-] -5-cyano-benzimidazol og hydrogenperoksyd. Smp.: 257-259°C. Manufactured analogously to e.g. 2 from 2-[2'-(2-methylmercaptoethoxy)-naphthyl-3-]-5-cyano-benzimidazole and hydrogen peroxide. M.p.: 257-259°C.
Utbytte: 72% av det teoretiske.Yield: 72% of the theoretical.
Eksempel 33 Example 33
2-[21 -(2-metylsulfoksimino-etoksy)-naftyl-3]-5-cyano-benzimidazol 2-[21-(2-methylsulfoximino-ethoxy)-naphthyl-3]-5-cyano-benzimidazole
Fremstilt analogt med eks. 4 fra 2-[2'-(2-metylsulfinyletoksy ) -naftyl-3]-5-cyano-benzimidazol og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-[2'-(2-methylsulfinylethoxy)-naphthyl-3]-5-cyano-benzimidazole and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 192-194°C. M.p.: 192-194°C.
Utbytte: 52% av det teoretiske.Yield: 52% of the theoretical.
Eksempel 34 Example 34
2- ( 2'- metoksy- 4'- amidosulfonyl- fenyl)- 5- acetyl- benzimidazol2-( 2'- methoxy- 4'- amidosulfonyl- phenyl)- 5- acetyl- benzimidazole
a) 16 g 2-metoksy-4-amidosulfonyl-benzosyre oppvarmes med 80 ml tionylklorid og 10 ml dimetylformamid i 150 ml absolutt a) 16 g of 2-methoxy-4-amidosulfonyl-benzoic acid are heated with 80 ml of thionyl chloride and 10 ml of dimethylformamide in 150 ml of absolute
toluen i 30 minutter til kokning og inndampes derefter til tørrhet i vakuum. Det oppnådde rå, krystallinske 2-metoksy-4-(dimetyl-amino-formimido-sulfonyl)-benzoylklorid anvendes umiddelbart til den påfølgende reaksjon. toluene for 30 minutes to boiling and then evaporated to dryness in vacuo. The obtained crude, crystalline 2-methoxy-4-(dimethyl-amino-formimido-sulfonyl)-benzoyl chloride is used immediately for the subsequent reaction.
Utbytte: 21,5 g (100% av det teoretiske).Yield: 21.5 g (100% of the theoretical).
b) 17,2 g 2-metoksy-4-(dimetylamino-formimido-sulfonyl)-benzoylklorid oppvarmes med 12,4 g 3-nitro-4-amino-acetofenon b) 17.2 g of 2-methoxy-4-(dimethylamino-formimido-sulfonyl)-benzoyl chloride is heated with 12.4 g of 3-nitro-4-amino-acetophenone
i 150 ml absolutt toluen i 2 timer til kokning. Herunder blir den i begynnelsen klare oppløsning uklar på grunn av utkrystalli-sert 2-metoksy-4-(dimetylamino-formimido-sulfonyl)-benz-(2-nitro-4-acetyl)-anilid, som avsuges efter avkjøling, vaskes med litt metyletylketon og tørres. in 150 ml of absolute toluene for 2 hours until boiling. Below this, the initially clear solution becomes cloudy due to crystallized 2-methoxy-4-(dimethylamino-formimido-sulfonyl)-benz-(2-nitro-4-acetyl)-anilide, which is filtered off after cooling, washed with a little methyl ethyl ketone and dried.
Smp.: 230-235°C. Melting point: 230-235°C.
Utbytte: 20,8 g (77% av det teoretiske).Yield: 20.8 g (77% of the theoretical).
c) 19 g 2-metoksy-4-(dimetylamino-formimido-sulfonyl)-benz-(2-nitro-4-acetyl)-anilid oppvarmes med 50,5 g natriumditionitt c) 19 g of 2-methoxy-4-(dimethylamino-formimido-sulfonyl)-benz-(2-nitro-4-acetyl)-anilide are heated with 50.5 g of sodium dithionite
i en blanding av 190 ml etanol og 200 ml vann i 2,5 timer til kokning. Man inndamper til tørrhet og fordeler mellom metylenklorid og vann. Ved inndampning av den organiske fase efter tørring over magnesiumsulfat får man 2-metoksy-4- (dimetylami.no-formimido-sulfonyl)-benz-(2-amino-4-acetyl)-anilid, som anvendes i rå form i den etterfølgende reaksjon. in a mixture of 190 ml of ethanol and 200 ml of water for 2.5 hours until boiling. Evaporate to dryness and partition between methylene chloride and water. Evaporation of the organic phase after drying over magnesium sulfate gives 2-methoxy-4-(dimethylamino-formimido-sulfonyl)-benz-(2-amino-4-acetyl)-anilide, which is used in crude form in the subsequent reaction.
Utbytte: 5,3 g (30% av det teoretiske).Yield: 5.3 g (30% of the theoretical).
d) 0,400 g 2-metoksy-4-(dimetylamino-formimido-sulfonyl)-benz-(2-amino-4-acetyl)-anilid oppvarmes i. 10 ml 5N saltsyre i 1 time til kokning. Det utkrystalliserende 2-(2<1->metoksy-4<1->amidosulfonyl-fenyl)-5-acetyl-benzimidazol avsuges efter av-kjøling, vaskes syrefritt og tørres. d) 0.400 g of 2-methoxy-4-(dimethylamino-formimido-sulfonyl)-benz-(2-amino-4-acetyl)-anilide is heated in 10 ml of 5N hydrochloric acid for 1 hour until boiling. The crystallized 2-(2<1->methoxy-4<1->amidosulfonyl-phenyl)-5-acetyl-benzimidazole is filtered off after cooling, washed acid-free and dried.
Smp.: 269-272°C. M.p.: 269-272°C.
Utbytte 280 mg (85% av det teoretiske).Yield 280 mg (85% of the theoretical).
Eksempel 35 Example 35
2-( 2'- metoksy- 4'- metylmerkapto- fenyl)- 5- acetyl- benzimidazol2-( 2'- methoxy- 4'- methylmercapto- phenyl)- 5- acetyl- benzimidazole
a) Analogt med eks. 34b) omsettes 2-metoksy-4-metylmerkapto-benzoylklori.d og 3-nitro-4-ami.no-acetofenon til (2-metoksy-4-metylmerkapto)-benz-(2-nitro-4-acetyl)-anilid, og dette b) reduseres med natriumditionitt til (2-metoksy-4-metylmerkapto)-benz-(2-amino-4-acetyl)-anilid analogt med eks. 34c), a) Analogous to e.g. 34b) 2-methoxy-4-methylmercapto-benzoyl chloride and 3-nitro-4-amino-acetophenone are converted to (2-methoxy-4-methylmercapto)-benz-(2-nitro-4-acetyl)-anilide , and this b) is reduced with sodium dithionite to (2-methoxy-4-methylmercapto)-benz-(2-amino-4-acetyl)-anilide analogously to ex. 34c),
som derefteras then
c) analogt med eks. 34d) omsettes med kokende saltsyre til 2-(2<1->metoksy-4'-metylmerkapto-fenyl)-5-acetyl-benzimidazol. c) analogous to e.g. 34d) is reacted with boiling hydrochloric acid to 2-(2<1->methoxy-4'-methylmercapto-phenyl)-5-acetyl-benzimidazole.
Smp.: 154-157°C. M.p.: 154-157°C.
Utbytte: 63% av det teoretiske.Yield: 63% of the theoretical.
Eksempel 36 Example 36
2-( 2'- metoksy- 4'- metylsulfinyl- fenyl)- 5- acetyl- benzimidazol 2-( 2'- methoxy- 4'- methylsulfinyl- phenyl)- 5- acetyl- benzimidazole
Fremstilt analogt med eks. 3 fra 2-(2'-metoksy-4'-metylmerkapto-f enyl ) -5-acetyl-benzimidazol og hydrogenperoksyd. Smp.: 184-187°C. Manufactured analogously to e.g. 3 from 2-(2'-methoxy-4'-methylmercapto-phenyl)-5-acetyl-benzimidazole and hydrogen peroxide. M.p.: 184-187°C.
Utbytte: 59% av det teoretiske.Yield: 59% of the theoretical.
Eksempel 37 Example 37
2-( 2'- metoksy- 4'- metylsulfonyl- fenyl)- 5- acetyl- benzimidazol 2-( 2'- methoxy- 4'- methylsulfonyl- phenyl)- 5- acetyl- benzimidazole
Fremstilt analogt med eks. 2 fra 2-(2<1->metoksy-4'-metylmerkapto-f enyl) -5-acetyl-benzimidazol og hydrogenperoksyd. Smp.: 203-205°C. Manufactured analogously to e.g. 2 from 2-(2<1->methoxy-4'-methylmercapto-phenyl)-5-acetyl-benzimidazole and hydrogen peroxide. M.p.: 203-205°C.
Utbytte: 78% av det teoretiske.Yield: 78% of the theoretical.
Eksempel. 38 Example. 38
2-(2'-metoksy-5-metylsulfoksimino-fenyl)-lH-imidazo[4,5-b]-pyridin 2-(2'-Methoxy-5-methylsulfoximino-phenyl)-1H-imidazo[4,5-b]-pyridine
Fremstilt analogt med eks. 4 fra 2-(2'-metoksy-5<1->metylsulf inyl-f enyl ) -1H-imidazo [4 , 5-b] pyridin og O-mesi.tylensulf onyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2'-methoxy-5<1->methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 26 3,5°C.M.p.: 26 3.5°C.
Utbytte: 83% av det teoretiske.Yield: 83% of the theoretical.
Eksempel 39 Example 39
2-(2<1->etoksy-5'-metylsulfoksimino-fenyl)-1H-imidazo[4,5-b]-pyridin 2-(2<1->ethoxy-5'-methylsulfoximino-phenyl)-1H-imidazo[4,5-b]-pyridine
Fremstilt analogt med eks. 4 fra 2-(2'-etoksy-5<1->metylsulf inyl-f enyl ) -lH-imidazo [ 4 , 5-b] pyridin og 0-mesi.tylensulf onyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2'-ethoxy-5<1->methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 277°C.M.p.: 277°C.
Utbytte: 6 2% av det teoretiske.Yield: 6 2% of the theoretical.
Eksempel 40 Example 40
2- (2'-etoksy-41-metylsulfoksimino-fenyl)-lH-imidazo[4,5-b]-pyridin 2-(2'-ethoxy-41-methylsulfoximino-phenyl)-1H-imidazo[4,5-b]-pyridine
Fremstilt analogt med eks. 4 fra 2-(2<1->etoksy-4'-metylsulf inyl-f enyl) -lH-imidazo[4,5-b]pyridin og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2<1->ethoxy-4'-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 176-178°C. M.p.: 176-178°C.
Utbytte: 80% av det teoretiske.Yield: 80% of the theoretical.
Eksempel 41 Example 41
2-(2,-etoksy-4'-n-propylsulfoksimino-fenyl)-lH-imidazo-[ 4, 5- b]- pyridin 2-(2,-ethoxy-4'-n-propylsulfoximino-phenyl)-1H-imidazo-[4,5-b]-pyridine
Fremstilt analogt med eks. 4 fra 2-(2<1->etoksy-4'-n-propylsulfinyl-fenyl)-lH-imidazo[4,5-b]-pyridin og O-mesitylen- Manufactured analogously to e.g. 4 from 2-(2<1->ethoxy-4'-n-propylsulfinyl-phenyl)-1H-imidazo[4,5-b]-pyridine and O-mesitylene-
sulfonyl-acethydroksamsyre-etylester.sulfonyl-acethydroxamic acid ethyl ester.
Smp.: 135-137°C. M.p.: 135-137°C.
Utbytte: 71% av det teoretiske.Yield: 71% of the theoretical.
Eksempel 4 2 Example 4 2
2-(2<1->metoksy-4'-metylsulfoksimino-fenyl)-6-metyl-imidazo-[ 4 , 5- b] - pyridin 2-(2<1->methoxy-4'-methylsulfoximino-phenyl)-6-methyl-imidazo-[4,5-b]-pyridine
Fremstilt analogt med eks. 4 fra 2-(2'-metoksy-4'-metylsulf inyl-f enyl) -6-metyl-lH-imidazo[4,5-b]pyridin og O-mesitylensulfonyl-acethydroksamsyre-etylester. Manufactured analogously to e.g. 4 from 2-(2'-methoxy-4'-methylsulfinyl-phenyl)-6-methyl-1H-imidazo[4,5-b]pyridine and O-mesitylenesulfonyl-acethydroxamic acid ethyl ester.
Smp.: 233°C.M.p.: 233°C.
Utbytte: 58% av det teoretiske.Yield: 58% of the theoretical.
Eksempel 4 3 Example 4 3
2-(2(2-metylsulfoksimino-etoksy)-4'-metoksy-fenyl]-1H-imidazo [ 45- b] pyridin- mesitylensulf onat 14 g O-mesitylensulfonyl-acethydroksamsyre-etylester, oppløst i 20 ml dioksan tilsettes dråpevis ved 22-24°C 10 ml 90%ig svovelsyre under lett utvendig avkjøling. Man omrører i 20 min. og heller blandingen derefter på 300 ml is og utrister det frie O-mesitylensulfonyl-hydroksylamin med metylenklorid og tørrer oppløsningen over natriumsulfat. Til denne opp-løsning settes 6,62 g 2-[2'-(2-metylsulfinyl-etoksy)-4'-metoksy-fenyl]-lH-imidazo[4,5-b]pyridin. Efter ca. 5 minutter begynner krystaller å utskilles, og man omrører natten over. Krystalli-satet avsuges og omkrystalliseres fra etanol. 2-(2(2-methylsulfoximino-ethoxy)-4'-methoxy-phenyl]-1H-imidazo [45-b] pyridine-mesitylenesulfonate 14 g of O-mesitylenesulfonyl-acethydroxamic acid ethyl ester, dissolved in 20 ml of dioxane is added dropwise at 22-24°C 10 ml of 90% sulfuric acid under slight external cooling. Stir for 20 min. and then pour the mixture onto 300 ml of ice and shake off the free O-mesitylenesulfonyl-hydroxylamine with methylene chloride and dry the solution over sodium sulfate. To this solution, 6.62 g of 2-[2'-(2-methylsulfinyl-ethoxy)-4'-methoxy-phenyl]-1H-imidazo[4,5-b]pyridine are added. After about 5 minutes, crystals begin to separate , and the mixture is stirred overnight.The crystalline precipitate is filtered off with suction and recrystallized from ethanol.
Smp.: 163°C.M.p.: 163°C.
Utbytte: 42% av det teoretiske.Yield: 42% of the theoretical.
Eksempel 4 4 Example 4 4
2-(2<1->metoksy-4<1->metylsulfoksimino-fenyl)-6-klor-lH-imidazo[ 4, 5- b] pyridin 2-(2<1->methoxy-4<1->methylsulfoximino-phenyl)-6-chloro-1H-imidazo[4,5-b]pyridine
0,453 g 2-(2'-metoksy-4'-metylsulfinyl-fenyl)-6-klor-lH-imidazo[4,5-b]pyridin innrøres ved 50°C i 9 g polyfosforsyre og tilsettes derefter porsjonsvis 0,5 g natriumazid. Efter henstand natten over utrører man med is og innstiller pH på 7,5 med 40%ig natronlut. De derved utfelte krystaller avsuges og omkrystalliseres fra etanol. 0.453 g of 2-(2'-methoxy-4'-methylsulfinyl-phenyl)-6-chloro-1H-imidazo[4,5-b]pyridine is stirred at 50°C into 9 g of polyphosphoric acid and then 0.5 g is added in portions sodium azide. After standing overnight, stir with ice and adjust the pH to 7.5 with 40% caustic soda. The thereby precipitated crystals are suctioned off and recrystallized from ethanol.
Smp.: 282°C.M.p.: 282°C.
Utbytte: 0,284 g (60% av det teoretiske).Yield: 0.284 g (60% of theoretical).
Eksempel 4 5 Example 4 5
2-(2'-metoksy-4'-metylsulfoksimino-fenyl)-lH-imidazo-[ 4, 5- b] pyridin : Fremstilt analogt med eks. 4 4 fra 2-(2'-metoksy-4'-metylsulf inyl-f enyl) -lH-imidazo [4 , 5-b] pyridin og natriumazid. 2-(2'-Methoxy-4'-methylsulfoximino-phenyl)-1H-imidazo-[4,5-b]pyridine: Prepared analogously to ex. 4 4 from 2-(2'-methoxy-4'-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine and sodium azide.
Smp.: 236-237°C. M.p.: 236-237°C.
Utbytte: 86% av det teoretiske.Yield: 86% of the theoretical.
Eksempel 46 Example 46
2- (2'-metoksy-4'-metylsulfoksimino-fenyl)-lH-imidazo-[ 4 , 5- c] pyridin 2-(2'-Methoxy-4'-methylsulfoximino-phenyl)-1H-imidazo-[4,5-c]pyridine
Fremstilt analogt med eks. 44 fra 2-(2'metoksy-4'-metylsulf inyl-fenyl) -lH-imidazo [4 ,5-c] pyridin og natriumazid. Manufactured analogously to e.g. 44 from 2-(2'methoxy-4'-methylsulfinyl-phenyl)-1H-imidazo[4,5-c]pyridine and sodium azide.
Smp.: 253-257°C. M.p.: 253-257°C.
Utbytte: 62% av det teoretiske.Yield: 62% of the theoretical.
Eksempel 47Example 47
8-( 2' metoksy- 4'- metylsulfoksimino- fenyl- fenyl)- purin8-( 2' methoxy- 4'- methylsulfoximino- phenyl- phenyl)- purine
Fremstilt analogt med eks. 44 fra 8-(2'-metoksy-4'-metylsulfinyl-fenyl)-purin og natriumazid. Manufactured analogously to e.g. 44 from 8-(2'-methoxy-4'-methylsulfinyl-phenyl)-purine and sodium azide.
Smp.: 261°C (dekomp.)M.p.: 261°C (decomp.)
Utbytte: 66% av det teoretiske.Yield: 66% of the theoretical.
Eksempel 48Example 48
8-(2'-metoksy-4'-metylsulfoksimino-fenyl)-teofyllin-mesitylensulfonat 8-(2'-Methoxy-4'-methylsulfoximino-phenyl)-theophylline mesitylene sulfonate
Fremstilt analogt med eks. 4 3 fra 8-(2'-metoksy-4'-metylsulf inyl-f enyl) -teofyllin og O-mesitylensulfonyl-hydroksylamin. Smp.: 238°C. Manufactured analogously to e.g. 4 3 from 8-(2'-methoxy-4'-methylsulfinyl-phenyl)-theophylline and O-mesitylenesulfonyl-hydroxylamine. M.p.: 238°C.
Utbytte: 32% av det teoretiske.Yield: 32% of the theoretical.
Eksempel 49 Example 49
2-( 2'- metoksy- 4'- benzyloksy- fenyl)- 5- metylmerkapto- benzimidazol 2-( 2'- methoxy- 4'- benzyloxy- phenyl)- 5- methyl mercapto- benzimidazole
a) Fremstilt analogt med eks. 34b fra 2-metoksy-4-benzyloksy-benzoylklorid og 2-nitro-4-metylmerkapto-anilin, b) det erholdte 2-metoksy-4-benzyloksy)benz-(2-nitro-4-metylmerkapto)-anilid reduseres analogt med eks. 34c med natriumditionitt, c) og det således oppnådde 2-metoksy-4-benzyloksy)-benz-(2- amino-4-metylmerkapto)-anilid ringsluttes analogt med eks. 34d med kokende saltsyre. a) Produced analogously to e.g. 34b from 2-methoxy-4-benzyloxy-benzoyl chloride and 2-nitro-4-methylmercapto-aniline, b) the obtained 2-methoxy-4-benzyloxy)benz-(2-nitro-4-methylmercapto)-anilide is reduced analogously with e.g. 34c with sodium dithionite, c) and the thus obtained 2-methoxy-4-benzyloxy)-benz-(2-amino-4-methylmercapto)-anilide are cyclized analogously to ex. 34d with boiling hydrochloric acid.
Smp.: 238-240°C. M.p.: 238-240°C.
Utbytte: 81% av det teoretiske.Yield: 81% of the theoretical.
Eksempel 50 Example 50
2- ( 2 ' - metoksy- 4'- benzyloksy- fenyl)- 5- metylsulfonyl- benzimidazol 2-(2'-methoxy-4'-benzyloxy-phenyl)-5-methylsulfonyl- benzimidazole
Fremstilt analogt med eks. 2 fra 2-(2<1->metoksy-4<1->benzyloksy-f enyl) -5-metylmerkapto-benzimidazol og hydrogenperoksyd. Utbytte: 92% av det teoretiske. Manufactured analogously to e.g. 2 from 2-(2<1->methoxy-4<1->benzyloxy-phenyl)-5-methylmercapto-benzimidazole and hydrogen peroxide. Yield: 92% of the theoretical.
Smp.: 156-159°C. M.p.: 156-159°C.
Eksempel 51 Example 51
2-( 2'- metoksy- 4'- hydroksy- fenyl)- 5- metylsulfonyl- benzimidazol 2-( 2'- methoxy- 4'- hydroxy- phenyl)- 5- methylsulfonyl- benzimidazole
Fremstilt fra 2-(2'-metoksy-5-benzyloksy-fenyl)-5-metylsulf onyl-benzimidazol ved katalytisk hydrogenering med hydrogen ved romtemperatur i dimetylformamid. Prepared from 2-(2'-methoxy-5-benzyloxy-phenyl)-5-methylsulfonyl-benzimidazole by catalytic hydrogenation with hydrogen at room temperature in dimethylformamide.
Utbytte: 60% av det teoretiske.Yield: 60% of the theoretical.
Smp.: 255-260°C. Melting point: 255-260°C.
Eksempel 52 Example 52
2-(2<1->metoksy-4<1->metansulfonyloksy-fenyl)-5-metylsulfonyl-benzimidazol 2-(2<1->methoxy-4<1->methanesulfonyloxy-phenyl)-5-methylsulfonyl-benzimidazole
Fremstilt fra 2-(2'-metoksy-4<1->hydroksy-fenyl)5-metylsulf onyl-benzimidazol og metansulfonylklorid i pyridin. Utbytte: 68% av det teoretiske. Prepared from 2-(2'-methoxy-4<1->hydroxy-phenyl)5-methylsulfonyl-benzimidazole and methanesulfonyl chloride in pyridine. Yield: 68% of the theoretical.
Smp.: 125-129°C. M.p.: 125-129°C.
Eksempel 53 Example 53
5- cyano- 2- ( 2'- metoksy- 4'- metansulfonylamino- fenyl)- benzimidazol 5- cyano- 2-( 2'- methoxy- 4'- methanesulfonylamino- phenyl)- benzimidazole
Fremstilt fra 2-metoksy-4-metansulfonylamino-benzosyre og 3,4-diamino-benzonitril analogt med eks. 7. Prepared from 2-methoxy-4-methanesulfonylamino-benzoic acid and 3,4-diamino-benzonitrile analogously to ex. 7.
Utbytte: 17,5% av det teoretiske.Yield: 17.5% of the theoretical.
Smp.: 293-295°C. M.p.: 293-295°C.
Eksempel 54 Example 54
2-(2'-metoksy-4'-metansulfonylamino-fenyl)-imidazo-[ 4 , 5- b] - naf talenhydrat 2-(2'-Methoxy-4'-methanesulfonylamino-phenyl)-imidazo-[4,5-b]-naphthalene hydrate
Fremstilt fra 2-metoksy-4-metansulfonylamino-benzosyre og 2,3-diamino-naftalen analogt med eks. 7. Prepared from 2-methoxy-4-methanesulfonylamino-benzoic acid and 2,3-diamino-naphthalene analogously to ex. 7.
Utbytte: 42% av det teoretiske.Yield: 42% of the theoretical.
Smp.: amorf, fra ca. 100°C.Melting point: amorphous, from approx. 100°C.
Eksempel 55 Example 55
5-aminosulfonyl-2-(2'-metoksy-4'-metylmerkapto-fenyl)-benzimidazol 5-aminosulfonyl-2-(2'-methoxy-4'-methylmercapto-phenyl)-benzimidazole
Fremstilt fra 2-metoksy-4-metylmerkapto-benzosyre og 4-aminosulfonyl-1,2-diamino-benzol analogt med eks. 7. Utbytte: 18,9% av det teoretiske. Prepared from 2-methoxy-4-methylmercapto-benzoic acid and 4-aminosulfonyl-1,2-diamino-benzene analogously to ex. 7. Yield: 18.9% of the theoretical.
Smp.: 274-276°C. M.p.: 274-276°C.
Eksempel 56 Example 56
5-acetyl-2-(2<1->metoksy-4'-metansulfonylamino-fenyl)-benzimidazol 5-acetyl-2-(2<1->methoxy-4'-methanesulfonylamino-phenyl)-benzimidazole
Fremstilt fra 2-metoksy-4-metansulfonylamino-benzosyre og 3,4-diamino-acetofenon analogt med eks. 7. Utbytte: 79% av det teoretiske. Prepared from 2-methoxy-4-methanesulfonylamino-benzoic acid and 3,4-diamino-acetophenone analogously to ex. 7. Yield: 79% of the theoretical.
Smp.: 141-143°C. M.p.: 141-143°C.
Eksempel 57 Example 57
5-benzoyl-2-(2'-metoksy-4'-metansulfonylamino-fenyl)-benzimidazol 5-benzoyl-2-(2'-methoxy-4'-methanesulfonylamino-phenyl)-benzimidazole
Fremstilt fra 2-metoksy-4-metansulfonylamino-benzosyre og 3,4-diamino-benzofenon analogt med eks. 7. Utbytte: 62% av det teoretiske. Prepared from 2-methoxy-4-methanesulfonylamino-benzoic acid and 3,4-diamino-benzophenone analogously to ex. 7. Yield: 62% of the theoretical.
Smp.: 139-141°C. M.p.: 139-141°C.
Eksempel 58 Example 58
2- amino- 8-(<2>'- me<t>oksy- 4'- metylmerka<p>to- fenyl)- purin 2- amino- 8-(<2>'- me<t>oxy- 4'- methylmerca<p>to- phenyl)- purine
Fremstilt fra 2-metoksy-4-metylmerkapto-benzosyre og 2,4,5-triamino-pyrimidin analogt med eks. 7. Utbytte: 17% av det teoretiske. Prepared from 2-methoxy-4-methylmercapto-benzoic acid and 2,4,5-triamino-pyrimidine analogously to ex. 7. Yield: 17% of the theoretical.
Smp.: 212-214°C. M.p.: 212-214°C.
Eksempel 59 Example 59
6-cyano-2-(2<1->metoksy-4'-metylmerkapto-fenyl)-imidazo-[ 4 , 5- b] pyridin 6-cyano-2-(2<1->methoxy-4'-methylmercapto-phenyl)-imidazo-[4,5-b]pyridine
Fremstilt fra 2-metoksy-4-metylmerkapto-benzosyre og 5-cyano-2,3-diami.no-pyridin analogt med eks. 7. Utbytte: 28% av det teoretiske. Prepared from 2-methoxy-4-methylmercapto-benzoic acid and 5-cyano-2,3-diami.no-pyridine analogously to ex. 7. Yield: 28% of the theoretical.
Smp.: 268-270°C. M.p.: 268-270°C.
Eksempel 6 0 Example 6 0
5-ami.nosulf onyl-2- (2 ' -metoksy-4 1 -metylsulf onyl-f enyl) - benz imidazol 5-aminosulfonyl-2-(2'-methoxy-41-methylsulfonyl-phenyl)-benzimidazole
Fremstilt fra 5-ami.nosulf onyl-2-(2 '-metoksy-4 '-metylmerkapto-f enyl)-benzimidazol og hydrogenperoksyd analogt med eks. 2. Prepared from 5-aminosulfonyl-2-(2'-methoxy-4'-methylmercapto-phenyl)-benzimidazole and hydrogen peroxide analogously to ex. 2.
Utbytte: 38,3% av det teoretiske.Yield: 38.3% of the theoretical.
Smp.: 298-300°C. Melting point: 298-300°C.
Eksempel 61 Example 61
2- amino- 8-( 2'- metoksy- 4'- metylsulfinyl- fenyl)- purin Fremstilt fra 2-amino-8-(2'-metoksy-4'-metylmerkapto-fenyl)-purin og hydrogenperoksyd analogt med eks. 3. Utbytte: 5 3% av det teoretiske. 2-amino-8-(2'-methoxy-4'-methylsulfinyl-phenyl)-purine Prepared from 2-amino-8-(2'-methoxy-4'-methylmercapto-phenyl)-purine and hydrogen peroxide analogously to ex. 3. Yield: 5 3% of the theoretical.
Smp.: amorf, fra ca. 150°C.Melting point: amorphous, from approx. 150°C.
Eksempel 62 2-(2<1->metoksy-4'-metoksykarbonylamino-fenyl)-imidazo-[ 4 , 5-c]pyridi n a) 3,27 g (30 mmol) 3,4-diamino-pyridin og 5,02 g (30 mmol) 4-amino-2-metoksy-benzosyre oppvarmes i 2 timer under kraftig omrøring til 130°C i 50 g polyfosforsyre. Efter avkjøling tilsettes ca. 100 ml vann, det utfelte, gule bunnfall avsuges, suspenderes i 50 ml vann og gjøres svakt alkalisk med konsentrert ammoniakk. Det uoppløste produkt avsuges og tørres i luftsirkulasjons-tørreskap ved 50°C. Man oppnår 6,8 g 2-(4'-amino-2<1->metoksy-fenyl)-imidazo[4,5-c]pyridin, som ikke renses ytterligere, men omsettes direkte videre. b) 1,2 g (5 mmol) 2-(4 '-ami.no-2 '-metoksy-f enyl)-imidazo-[4,5-c] pyridin, oppløst i. 20 ml pyridin, tilsettes 0,7 ml klor-maursyremetylester ved -10°C. Derefter oppvarmes langsomt til romtemperatur og omrører i ytterligere 2 timer. Reaksjonsblandingen inndampes derefter til tørrhet, residuet omrøres i 1 time i. 30 ml 5%ig natriumhydrogenkarbonat-oppløsning, avsuges, tørres og renses ved kolonnekromatografi over silikagel (elueringsmiddel: metylenklorid med 1-12% etanol). Example 62 2-(2<1->methoxy-4'-methoxycarbonylamino-phenyl)-imidazo-[4,5-c]pyridine a) 3.27 g (30 mmol) of 3,4-diamino-pyridine and 5, 02 g (30 mmol) of 4-amino-2-methoxy-benzoic acid is heated for 2 hours with vigorous stirring to 130°C in 50 g of polyphosphoric acid. After cooling, add approx. 100 ml of water, the precipitated yellow precipitate is filtered off, suspended in 50 ml of water and made weakly alkaline with concentrated ammonia. The undissolved product is extracted and dried in an air circulation drying cabinet at 50°C. 6.8 g of 2-(4'-amino-2<1->methoxy-phenyl)-imidazo[4,5-c]pyridine is obtained, which is not purified further, but reacted directly further. b) 1.2 g (5 mmol) of 2-(4'-amino.no-2'-methoxy-phenyl)-imidazo-[4,5-c]pyridine, dissolved in 20 ml of pyridine, add 0, 7 ml of chloroformic acid methyl ester at -10°C. It is then slowly warmed to room temperature and stirred for a further 2 hours. The reaction mixture is then evaporated to dryness, the residue is stirred for 1 hour in 30 ml of 5% sodium bicarbonate solution, filtered off with suction, dried and purified by column chromatography over silica gel (eluent: methylene chloride with 1-12% ethanol).
Utbytte: 67% av der teoretiske.Yield: 67% of that theoretical.
Smp.: 229-230°C. M.p.: 229-230°C.
Eksempel 6 3 Example 6 3
5-etylaminokarbonylamino-2-(2'metoksy-4'-metansulfonyloksy-fenyl)- benzimidazol 5-ethylaminocarbonylamino-2-(2'methoxy-4'-methanesulfonyloxy-phenyl)- benzimidazole
1,0 g (3 mmol) 5-amino-2-(4'-metansulfonyloksy-2'-metoksy-fenyl)-benzimidazol oppløses i 30 ml tetrahydrofuran, tilsettes 2,5 ml etylisocyanat og oppvarmes til tilbakeløpstemperatur. Efter 15 minutter avdamper man oppløsningsmidlet og overskudd av etylisocyanat i. vakuum. Det oppnådde residuum kromatograferes over 250 g aluminiumoksyd (nøytral) (elueringsmiddel: metylenklorid med 4% etanol). 1.0 g (3 mmol) of 5-amino-2-(4'-methanesulfonyloxy-2'-methoxy-phenyl)-benzimidazole is dissolved in 30 ml of tetrahydrofuran, 2.5 ml of ethyl isocyanate is added and heated to reflux temperature. After 15 minutes, the solvent and excess ethyl isocyanate are evaporated in vacuo. The obtained residue is chromatographed over 250 g of aluminum oxide (neutral) (eluent: methylene chloride with 4% ethanol).
Utbytte: 2 7,5% av det teoretiske.Yield: 2 7.5% of the theoretical.
Smp.: 194-196°C. M.p.: 194-196°C.
Eksempel 64 Example 64
5-isopropylaminokarbonylamino-2-(2'-metoksy-4'-metansulfonyloksy-f enyl) -benzimidazol 5-isopropylaminocarbonylamino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole
Fremstilt fra 5-amino-2-(2'-metoksy-4<1->metansulfonyloksy-fenyl)-benzimidazol og isopropylisocyanat analogt med eks. 63. Utbytte: 27,1% av det teoretiske. Prepared from 5-amino-2-(2'-methoxy-4<1->methanesulfonyloxy-phenyl)-benzimidazole and isopropylisocyanate analogous to ex. 63. Yield: 27.1% of the theoretical.
Smp.: 189-190°C. M.p.: 189-190°C.
Eksempel 65 Example 65
8-( 2'- metoksy- 4'- metylami nokarbonylamino- fenyl)- purin Fremstilt fra 8-(4'-amino-2'-metoksy-fenyl)-purin og metylisocyanat analogt med eks. 63. 8-(2'-Methoxy-4'-methylaminocarbonylamino-phenyl)-purine Prepared from 8-(4'-amino-2'-methoxy-phenyl)-purine and methyl isocyanate analogous to ex. 63.
Utbytte: 17,3% av det teoretiske.Yield: 17.3% of the theoretical.
Smp.: 269-271°C. M.p.: 269-271°C.
Eksempel 66 Example 66
' 4- cyano- 2-( 4'- metansulfonyloksy- 2'- metoksy- fenyl)- benzimidazol ' 4- cyano- 2-( 4'- methanesulfonyloxy- 2'- methoxy- phenyl)- benzimidazole
3,0 g (11,3 mmol) 4-cyano-2-(4'-hydroksy-2'-metoksy-fenyl)-benzimidazol, oppløst i 90 ml IN natronlut, tilsettes dråpevis 5 ml metansulfonylklorid under omrøring. Ved gradvis tilsetning 3.0 g (11.3 mmol) of 4-cyano-2-(4'-hydroxy-2'-methoxy-phenyl)-benzimidazole, dissolved in 90 ml of 1N caustic soda, is added dropwise to 5 ml of methanesulfonyl chloride while stirring. By gradual addition
av ytterligere IN natronlut holdes pH-verdien i reaksjons-oppløsningen ved 10,0 til 10,5. Det utfelte produkt avsuges derefter, vaskes med vann, tørres og renses ved kolonnekromatografi. over 300 g aluminiumoksyd (nøytral, aktivitetstrinn II) of further IN caustic soda, the pH value in the reaction solution is kept at 10.0 to 10.5. The precipitated product is then filtered off, washed with water, dried and purified by column chromatography. over 300 g aluminum oxide (neutral, activity level II)
(elueringsmiddel: metylenklorid).(eluent: methylene chloride).
Utbytte: 72% av det teoretiske.Yield: 72% of the theoretical.
Smp.: 225-227°C. M.p.: 225-227°C.
Eksempel 6 7 4-aminokarbonyl-2-(4'-metansulfonyloksy-2'-metoksy-fenyl)-benzimidazol 1,0 g (2,9 mmol) 4-cyano-2-(4'-metansulfonyloksy-2'-metoksy-fenyl)-benzimidazol omrøres i 20 ml konsentrert svovelsyre i 18 timer ved romtemperatur, oppløsningen helles derefter på 50 g is og nøytraliseres med konsentrert ammoniakk under is-avkjøling. Det utfelte produkt avsuges, tørres og renses ved kolonnekromatografi over silikagel (elueringsmiddel: metylenklorid med 5% etanol). Example 6 7 4-aminocarbonyl-2-(4'-methanesulfonyloxy-2'-methoxy-phenyl)-benzimidazole 1.0 g (2.9 mmol) 4-cyano-2-(4'-methanesulfonyloxy-2'-methoxy -phenyl)-benzimidazole is stirred in 20 ml of concentrated sulfuric acid for 18 hours at room temperature, the solution is then poured onto 50 g of ice and neutralized with concentrated ammonia under ice-cooling. The precipitated product is filtered off, dried and purified by column chromatography over silica gel (eluent: methylene chloride with 5% ethanol).
Utbytte: 79% av det teoretiske.Yield: 79% of the theoretical.
Smp.: fra 250°C (sintrer).Melting point: from 250°C (sinters).
Eksempel 68 Example 68
5-metylami.nokarbonylmetylami.no-2- (4 1-metansulfonyloksy-2'- metoksy- fenyl)- benzimidazol 5-methylaminocarbonylmethylamino-2-(4 1-methanesulfonyloxy-2'- methoxy-phenyl)- benzimidazole
Fremstilt fra 5-metylami.nokarbonylmetylamino-2-(4 1-hydroksy-2'-metoksy-fenyl)-benzimidazol og metansulfonylklorid analogt med eks. 66. Prepared from 5-methylaminocarbonylmethylamino-2-(4 1-hydroxy-2'-methoxy-phenyl)-benzimidazole and methanesulfonyl chloride analogously to ex. 66.
Utbytte: 6 3% av det teoretiske.Yield: 6 3% of the theoretical.
Smp.: 210-212°C. M.p.: 210-212°C.
Eksempel 69 Example 69
4-metyl-2-(4'-metansulfonyloksy-2<1->metoksy-fenyl)-benzimidazol 4-methyl-2-(4'-methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole
Fremstilt fra 4-metyl-2-(4'-hydroksy-2'-metoksy-fenyl)-benzimidazol og metansulfonylklorid analogt med eks. 66. Utbytte: 6 0% av det teoretiske. Prepared from 4-methyl-2-(4'-hydroxy-2'-methoxy-phenyl)-benzimidazole and methanesulfonyl chloride analogously to ex. 66. Yield: 6 0% of the theoretical.
Smp.: 195-196°C. M.p.: 195-196°C.
Eksempel 70 Example 70
2-amino-8- ( 4'- metansulfonyloksy- 2'- metoksy- fenyl)- purin Fremstilt fra 2-ami.no-8-(4 1-metansulfonyloksy-2 1-metoksy-fenyl)-purin og metansulfonylklorid analogt med eks. 66. Utbytte: 41% av det teoretiske. 2-amino-8-(4'-methanesulfonyloxy-2'-methoxy-phenyl)-purine Prepared from 2-amino-8-(4 1-methanesulfonyloxy-2 1-methoxy-phenyl)-purine and methanesulfonyl chloride analogously to e.g. 66. Yield: 41% of the theoretical.
Smp.: 246-247°C. M.p.: 246-247°C.
Eksempel 71 Example 71
4-metoksykarbonyl-2-(4'-metansulfonyloksy-2<1->metoksy-fenyl)-benz i mi dazol 4-Methoxycarbonyl-2-(4'-methanesulfonyloxy-2<1->methoxy-phenyl)-benzimidazole
En oppløsning av 400 mg (1/34 mmol/ 4-metoksykarbonyl-2-(4'-hydroksy-2'-metoksy-fenyl)-benzimidazol, 10 ml pyridin og 0,8 ml metansulfonylklorid omrøres i 18 timer ved romtemperatur, inndampes derefter i vakuum, og residuet utrøres med 15 ml vann og innstilles på pH 8 med 0,5N saltsyre. Den således oppnådde oppløsning ekstraheres tre ganger med 10 ml metylenklorid hver gang, ekstraktene tørres og inndampes. Det faste residuum renses ved kolonnekromatografi over 150 g silikagel (elueringsmiddel: metylenklorid med 1% etanol). A solution of 400 mg (1/34 mmol/ 4-methoxycarbonyl-2-(4'-hydroxy-2'-methoxy-phenyl)-benzimidazole, 10 ml of pyridine and 0.8 ml of methanesulfonyl chloride is stirred for 18 hours at room temperature, evaporated then in vacuum, and the residue is stirred with 15 ml of water and adjusted to pH 8 with 0.5N hydrochloric acid. The solution thus obtained is extracted three times with 10 ml of methylene chloride each time, the extracts are dried and evaporated. The solid residue is purified by column chromatography over 150 g silica gel (eluent: methylene chloride with 1% ethanol).
Utbytte: 79,5% av det teoretiske.Yield: 79.5% of the theoretical.
Smp.: 182-183°C. M.p.: 182-183°C.
Eksempel 72 Example 72
2-(4'-metansulfonyloksy-2'-metoksy-fenyl)-imidazo[4,5-b]-naftalen 2-(4'-methanesulfonyloxy-2'-methoxy-phenyl)-imidazo[4,5-b]-naphthalene
Fremstilt fra 2-(4<1->hydroksy-2'-metoksy-fenyl)-imidazo-[4,5-b]naftalen og metansulfonylklorid analogt med eks. 71. Utbytte: 9% av det teoretiske. Prepared from 2-(4<1->hydroxy-2'-methoxy-phenyl)-imidazo-[4,5-b]naphthalene and methanesulfonyl chloride analogously to ex. 71. Yield: 9% of the theoretical.
Smp.: 195-197°C. M.p.: 195-197°C.
Eksempel 73 Example 73
5-acetaminometyl-2-(2'-metoksy-4'-metansulfonyloksy-fenyl)-benzimidazol 5-acetaminomethyl-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole
Fremstilt fra 5-acetaminoetyl-2-(4<1->hydroksy-2'-metoksy-fenyl)-benzimidazol og metansulfonylklorid analogt med eks. 71. Utbytte: 17,3% av det teoretiske. Prepared from 5-acetaminoethyl-2-(4<1->hydroxy-2'-methoxy-phenyl)-benzimidazole and methanesulfonyl chloride analogously to ex. 71. Yield: 17.3% of the theoretical.
Eksempel 74 Example 74
5-acetyl-2-(4<1->metansulfonyloksy-2'-metoksy-fenyl)-benzimidazol 5-acetyl-2-(4<1->methanesulfonyloxy-2'-methoxy-phenyl)-benzimidazole
Fremstilt fra 5-acetyl-2-(4<1->hydroksy-2<1->metoksy-fenyl)-benzimidazol og metansulfonylklorid analogt med eks. 71. Utbytte: 44% av det teoretiske. Prepared from 5-acetyl-2-(4<1->hydroxy-2<1->methoxy-phenyl)-benzimidazole and methanesulfonyl chloride analogously to ex. 71. Yield: 44% of the theoretical.
Smp.: 182-184°C. M.p.: 182-184°C.
Eksempel 75 Example 75
5-(fenyl-metoksymetyl)-2-(4'-metansulfonyloksy-2'-metoksy-fenyl)- benzimidazoT 5-(phenyl-methoxymethyl)-2-(4'-methanesulfonyloxy-2'-methoxy-phenyl)- benzimidazoT
Fremstilt fra 5-(fenyl-metoksymetyl-2-(4<1->hydroksy-2<1->metoksy-fenyl)-benzimidazol og metansulfonylklorid analogt med eks. 71. Prepared from 5-(phenyl-methoxymethyl-2-(4<1->hydroxy-2<1->methoxy-phenyl)-benzimidazole and methanesulfonyl chloride analogously to ex. 71.
Utbytte: 8% av det teoretiske..Yield: 8% of the theoretical..
Smp.: amorf.M.p.: amorphous.
Claims (3)
Applications Claiming Priority (1)
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DE19853522230 DE3522230A1 (en) | 1985-06-21 | 1985-06-21 | NEW 2-ARYLIMIDAZOLES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, AND METHOD FOR THE PRODUCTION THEREOF |
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EP (1) | EP0209707A3 (en) |
JP (1) | JPS62471A (en) |
AU (1) | AU5893286A (en) |
DE (1) | DE3522230A1 (en) |
DK (1) | DK290986A (en) |
ES (3) | ES8800907A1 (en) |
FI (1) | FI862623A (en) |
GR (1) | GR861583B (en) |
HU (1) | HUT42452A (en) |
NO (1) | NO862477L (en) |
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-
1985
- 1985-06-21 DE DE19853522230 patent/DE3522230A1/en not_active Withdrawn
-
1986
- 1986-06-11 EP EP86107969A patent/EP0209707A3/en not_active Withdrawn
- 1986-06-18 GR GR861583A patent/GR861583B/en unknown
- 1986-06-19 PT PT82789A patent/PT82789B/en unknown
- 1986-06-19 FI FI862623A patent/FI862623A/en not_active IP Right Cessation
- 1986-06-20 HU HU862615A patent/HUT42452A/en unknown
- 1986-06-20 ZA ZA864602A patent/ZA864602B/en unknown
- 1986-06-20 JP JP61144658A patent/JPS62471A/en active Pending
- 1986-06-20 NO NO862477A patent/NO862477L/en unknown
- 1986-06-20 ES ES556338A patent/ES8800907A1/en not_active Expired
- 1986-06-20 AU AU58932/86A patent/AU5893286A/en not_active Abandoned
- 1986-06-20 DK DK290986A patent/DK290986A/en not_active Application Discontinuation
- 1986-12-04 ES ES557241A patent/ES8705864A1/en not_active Expired
- 1986-12-04 ES ES557240A patent/ES8705863A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
EP0209707A2 (en) | 1987-01-28 |
FI862623A (en) | 1986-12-22 |
ES8705864A1 (en) | 1987-05-16 |
ES8705863A1 (en) | 1987-05-16 |
ES556338A0 (en) | 1987-12-01 |
PT82789B (en) | 1988-05-17 |
EP0209707A3 (en) | 1989-02-01 |
DE3522230A1 (en) | 1987-01-02 |
GR861583B (en) | 1986-10-21 |
HUT42452A (en) | 1987-07-28 |
NO862477D0 (en) | 1986-06-20 |
ES8800907A1 (en) | 1987-12-01 |
JPS62471A (en) | 1987-01-06 |
ES557240A0 (en) | 1987-05-16 |
PT82789A (en) | 1986-07-01 |
ZA864602B (en) | 1988-02-24 |
DK290986A (en) | 1986-12-22 |
ES557241A0 (en) | 1987-05-16 |
AU5893286A (en) | 1986-12-24 |
DK290986D0 (en) | 1986-06-20 |
FI862623A0 (en) | 1986-06-19 |
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