NO790409L - PROCEDURE FOR PREPARING NEW PREFERRED HYDROXYBENZODIETHERICCYCLES - Google Patents
PROCEDURE FOR PREPARING NEW PREFERRED HYDROXYBENZODIETHERICCYCLESInfo
- Publication number
- NO790409L NO790409L NO790409A NO790409A NO790409L NO 790409 L NO790409 L NO 790409L NO 790409 A NO790409 A NO 790409A NO 790409 A NO790409 A NO 790409A NO 790409 L NO790409 L NO 790409L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compound
- group
- acid
- residue
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 41
- 239000002253 acid Substances 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- 239000005977 Ethylene Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000003700 epoxy group Chemical group 0.000 claims description 2
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- -1 cycloaliphatic Chemical group 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000007858 starting material Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000000155 melt Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 5
- ZCOSPVZFETZHPV-UHFFFAOYSA-N 4-(3-amino-2-hydroxypropoxy)benzimidazol-2-one Chemical compound NCC(O)COC1=CC=CC2=NC(=O)N=C12 ZCOSPVZFETZHPV-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000005336 allyloxy group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 229940039009 isoproterenol Drugs 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VKTNUGNLKWRDNY-UHFFFAOYSA-N 4-(oxiran-2-ylmethoxy)benzimidazol-2-one Chemical compound C12=NC(=O)N=C2C=CC=C1OCC1CO1 VKTNUGNLKWRDNY-UHFFFAOYSA-N 0.000 description 2
- RIMQYFWEWZWWCK-UHFFFAOYSA-N 4-[3-(benzylamino)-2-hydroxypropoxy]benzimidazol-2-one Chemical compound C=1C=CC2=NC(=O)N=C2C=1OCC(O)CNCC1=CC=CC=C1 RIMQYFWEWZWWCK-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000001325 cardiostimulating effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004807 2-methylethylene group Chemical group [H]C([H])([H])C([H])([*:2])C([H])([H])[*:1] 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- YKHKGUAWZWOFDH-UHFFFAOYSA-N 4-(2-bromoethoxy)phenol Chemical compound OC1=CC=C(OCCBr)C=C1 YKHKGUAWZWOFDH-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- IIZBJGFAJYUHQI-UHFFFAOYSA-N 4-hydroxybenzimidazol-2-one Chemical compound OC1=CC=CC2=NC(=O)N=C12 IIZBJGFAJYUHQI-UHFFFAOYSA-N 0.000 description 1
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- 230000024883 vasodilation Effects 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Description
Fremgangsmåte til fremstilling av nyeProcedure for the production of new
foretrede hydroksy-benzodiheterocykler.etherified hydroxy-benzodiheterocycles.
Oppfinnelsen vedrører fremgangsmåte til fremstilling av foretrete hydroksybenzodiheterocykler, spesielt av forbindelser med formel The invention relates to a process for the production of etherified hydroxybenzodiheterocycles, in particular to compounds of the formula
hvori in which
alk betyr vicinalt alkylen med 2-3 karbonatomer, samt deres syreaddisjonssalter. alk means vicinal alkylene of 2-3 carbon atoms, as well as their acid addition salts.
I forbindelsene med formel I er vicinalt alkylenIn the compounds of formula I, vicinal is alkylene
alk 1- eller 2-metyletylen og fremfor alt etylen. alk 1- or 2-methylethylene and above all ethylene.
Syreaddisjonssalter av forbindelser med formel I er Acid addition salts of compounds of formula I are
spesielt farmasøytisk godtagbare, ikke-toksiske syreaddisjonssalter med egnet uorganiske syrer, som klorhydrogensyre, bromhydrogensyre, svovelsyre eller fosforsyre, eller med egnede organiske alifatiske, cykloalifatiske, aromatiske, aralifatiske eller heterocykliske in particular pharmaceutically acceptable, non-toxic acid addition salts with suitable inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic
karboksyl- eller sulfonsyrer, som maursyre, eddiksyre, propion-syre, ravsyre, glykolsyre, melkesyre, eplesyre, vinsyre, sitron-syre, maléinsyre, fumarsyre, pyrodruesyre, benzosyre, anthranil-syre, 4-hydroksybenzosyre, salicylsyre, fenyleddiksyre, embonsyre,' metansulfonsyre, etansulfonsyre, hydroksyetansulfonsyre,etylen-sulfonsyre, 4-klorbenzensulfonsyre, toluensulfonsyre, naftalinsul-fonsyre, sulfanilsyre eller cyklohexylaminsulfonsyre, eller ytterligere sure organiske stoffer, som ascorbinsyre. carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene sulfonic acid, 4-chlorobenzenesulfonic acid, toluenesulfonic acid, naphthalene sulfonic acid, sulfanilic acid or cyclohexylamine sulfonic acid, or further acidic organic substances, such as ascorbic acid.
På grunn av det snevre forhold meliom de nye forbin- deiser i fri form og i form av deres syreaddisjonssalter er det under de frie forbindelser og under saltene også å forstå de tilsvarende salter, resp. frie forbindelser. De nye forbindelser kan foreligge i form av racemater eller antipoder. Due to the narrow relationship between the new compounds in free form and in the form of their acid addition salts, the free compounds and the salts also mean the corresponding salts, resp. free connections. The new compounds may exist in the form of racemates or antipodes.
De nye forbindelser har verdifulle farmakologiske egenskaper, spesielt sterk og langvarig betareseptor-blokkerende virkninger som kan påvises ved hjelp av tilsvarende farmakologiske forsøk (se f.eks. Meier et al., Arzneimittelforschung, bind 20, side 1890 (1970). Således vider de nye forbindelser en 50 %-ig hemming av isoproterenol-tachykardi på isolerte marsvinhjerter (ifølge Langendorff) i konsentrasjoner på ca. 0,001 til 0,003yg/ml og-en 5 0 %-ig hemming av isoproterenol-tachykardi resp. -vasodila-tasjon på narkotisert katt i doser fra ca. 0,001 til 0,003 mg/kg resp. ca. 0,01 til 0,1 mg/kg ved intravenøs administrering. De nye forbindelser hører således til klassen av kardioselektive 8-reseptorblokkerere, dvs. de hemmer fortrinnsvis de kardiale effekter av isoproterenol i forhold til det vaskulære. De nye forbindelser kan anvendes som B-reseptorblokkerere f.eks. ved behandling av hjerterytmeforstyrrelser (Arrhytmer) og coronære hjertesykdommer, som angina pectoris, samt som blodtrykksenkende midler i behandling av hypertoni.<*>Dessuten har forbindelsene en kardiostimulerende virkning, som lar seg påvise f.eks. på isolert forgård av marsvin som økning i hjertefrekvensen i konsentrasjons-området fra ca. 0,01 til ca. 1 ug/ml. Denne virkningskvalitet lar seg videre påvise på narkotisert,resepin- forbehandlede.katter. eventuelt i form av en økning av hjertefrekvensen i et dosisområde fra ca. 0,0003 til ca. 0,3 mg/kg.i.v. Forbindelser med en slik kardiostimulerende virkning påvirker hjertefunksjonen mindre enn stoffer, som. ikke har disse ekstra egenskaper. The new compounds have valuable pharmacological properties, particularly strong and long-lasting beta-receptor-blocking effects which can be demonstrated with the help of corresponding pharmacological experiments (see, for example, Meier et al., Arzneimittelforschung, volume 20, page 1890 (1970). Thus, they new compounds a 50% inhibition of isoproterenol tachycardia on isolated guinea pig hearts (according to Langendorff) in concentrations of approximately 0.001 to 0.003 µg/ml and a 50% inhibition of isoproterenol tachycardia or vasodilatation on anesthetized cat in doses from about 0.001 to 0.003 mg/kg or about 0.01 to 0.1 mg/kg by intravenous administration. The new compounds thus belong to the class of cardioselective 8-receptor blockers, i.e. they preferentially inhibit the cardiac effects of isoproterenol in relation to the vascular The new compounds can be used as B-receptor blockers, for example in the treatment of heart rhythm disturbances (arrhythmias) and coronary heart diseases, such as angina pectoris, as well as as blood pressure antihypertensive agents in the treatment of hypertension.<*>Furthermore, the compounds have a cardiostimulating effect, which can be demonstrated e.g. in an isolated guinea pig yard as an increase in the heart rate in the concentration range from approx. 0.01 to approx. 1 ug/ml. This quality of action can also be demonstrated on drugged, prescription-pretreated cats. possibly in the form of an increase in heart rate in a dose range from approx. 0.0003 to approx. 0.3 mg/kg i.v. Compounds with such a cardiostimulating effect affect heart function less than substances, such as do not have these additional properties.
Forbindelsene viser dessuten a-reseptorblokkerehde egenskaper som i konsentrasjoner fra ca. 0,03 til ca. 0,3 yg/ml f.eks. på isolert-gjennomstrømmede mesenteriallag a<y>rotter ytrer seg som hemming av en noradrenalin-indusert vasokonstriksjon eller på isolert vas deferens hos rotter som hemming av noradrenalin-indusert kontraksjon. Videre har forbindelsene en langvarig blodtrykksenkendé virkning på narkotisert katt i dosisom-rådet fra 0,03 til 3 mg/kg i. v. Ved disse virkningskomponenter kan eksempelvis en blodtrykksenkendé virkning begunstiges. The compounds also show α-receptor blocking properties which in concentrations from approx. 0.03 to approx. 0.3 yg/ml e.g. on isolated perfused mesenteric layers a<y>rats manifests itself as inhibition of a noradrenaline-induced vasoconstriction or on isolated vas deferens in rats as inhibition of noradrenaline-induced contraction. Furthermore, the compounds have a long-lasting blood pressure-inducing effect on anesthetized cats in the dose range from 0.03 to 3 mg/kg i.v. With these action components, for example, a blood pressure-inducing effect can be favored.
Oppfinnelsen vedrører spesielt forbindelser med formel I, hvori alk betyr etylenresten, og farmasøytisk godtagbare syreaddisjonssalter av slike forbindelser. The invention relates in particular to compounds of formula I, in which alk means the ethylene residue, and pharmaceutically acceptable acid addition salts of such compounds.
Oppfinnelsen vedrører i første rekke følgende i eksemplene omtalte forbindelser med formel I, samt farmasøytisk godtagbare syreaddisjonssalter av disse forbindelser: 4-/3-/2- (4-hydroksyfenoksy)-etylamino/-2-hydroksypropoksy_7-benz-imidazol-2-on og The invention primarily relates to the following compounds of formula I mentioned in the examples, as well as pharmaceutically acceptable acid addition salts of these compounds: 4-(3-(2-(4-hydroxyphenoxy)-ethylamino)-2-hydroxypropoxy_7-benz-imidazol-2-one and
4-/3-/2- (2-hydroksyf enoksy) -etylamino_7-2-hydroksypropoksy_7-benz-imidazol-2-on. 4-/3-/2-(2-Hydroxyphenoxy)-ethylamino_7-2-hydroxypropoxy_7-benz-imidazol-2-one.
De nye forbindelser ifølge oppfinnelsen fremstilles på i og for seg kjent måte. The new compounds according to the invention are produced in a manner known per se.
Således kan man f.eks. få de nye forbindelser når en forbindelse med formel: omsettes med en forbindelse med formel Thus, one can e.g. get the new compounds when a compound of formula: is reacted with a compound of formula
hvori en av gruppene X1og X3betyr en reaksjonsdyktig forestret hydroksygruppe og de andre betyr den primære aminogruppe og X2betyr hydroksy, eller hvori X-^ og X2sammen betyr epoksygruppen og X^betyr den primære aminogruppe, og hvis ønsket overføres en dannet fri forbindelse i et salt eller et dannet salt i en fri forbindelse og/eller hvis ønsket oppdeles et dannes racemat i antipodene. in which one of the groups X1 and X3 means a reactive esterified hydroxy group and the others means the primary amino group and X2 means hydroxy, or in which X-^ and X2 together means the epoxy group and X^ means the primary amino group, and if desired a free compound formed is transferred in a salt or a formed salt in a free compound and/or if desired splits a racemate is formed in the antipodes.
En reaks jonsdyktig forestret hydroksygruppe X-^ resp. X^er en hydroksygruppe forestret med en sterk syre, spesielt en sterk uorganisk syre som en halogenhydrogensyre, spesielt klor-, brom- eller jodhydrogensyre, eller svovelsyre, eller én sterk organisk syre, spesielt en sterk organisk sulfonsyré, som en alifatisk eller aromatisk sulfonsyré, f.eks. metansulfonsyre, 4-metyl- fenylsulfonsyre eller 4-bromfenylsulfonsyre,og betyr i første rekke halogen, f.eks. klor, brom, eller jod, eller alifatiske eller aromatisk substituert sulfonyloksy, f.eks. metylsulfonyl-oksy eller 4-metylfenylsulfonyloksy. A reactive ionizable esterified hydroxy group X-^ resp. X^ is a hydroxy group esterified with a strong acid, especially a strong inorganic acid such as a hydrohalic acid, especially hydrochloric, bromic or hydroiodic acid, or sulfuric acid, or one strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid , e.g. methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, and primarily means halogen, e.g. chlorine, bromine, or iodine, or aliphatic or aromatically substituted sulfonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy.
Ovennevnte reaksjon gjennomføres på i og for seg kjent måte, idet man spesielt ved anvendelse av et utgangsmaterial med en reaksjonsdyktig forestret hydroksygruppe fortrinnsvis arbeider i nærvær av.et basisk middel som en uorganisk base, f.eks. et"'alkalimetall- eller jordalkalimetallkarbonat eller -hydroksyd, eller et organisk basisk middel som et alkalimetall-laverealkanolat, og/eller et overskudd av den basiske reaksjons-deltager og vanligvis i nærvær av et oppløsningsmiddel eller en oppløsningsmiddelblanding, og hvis nødvendig under avkjøling eller oppvarmning, f.eks. i et temperaturområde fra ca. -20° til ca. +150°C, i et åpent eller lukket kar og/eller i en inertgassatmosfære, f.eks. i en nitrogenatmosfære. The above-mentioned reaction is carried out in a manner known per se, particularly when using a starting material with a reactive esterified hydroxy group preferably working in the presence of a basic agent such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent such as an alkali metal low-alkaline anolate, and/or an excess of the basic reactant and usually in the presence of a solvent or solvent mixture, and if necessary under cooling or heating, for example in a temperature range from about -20° to about +150°C, in an open or closed vessel and/or in an inert gas atmosphere, for example in a nitrogen atmosphere.
Utgangsstoffer med formel II kan fremstilles på i og for seg kjent måte, f.eks. idet man i 4-hydroksybenzimidazol-2-on Starting substances with formula II can be prepared in a manner known per se, e.g. whereas in 4-hydroxybenzimidazol-2-one
eller i et eventuelt monocyklisk fortrinn herav overfører den fenoliske hydroksygruppe til allyloksygruppen og omdanner denne til den ønskede gruppe med formel X-^-CI^-CH (X2)-CH2-0 (Ila). Således kan man f.eks. i en 3-hydroksy-ftalsyre-dilaverealkyl-ester omdanne den fenoliske hydroksygruppe ved behandling med et allylhalogenid, f.eks. -bromid, i nærvær av en egnet base som et alkalimetall-, f.eks. kaliumkarbonat, til en allyloksy-gruppe, frigjøre 3-allyloksy-ftalsyren fra esteren ved hydrolyse, f.eks. ved behandling med et alkalimetallhydroksyd, og f.eks. ved behandling med eddiksyre overføre i det tilsvarende anhydrid. Ved modifisert Curtius-avbygning av det således dannede 3-allyloksy-f talsyreanhydrid, f.eks. ved behandling med en egnet azid-forbindelse som trilaverealkylsilylazid, spesielt trimetylsilyl-azid, får man etter etterfølgende hydrolyse 4-allyloksybenzimida-zol-2-on. Allylgruppen overføres f.eks. ved oksydasjon med hydrogenperoksyd eller en egnet uorganisk eller organisk persyre, f.eks. 3-klorperbenzosyre, i den ønskede 2,3-epoksy-propylgruppe, denne kan man ved behandling av den tilsvarende forbindelse med en egnet sterk syre, som en halogenhydrogensyre, omdanne til en 2-hydroksy-3-(reaksjonsdyktig-hydroksy)-propylgruppe. or in a possibly monocyclic preference thereof transfers the phenolic hydroxy group to the allyloxy group and converts this to the desired group of formula X-^-CI^-CH (X2)-CH2-0 (Ila). Thus, one can e.g. in a 3-hydroxyphthalic dilave alkyl ester convert the phenolic hydroxy group by treatment with an allyl halide, e.g. -bromide, in the presence of a suitable base such as an alkali metal-, e.g. potassium carbonate, to an allyloxy group, release the 3-allyloxyphthalic acid from the ester by hydrolysis, e.g. by treatment with an alkali metal hydroxide, and e.g. on treatment with acetic acid transfer into the corresponding anhydride. By modified Curtius decomposition of the thus formed 3-allyloxyphthalic anhydride, e.g. by treatment with a suitable azide compound such as trilower alkylsilyl azide, especially trimethylsilyl azide, 4-allyloxybenzimidazol-2-one is obtained after subsequent hydrolysis. The allyl group is transferred e.g. by oxidation with hydrogen peroxide or a suitable inorganic or organic peracid, e.g. 3-chloroperbenzoic acid, in the desired 2,3-epoxy-propyl group, this can be converted into a 2-hydroxy-3-(reactive-hydroxy)-propyl group by treating the corresponding compound with a suitable strong acid, such as a hydrohalic acid .
En ytterligere fremgangsmåter til fremstilling av forbindelse med formel I består i at i en forbindelse med formel: A further method for preparing a compound of formula I consists in that in a compound of formula:
idet alkQbetyr den til en vicinal alkylenrest alk svarende .alkylylidenrest, reduseres grupperingen med formel -alkQ=N-(IVa) til grupperingen med formel -alk-NH- (IVb) og hvis ønsket gjennomføres de ekstra fremgangsmåtetrinn. since alkQ means it is a vicinal alkylene residue alk corresponding to an alkylylidene residue, the grouping with the formula -alkQ=N-(IVa) is reduced to the grouping with the formula -alk-NH-(IVb) and, if desired, the additional method steps are carried out.
Den ovennevnte reduktive overføring av resten med formel IVa til den ønskede gruppering med formel IVb kan gjennom-føres på i og for seg kjent måte, idet man som egnet reduksjonsmiddel spesielt kan anvende lettmetallhydridreduksjonsmiddel, The above-mentioned reductive transfer of the residue with formula IVa to the desired grouping with formula IVb can be carried out in a manner known per se, as a suitable reducing agent can in particular be used light metal hydride reducing agent,
som alkalimetallborhydrid, f.eks. natriumborhydrid, samt alkali-metallcyanborhydrid, f.eks. natriumcyanborhydrid eller borhydrid, f.eks. diboran, videre katalytisk aktivert hydrogen, f.eks. hydrogen i nærvær av en tungmetallkatalysator, f.eks. Raney-nikkel, platin->oksyd eller palladium. such as alkali metal borohydride, e.g. sodium borohydride, as well as alkali metal cyanoborohydride, e.g. sodium cyanoborohydride or borohydride, e.g. diborane, further catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal catalyst, e.g. Raney nickel, platinum oxide or palladium.
Ovennevnte reduksjon gjennomføres på i og for seg kjent måte, vanligvis i nærvær av et inert oppløsningsmiddel, og hvis nødvendig under avkjøling eller oppvarming, f.eks. i et temperaturområde fra ca. -20° til ca. +15 0°C og/eller i et lukket kar under trykk, og/eller i en inertgass-, f.eks. nitrogenatmosfære. The above-mentioned reduction is carried out in a manner known per se, usually in the presence of an inert solvent, and if necessary during cooling or heating, e.g. in a temperature range from approx. -20° to approx. +15 0°C and/or in a closed vessel under pressure, and/or in an inert gas, e.g. nitrogen atmosphere.
Utgangsstoffer med formel IV kan man få på i og for seg kjent måte idet f.eks. 4-(2,3-epoksy-propyloksy)-benzimidazol-2-on behandles med ammoniakk og det således dannede (3-amino-2--hydroksy-propyloksy)-benzimidazol-2-on omsettes med en karbonyl-forbindelse med formel: Starting substances with formula IV can be obtained in a manner known per se, since e.g. 4-(2,3-epoxy-propyloxy)-benzimidazol-2-one is treated with ammonia and the thus formed (3-amino-2-hydroxy-propyloxy)-benzimidazol-2-one is reacted with a carbonyl compound of formula :
hvori alkQhar den angitte betydning. in which alkQ has the specified meaning.
Derved kan fremstillingen av utgangsmateriale med formel IV samtidig foregå med denne overføring i den ønskede for bindelse med formel I når man foretar reaksjonen av aminofor- . bindelsen med karbonylforbindelsen med formel V i nærvær av et egnet reduksjonsmiddel, f.eks. i nærvær av katalytisk aktivert hydrogen eller fortrinnsvis et hydridreduksjonsmiddel, f.eks. natriumcyanborhydrid. Thereby, the production of starting material with formula IV can take place at the same time as this transfer into the desired bond with formula I when carrying out the reaction of the amino form. the bond with the carbonyl compound of formula V in the presence of a suitable reducing agent, e.g. in the presence of catalytically activated hydrogen or preferably a hydride reducing agent, e.g. sodium cyanoborohydride.
De nye forbindelser med formel I kan likeledes fåes når i en forbindelse med formel: The new compounds of formula I can likewise be obtained when in a compound of formula:
hvori minst en av gruppene X^, X^og Xg betyr en med hydrogen erstattbar gruppe og de andre grupper betyr hydrogen eller en med hydrogen erstattbar gruppe og X^og X^sammen også betyr en avspaitbar med to med oksygen- resp. nitrogenatom forbundet hydrogenatom erstattbar rest, eller i et éalt herav erstatter de fra hydrogen forskjellige av restene X^, X^og Xg med hydrogen og hvis ønsket gjennomfører de resterende fremgahgsmåtetrinn. in which at least one of the groups X^, X^ and Xg means a hydrogen-replaceable group and the other groups mean hydrogen or a hydrogen-replaceable group and X^ and X^ together also mean a despaitable with two oxygen-resp. nitrogen atom connected hydrogen atom replaceable residue, or in all of these replace from hydrogen different of the residues X^, X^ and Xg with hydrogen and, if desired, carry out the remaining process steps.
Avspaltningen av gruppene X4og/eller X5og/eller Xg foretas ved hjelp av solvolyse eller reduksjon. Derved er i de ovennevnte utgangsstoffer med formel VI X4fortrinnsvis en med hydrogen erstattbar gruppe, mens X^. og Xg i første rekke betyr hydrogen. The removal of the groups X4 and/or X5 and/or Xg is carried out by means of solvolysis or reduction. Thereby, in the above-mentioned starting materials of formula VI, X4 is preferably a hydrogen-replaceable group, while X^. and Xg primarily means hydrogen.
En spesielt egnet avspaitbar gruppe X^er i første rekke en hydrogenolytisk avspaitbar a-aryllaverealkylgruppe som en eventuelt substituert 1-fenyllaverealkylgruppe, hvori substituentene, spesielt av fenyldelen, f.eks. kan være laverealkyl, A particularly suitable removable group X is primarily a hydrogenolytically removable α-aryl lower alkyl group such as an optionally substituted 1-phenyl lower alkyl group, in which the substituents, especially of the phenyl part, e.g. may be lower alkyl,
som metyl eller tert.-butyl, hydroksy, laverealkoksy, som metoksy, halogen, f.eks. klor eller brom, og/eller nitro, og i første rekke benzyl. En gruppe X^kan også være en solvolytisk, som hydrolytisk, eller.acidolytisk, videre en reduktiv, inkl. hydrogenolytisk, avspaitbar rest, spesielt en tilsvarende acylrest som acylresten av en organisk karboksylsyre, f.eks. laverealkanoyl, som acetyl, eller aroyl, som benzoyl, videre acylresten av en halv-ester av karbonsyre, som laverealkoksykarbonyl, f.eks. metoksykarbonyl, etoksykarbonyl, eller tert.-butyloksykarbonyl, 2-halogen-laverealkoksykarbonyl, f.eks. 2,2,2-trikloretoksykarbonyl eller such as methyl or tert.-butyl, hydroxy, lower alkoxy, such as methoxy, halogen, e.g. chlorine or bromine, and/or nitro, and primarily benzyl. A group X can also be a solvolytic, such as hydrolytic, or acidolytic, further a reductive, incl. hydrogenolytic, removable residue, especially an acyl residue corresponding to the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, further the acyl residue of a half-ester of carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, or tert-butyloxycarbonyl, 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or
2-jodetoksykarbonyl, eventuelt substituert 1-fenyllaverealkoksykarbonyl, f.eks., benzyloksykarbonyl eller difenylmetoksykarbonyl, eller aroylmetoksykarbonyl, f.eks. fenacyloksykarbonyl, eller acylresten av en organisk sulfonsyré, som en aromatisk sulfonsyré, 2-iodoethoxycarbonyl, optionally substituted 1-phenyllower oxycarbonyl, e.g., benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, or the acyl residue of an organic sulfonic acid, such as an aromatic sulfonic acid,
i første rekke en eventuelt substituert fenylsulfonylrest,"hvori substituentene f.eks. har den for ovennevnte 1-fenyllaverealkyl-rest angitte betydning, og spesielt betyr 4-metyl-fenylsulfonyl, videre en eventuelt substituert 1-polyfenyl-laverealkylgruppe, hvori substituenten i første rekke av fenyldeleh, f.eks. har den ovenfor angitte betydning og i.første rekke trityl. primarily an optionally substituted phenylsulfonyl residue," in which the substituents e.g. have the meaning specified for the above-mentioned 1-phenyl lower alkyl residue, and in particular means 4-methyl-phenylsulfonyl, further an optionally substituted 1-polyphenyl lower alkyl group, in which the substituent in the first series of phenyldeleh, for example, has the above meaning and primarily trityl.
Med hydrogen erstattbare grupper Xr og/eller Xg er .fortrinnsvis likeledes hydrogenolytisk avspaltbare grupper som en av de ovennevnte, eventuelt substituerte 1-fenyl-laverealkyl-grupper og i første rekke benzyl. Således kan videre også en av de for gruppen X^nevnte solvolytisk, inkl. alkoholytisk, eller reduktiv avspaltbare acylgruppervære videre en ved sammenknytnings-karbonatomet polyforgrenet, eventuelt substituert alifatisk eller aralifatisk hydrokarbonrest, som tert.-laverealkyl, f.eks. tert.-butyl, eller trityl. Hydrogen-replaceable groups Xr and/or Xg are also preferably hydrogenolytically cleavable groups such as one of the above-mentioned, optionally substituted 1-phenyl-lower alkyl groups and primarily benzyl. Thus, one of the solvolytically, including alcoholically, or reductively cleavable acyl groups mentioned for the group X can also be a polybranched at the linking carbon atom, optionally substituted aliphatic or araliphatic hydrocarbon residue, such as tert.-lower alkyl, e.g. tert-butyl, or trityl.
En med X4og X^sammen dannet avspaitbar rest erA detachable residue formed with X4 and X^ together is
i første rekke igjen en hydrogenolytisk avspaitbar gruppe, som eventuelt substituert 1-fenyl-laverealkyliden, hvori substituenten f.eks. kan være laverealkyl, som tert.-butyl, hydroksy, laverealkoksy, halogen, og/eller nitro, og spesielt benzyliden, samt solvolytisk, spesielt hydrolytisk spaltbare grupper, som laverealkyliden, f.eks. metylen eller isopropyliden, eller cykloalkyliden, f.eks. cyklohexyliden. En ytterligere,ved hjelp av gruppene X4primarily again a hydrogenolytically decapitable group, as optionally substituted 1-phenyl-lower alkylidene, in which the substituent e.g. can be lower alkyl, such as tert.-butyl, hydroxy, lower alkoxy, halogen, and/or nitro, and especially benzylidene, as well as solvolytically, especially hydrolytically cleavable groups, such as lower alkylidene, e.g. methylene or isopropylidene, or cycloalkylidene, e.g. the cyclohexylidene. A further one, using the groups X4
og Xg sammen dannet rest er diacylresten av karbonsyre eller tio-karbonsyre, dvs. karbonyl- resp. tiokarbonylgruppen. and Xg together formed residue is the diacyl residue of carboxylic acid or thio-carboxylic acid, i.e. carbonyl or the thiocarbonyl group.
Utgangsstoffer anvendbare i form av salter anvendesStarting materials usable in the form of salts are used
i første rekke i form av syreaddisjonssaltene, spesielt av tilsvarende salter med uorganiske syrer, f.eks. mineralsyrer, samt med organiske syrer. primarily in the form of the acid addition salts, especially of corresponding salts with inorganic acids, e.g. mineral acids, as well as with organic acids.
Hydrogenolytisk avspaltbare rester X^og/eller X^og/eller Xg, spesielt eventuelt substituerte 1-fenyl-laverealkyl-grupper, videre også egnede acylgrupper som eventuelt substituert 1-fenyllaverealkoksykarbonyl, samt med gruppen X^og X^ sammen dannede, eventuelt substituerte 1-fenyllaverealkylidengrupper, Hydrogenolytically cleavable residues X^ and/or X^ and/or Xg, in particular optionally substituted 1-phenyl-lower alkyl groups, further also suitable acyl groups such as optionally substituted 1-phenyl lower oxycarbonyl, as well as with the group X^ and X^ formed together, optionally substituted 1-phenyl lower alkylidene groups,
kan avspaltes ved behandling med katalytisk aktivert hydrogen, f.eks. can be split off by treatment with catalytically activated hydrogen, e.g.
med hydrogen i nærvær av en nikkelkatalysator som Raney-nikkel, eller en egnet edelmetallkatalysator. with hydrogen in the presence of a nickel catalyst such as Raney nickel, or a suitable noble metal catalyst.
Hydrolytisk avspaltbare grupper X4og/eller X^, og/ eller Xg, som acylrester av organiske karboksylsyirer, f.eks. Hydrolytically cleavable groups X4 and/or X^, and/or Xg, such as acyl residues of organic carboxylic acids, e.g.
lavere alkanoyl, og halvestere av karbonsyre, f.eks. laverealkoksykarbonyl, videre f.eks. tritylrester, samt med restene X^og X5sammen dannede laverealkylidengrupper eller karbonyl-grupper, kan alt etter typen av slike rester avspaltes ved behandling med vann under sure og/eller basiske betingelser, f.eks. i nærvær av en mineralsyre som klorhydrogen- eller svovelsyre eller et alkalimetall- eller jordalkalimetallhydroksyd eller lower alkanoyl, and half-esters of carboxylic acid, e.g. lower alkoxycarbonyl, further e.g. trityl residues, as well as lower alkylidene groups or carbonyl groups formed together with the residues X^ and X5, depending on the type of such residues, can be split off by treatment with water under acidic and/or basic conditions, e.g. in the presence of a mineral acid such as hydrochloric or sulfuric acid or an alkali metal or alkaline earth metal hydroxide or
-karbonat.-carbonate.
Acidolytisk avspaltbare rester er spesielt visse acylrester av halvestere av karbonsyre, som f.eks. tert.-laverealkoksykarbonyl eller eventuelt substituerte difenylmetoksykar-bonylrester, videre også tert.-laverealkylrester X^ og/eller Xg, de kan avspaltes ved behandling med egnede sterke organiske karboksylsyrer, som eventuelt med halogen, spesielt fluor, substituerte laverealkankarboksylsyrer, i første rekke med trifluor-eddiksyre, hvis nødvendig, i nærvær av et aktiverende middel, Acidolytically cleavable residues are in particular certain acyl residues of carboxylic acid half-esters, such as e.g. tert.-lower oxycarbonyl or optionally substituted diphenylmethoxycarbonyl residues, further also tert.-lower alkyl residues X^ and/or Xg, they can be cleaved by treatment with suitable strong organic carboxylic acids, such as optionally halogen, especially fluorine, substituted lower alkane carboxylic acids, primarily with trifluoroacetic acid, if necessary, in the presence of an activating agent,
som anisol, samt med maursyre.as anisole, as well as with formic acid.
Med reduktiv avspaltbare rester X^og/eller X,- og/ eller Xg forstås også slike grupper som avspaltes ved behandling med et kjemisk reduksjonsmiddel, spesielt med et reduserende metall eller en reduserende metallforbindelse. Slike rester er spesielt 2-halogen-laverealkoksykarbonyl eller aroylmetoksykarbonyl, som f.eks. kan avspalte ved behandling med et reduserende tungmetall som sink eller med ét reduserende tungmetallsalt som et krom(II)salt, f.eks. -klorid eller -acetat, vanligvis i nærvær av en organisk karboksylsyre, som maursyre eller eddiksyre og av vann. Reduktive avspaltbare arylsulfonylrester, spesielt de som i første rekke betyr resten X^kan f.eks. ved behandling méd et alkalimetall, f.eks. litium eller natrium, i ammoniakk eller ved hjelp av elektrolytisk reduksjon erstattes med hydrogen. Reductively cleavable residues X^ and/or X,- and/or Xg also mean such groups which are cleaved by treatment with a chemical reducing agent, in particular with a reducing metal or a reducing metal compound. Such residues are in particular 2-halo-lower oxycarbonyl or aroylmethoxycarbonyl, such as e.g. can split off when treated with a reducing heavy metal such as zinc or with a reducing heavy metal salt such as a chromium (II) salt, e.g. -chloride or -acetate, usually in the presence of an organic carboxylic acid, such as formic or acetic acid, and of water. Reductive cleavable arylsulfonyl residues, especially those which primarily mean the residue X^ can e.g. by treatment with an alkali metal, e.g. lithium or sodium, in ammonia or by means of electrolytic reduction is replaced by hydrogen.
De ovennevnte reaksjoner gjennomføres på i og forThe above reactions are carried out on i and for
seg kjent måte, vanligvis i nærvær av et oppløsningsmiddel eller oppløsningsmiddelblanding, idet egnede reduksjonsdeltagere samtidig også kan virke som sådanne, og hvis nødvendig under avkjøling eller oppvarming, f.eks. i et temperaturområde fra -20° til ca. 150°C i et åpent eller lukket kar og/eller i atmosfæren av en inertgass, known manner, usually in the presence of a solvent or solvent mixture, as suitable reduction participants can also act as such at the same time, and if necessary during cooling or heating, e.g. in a temperature range from -20° to approx. 150°C in an open or closed vessel and/or in the atmosphere of an inert gas,
f.eks. nitrogen.e.g. nitrogen.
Utgangsstoffene med formel VI kan fremstilles på i og for seg kjent måte, f.eks. ved behandling av en forbindelse med formel: med en forbindelse med formel: The starting substances with formula VI can be prepared in a manner known per se, e.g. by treating a compound of formula: with a compound of formula:
hvori X° 5 har den ovenfor for X^ angitte betydning og en av gruppene X°^og X°g betyr en reaksjonsdyktig forestret hydroksygruppe, og den annen betyr gruppen av formel -NH(X^), hvori X^hair den ovenfor angitte betydning.med den forholdsregel at minst en av gruppene X^, X^og Xg er forskjellig fra hydrogen, eller hvori X°^ og X°^sammen danner en binding og X°g betyr gruppen med formel -NH(X4), idet X^er forskjellige fra. hydrogen. Ovennevnte reaksjoner gjennomføres på i og for seg kjent måte. in which X° 5 has the meaning given above for X^ and one of the groups X°^ and X°g means a reactive esterified hydroxy group, and the other means the group of formula -NH(X^), in which X^hair the above meaning. with the precaution that at least one of the groups X^, X^ and Xg is different from hydrogen, or in which X°^ and X°^ together form a bond and X°g means the group with formula -NH(X4), as X^are different from. hydrogen. The above-mentioned reactions are carried out in a manner known per se.
De nye forbindelser ifølge oppfinnelsen kan likeledes fåes når det fra en forbindelse med formel: The new compounds according to the invention can likewise be obtained when from a compound of formula:
hvori Xg og X1Qbetyr rester, som er avspaltbare under dannelse av. den i forbindelsen med formel I med de to nitrogenatomer forbundet karbonylgruppe, eller i et salt herav avspaltes restene wherein Xg and X1Q represent residues, which are cleavable during formation of. the carbonyl group connected to the two nitrogen atoms in the compound of formula I, or in a salt thereof, the residues are split off
Xg og X^q under dannelse av karbonylgruppen og hvis ønsket gjennom-føres de ekstra fremgangsmåtetrinn. Xg and X^q during formation of the carbonyl group and, if desired, the additional method steps are carried out.
Utg.angsmaterialet med formel IX i form av et syre-addisjonssalt er f.eks. dette med en mineralsyre. The starting material with formula IX in the form of an acid addition salt is e.g. this with a mineral acid.
Vanligvis betyr en av restene Xg og X-^g hydrogen,Usually one of the residues Xg and X-^g means hydrogen,
mens den andre betyr acylresten av et karbonsyrederivat, som en tilsvarende ester, halogenid eller amid og f.eks. betyr laverealkoksykarbonyl, som metoksykarbonyl eller etoksykarbonyl, eller halogenkarbonyl, som klorkarbonyl eller aminokarbonyl. while the other means the acyl residue of a carboxylic acid derivative, such as a corresponding ester, halide or amide and e.g. means lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or halocarbonyl, such as chlorocarbonyl or aminocarbonyl.
Reaksjonen gjennomføres i fravær eller nærvær av ét egnet oppløsnings- eller fortynningsmiddel som et eventuelt substituert, f.eks. klorert, alifatisk, cykloalifatisk eller aromatisk hydrokarbon, som benzen, og hvis det er nødvendig, under av-kjøling eller oppvarming f.eks. i et temperaturområde fra ca. 0° The reaction is carried out in the absence or presence of a suitable solvent or diluent such as an optionally substituted one, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as benzene, and if necessary, during cooling or heating e.g. in a temperature range from approx. 0°
til ca. 100°C i et lukket kar og/eller i en inertgassatmosfære, f.eks. nitrogenatmosfære. Eventuelt, og fortrinnsvis, da når to approx. 100°C in a closed vessel and/or in an inert gas atmosphere, e.g. nitrogen atmosphere. Possibly, and preferably, then when
en av restene Xg eller X^g betyr aminokarbonyl gjennomfører man; omsetningen i nærvær av et basisk kondensasjonsmiddel, f.eks. one of the residues Xg or X^g means aminocarbonyl one carries out; the reaction in the presence of a basic condensing agent, e.g.
et metallalkoholat, som alkalialkoholat f.eks. natriumetylat,a metal alcoholate, such as alkali alcoholate e.g. sodium ethylate,
i et oppløsningsmiddel, f.eks. en laverealkanol, som etanol. Her-ved arbeider man hensiktsmessig i et temperaturområde på* ca. 0-150°C, fortrinnsvis på 10-120°C. in a solvent, e.g. a lower alkanol, such as ethanol. Here, one works appropriately in a temperature range of* approx. 0-150°C, preferably at 10-120°C.
Utgangsstoffer med formel IX kan fremstilles på iStarting substances with formula IX can be prepared on i
og for seg kjent måte og eventuelt in situ. Således kan man få foretrukne utgangsstof fer idet man f.eks. i 2 , 3-dinitrof eno.l overfører den fenoliske hydroksygruppe, som ved behandling med et allylhalogenid, f.eks. -bromid, i nærvær av en base, f.eks. kaliumkarbonat, til allyloksygruppen, omdanner denne ved behandling av mellomproduktene med hydrogenperoksyd, f.eks i nærvær av kaliumhydrogenkarbonat, eller med et egnet uorganisk eller organisk perkarboksylsyre, f. eks. 3-^klor-perbenzosyre, til 2,3-epoksy-propyloksygruppen og denne f.eks. ved behandling av mellomproduktet med et amin med formel: and in a known manner and possibly in situ. Thus, preferred starting materials can be obtained by e.g. i 2 , 3-dinitroph eno.l transfers the phenolic hydroxy group, which on treatment with an allyl halide, e.g. -bromide, in the presence of a base, e.g. potassium carbonate, to the allyloxy group, converts this by treating the intermediate products with hydrogen peroxide, e.g. in the presence of potassium hydrogen carbonate, or with a suitable inorganic or organic percarboxylic acid, e.g. 3-^chloro-perbenzoic acid, to the 2,3-epoxy-propyloxy group and this e.g. by treating the intermediate with an amine of formula:
til den tilsvarende substituerte 3-amino-2-hydroksypropyloksy-gruppe. Derpå reduseres de to nitrogrupper, f.eks. ved behandling med katalytisk aktivert hydrogen, til aminogruppen. Ved omsetning med et egnet reaksjonsdyktig karbonsyrederivat, f.eks. en tilsvarende ester, som et dilaverealkylkarbonat, f.eks. dimetyl-eller dietylkarbonat, et blandet anhydrid, som karbonsyredihaloge- to the correspondingly substituted 3-amino-2-hydroxypropyloxy group. The two nitro groups are then reduced, e.g. on treatment with catalytically activated hydrogen, to the amino group. By reaction with a suitable reactive carbonic acid derivative, e.g. a corresponding ester, such as a dilave alkyl carbonate, e.g. dimethyl or diethyl carbonate, a mixed anhydride, as carbonic acid dihalo-
nid, f.eks. fosgen eller et amid, f.eks. urinstoff eller N,N'-karbonyldiimidazol, får man et foretrukket utgangsmateriale som fortrinnsvis bare dannes in situ og direkte omdannes i en forbindelse med formel I. jealous, e.g. phosgene or an amide, e.g. urea or N,N'-carbonyldiimidazole, a preferred starting material is obtained which is preferably only formed in situ and directly converted into a compound of formula I.
De nye forbindelser med formel I kan likeledes fåes idet i en forbindelse med formel: hvori X-L1betyr en rest med formel -alk-NH-(C=X12 ) - (C=X11) - (Xa) eller -alk -(C-X12)-NH-CH2- (Xb), idet alkabetyr en metylen-eller etylidengruppe og X^2betyr okso- eller tioksoresten reduseres gruppen med formel X^ til resten med formel: The new compounds of formula I can likewise be obtained in a compound of formula: in which X-L1 denotes a residue of formula -alk-NH-(C=X12 ) - (C=X11) - (Xa) or -alk -(C -X12)-NH-CH2- (Xb), since alkaba means a methylene or ethylidene group and X^2 means the oxo or thioxore residue, the group with formula X^ is reduced to the residue with formula:
og hvis ønsket gjennomføres de ekstra fremgangsmåtetrinn. and if desired, the additional procedure steps are carried out.
Spesielt egnét til reduksjon av gruppene Xa og Xb, tilsvarende en oksorest X^2, inneholder.en karbamoylgruppering, er lett-metallhydridreduksjonsmidler, som ålkalimetallaluminiumhydrider, f.eks. litiumaluminiumhydrid, som egner seg spesielt til reduksjon av karbamoylgruppene eller alkalimetallborhydrid, f.eks. natriumcyanborhydrid eller borhydrid, f.eks. diboran. Light metal hydride reducing agents, such as alkali metal aluminum hydrides, e.g. lithium aluminum hydride, which is particularly suitable for the reduction of the carbamoyl groups or alkali metal borohydride, e.g. sodium cyanoborohydride or borohydride, e.g. diborane.
Grupperinger med formler (Xa) og (Xb), hvori X12hver gang betyr en tioksorest, omdannes ved reduktiv avsvovling, f.eks. ved behandling med en hydrogeneringskatalysator som Raney-nikkel til grupperingen med formel (XI). Groups of formulas (Xa) and (Xb), in which X12 each time means a thioxore residue, are converted by reductive desulphurisation, e.g. by treatment with a hydrogenation catalyst such as Raney nickel to the group of formula (XI).
Ovennevnte reduksjonsreaksjoner gjennomføres på iThe above reduction reactions are carried out on i
og for seg kjent måte, vanligvis i nærvær av et inert oppløsnings-middel, og hvis nødvendig under avkjøling eller oppvarmning, f.eks. i et temperaturområde fra ca. -20°C til ca. +150°C, og/eller i et lukket kar under trykk og/eller i.en inertgass-, f.eks. nitrogenatmosfære. and in a manner known per se, usually in the presence of an inert solvent, and if necessary during cooling or heating, e.g. in a temperature range from approx. -20°C to approx. +150°C, and/or in a closed vessel under pressure and/or in an inert gas, e.g. nitrogen atmosphere.
Utgangsstoffer med formel (X) kan fåes ved omsetning av aminoforbindelser med formel: Starting substances with formula (X) can be obtained by reacting amino compounds with formula:
hvori hydroksygruppen eventuelt foreligger i beskyttet,, f.eks. i forestret eller egnet foretret form med karboksylsyrefor-bindelser med formel: hvori alk har ovennevnte betydning, eller deres reaksjonsdyktige derivater, hvori den fenoliske hydroksygruppe eventuelt er beskyttet, som halogenidene, f.eks. kloridene, eller ved omsetning av aminoforbindelser med formel: hvori hydroksygruppen eventuelt er beskyttet med karboksylsyre med formel: in which the hydroxy group is optionally present in protected,, e.g. in esterified or suitably etherified form with carboxylic acid compounds of formula: in which alk has the above meaning, or their reactive derivatives, in which the phenolic hydroxy group is optionally protected, such as the halides, e.g. the chlorides, or by reacting amino compounds with formula: in which the hydroxy group is possibly protected with a carboxylic acid with formula:
hvori hydroksygruppen eventuelt foreligger i beskyttet, f.eks. i forestret eller egnet foretret form, eller deres reaksjonsdyktige funksjonelle derivater. I et mellomprodukt med en eller to be-skyttede hydroksygrupper overføres disse i den fri form. Ovennevnte reaksjoner gjennomføres på i og for seg kjent måte. in which the hydroxy group is optionally present in protected, e.g. in esterified or suitably etherified form, or their reactive functional derivatives. In an intermediate product with one or two protected hydroxy groups, these are transferred in the free form. The above-mentioned reactions are carried out in a manner known per se.
Alt etter fremgangsmåtebetingelsene og utgangsstoffene får man de nye forbindelser i fri form eller i den likeledes som av oppfinnelsen omfattede form av deres syreaddisjonssalter idet de nye forbindelser eller salter herav også kan foreligge som hemi-, mono-, sesqui- eller polyhydrater herav. Syreaddisjonssalter av de nye forbindelser kan på i og for seg kjent måte, f.eks. ved behandling med basiske midler som alkalimetallhydrok-syder, -karbonater eller -hydrogenkarbonater, eller ioneutvek-slere, overføres i de frie forbindelser. På den annen side kan dannede frie forbindelser på i og for seg kjent måte, f.eks. ved behandling med organiske eller uorganiske syrer som de ovennevnte syrer, danner syreaddisjonssalter, idet til fremstillingen anvendes spesielt slike syrer, som egner seg til dannelse av farma-søytisk godtagbare salter. Depending on the process conditions and starting materials, the new compounds are obtained in free form or in the form of their acid addition salts, which is also covered by the invention, since the new compounds or salts thereof can also be present as hemi-, mono-, sesqui- or polyhydrates thereof. Acid addition salts of the new compounds can in a manner known per se, e.g. when treated with basic agents such as alkali metal hydroxides, carbonates or hydrogen carbonates, or ion exchangers, are transferred in the free compounds. On the other hand, free compounds formed can be used in a manner known per se, e.g. by treatment with organic or inorganic acids such as the above-mentioned acids, acid addition salts are formed, the preparation being used in particular such acids, which are suitable for the formation of pharmaceutically acceptable salts.
Disse og andre syreaddisjonssalter av de nye forbindelser, som f.eks. pikratene- eller perkloratene, kan også tjene til rensing av de dannede frie baser, idet man overfører de frie forbindelser i salter, adskiller disse og renser dem, og fra saltene igjen danner de frie forbindelser. These and other acid addition salts of the new compounds, such as e.g. the picrates or perchlorates, can also serve to purify the free bases formed, as one transfers the free compounds into salts, separates these and purifies them, and from the salts they again form free compounds.
De nye forbindelser kan alt etter valg av utgangsstoffer og arbeidsmåte foreligge som optiske antipoder eller racemater. Depending on the choice of starting materials and working method, the new compounds can exist as optical antipodes or racemates.
Dannede racemater lar seg spalte etter i og for seg kjente metoder, til antipodene, f.eks. ved omkrystallisering fra et optisk aktivt oppløsningsmiddel, ved behandling med egnede mikroorganismer eller ved omsetning med en.optisk aktiv forbindelse som med den racemiske forbindelse danner et salt, spesielt av en tilsvarende syre og adskillelse av den på denne måte salt-blanding, f.eks. på grunn av forskjellige oppløseligheter i de dia-stereomere salter, hvorav de frie antipoder kan frigjøres ved innvirkning av egnede midler. Spesielt vanlig som optisk aktive syrer er f.eks. D- og L-formen av vinsyre, bis-0,0'-(p-toluoyl)-vinsyre, eplesyre, mandelsyre, kamfersulfonsyre, glutaminsyre, asparaginsyre eller kinsasyre. Fortrinnsvis isolerer man den mest virksomme av de to antipoder. Formed racemates can be split according to methods known per se, to the antipodes, e.g. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active compound which with the racemic compound forms a salt, especially of a corresponding acid and separation of the salt mixture in this way, e.g. . due to different solubilities in the diastereomeric salts, of which the free antipodes can be liberated by the action of suitable agents. Particularly common as optically active acids are e.g. The D and L form of tartaric acid, bis-0,0'-(p-toluoyl)-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the most effective of the two antipodes is isolated.
Oppfinnelsen vedrører også de utførelsesformer av fremgangsmåten ifølge hvilke man går ut fra på ett eller annet trinn.av fremgangsmåten som mellomprodukt dannet forbindelse og gjennomfører de manglende fremgangsmåtetrinn, eller avbryter fremgangsmåten på ett eller annet trinn, eller hvor man danner et utgangsstoff under reaksjonsbetingelsene, eller hvor en reaksjonskomponent eventuelt foreligger i form av dets salt. The invention also relates to the embodiments of the method according to which one starts from one or another step of the method as an intermediate formed a compound and carries out the missing method steps, or interrupts the method at one or other step, or where a starting substance is formed under the reaction conditions, or where a reaction component is optionally present in the form of its salt.
Hensiktsmessig anvender man for gjennomføring av reaksjonen ifølge oppfinnelsen slike utgangsstoffer som fører til de innledningsvis spesielt nevnte grupper av sluttstoffer og spesielt til de spesielt omtalte og fremhevede sluttstoffer. Expediently, for carrying out the reaction according to the invention, such starting substances are used which lead to the groups of end substances specifically mentioned at the outset and in particular to the particularly mentioned and emphasized end substances.
Utgangsstoffene er kjent og kan, hvis de er nye, fåes etter i og for seg kjente metoder, f.eks. som omtalt ovenfor. Nye utgangsstoffer danner likeledes en gjenstand for oppfinnelsen. Oppfinnelsen vedrører også fremgangsmåtemessig oppnådde mellom-produkter. The starting materials are known and, if they are new, can be obtained by methods known per se, e.g. as discussed above. New starting materials also form an object of the invention. The invention also relates to methodically obtained intermediate products.
De nye forbindelser kan f.eks. finne anvendelse i form av farmasøytiske preparater som inneholder en farmasøytisk virskom mengde av det aktive stoff, eventuelt sammen med uorganiske eller organiske, faste eller flytende, farmasøytisk anvendbare bærestoffer som egner seg til enteral, f.eks., oral, eller paren-teral administrering. Således anvender man tabletter eller gela-tinkapsler som inneholder det virksomme stoff sammen med for-tynningsmidler, f.eks. laktose, dextrose, sukrose, mannitol, sor-bitol, cellulose og/eller glycin, og/eller smøremidler f.eks. kiseljord, talkum, stearinsyre eller salter herav, som magnesium-eller kalsiumstearat, og/eller polyetylenglykol. Tabletter kan likeledes inneholde bindemidler f*.eks. magnesiumaluminiumsilikat, stivelser som mais-, hvete-, ris- eller pilrotstivelse, gelatiner, tragaht, metylcellulose, natriumkarboksymetylcellulose og/eller polyvinylpyrrolidon, og hvis ønsket sprengmiddel, f.eks. stivelse, agar, alginsyre eller et salt herav, som natriumalginat og/eller bruseblandinger, eller adsorbsjonsmiddel, farvestoffer, smaks-stoffer og søtningsmidler. Videre kan man anvende de nye farmakologiske virksomme forbindelser i form av parenteralt administrer-bare preparater eller infusjonsoppløsninger. Slike oppløsninger er fortrinnsvis isotoniske vandige oppløsninger eller suspensjoner, idet disse f.eks. ved lyofiliserte preparater, som inneholder det virksomme stoff alene eller sammen med et bæremateriale, f.eks. mannit, kan fremstilles før bruk. De farmasøytiske preparater kan være sterilisert og/eller inneholde hjelpestoffer, f.eks. konser-verings-, stabiliserings-, fukte- og/eller emulgeringsmiddel, oppløselighetsformidlere, salter til regulering av det osmotiske trykk og/eller puffere. De foreliggende farmasøytiske preparater som hvis ønsket kan inneholde ytterligere farmakologiske virksomme stoffer, fremstilles på i og for seg kjent måte, f.eks. ved vanlig blande-, granulerings-^, dragérings-, oppløsnings- eller lyofili-seringsfremgangsmåter, og inneholder fra ca. 0,1% til 100%, spesielt fra ca. 1% til ca. 50% lyofilisater inntil 100% av det aktive stoff. The new connections can e.g. find use in the form of pharmaceutical preparations containing a pharmaceutically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable carriers suitable for enteral, e.g., oral, or parenteral administration . Thus, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and/or lubricants e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contain binding agents, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatins, tragacht, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired explosives, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or fizzy mixes, or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, as these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservative, stabiliser, wetting and/or emulsifying agent, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which if desired may contain additional pharmacologically active substances, are prepared in a manner known per se, e.g. by usual mixing, granulation, coating, dissolving or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50% lyophilisates up to 100% of the active substance.
Doseringen kan avhenge av forskjellige faktorer som applikasjonsmåte, type, alder og/eller individuell tilstand. Den daglige dose som skal administreres ligger ved oral applikasjon mellom ca. 1 mg og ca. 15 mg for varmblodsdyr med en vekt på ca. The dosage may depend on various factors such as method of application, type, age and/or individual condition. The daily dose to be administered lies between approx. 1 mg and approx. 15 mg for warm-blooded animals with a weight of approx.
70 kg.70 kg.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler. The invention will be explained in more detail with the help of some examples.
Eksempel 1Example 1
Til en suspensjon av 22,4 g 4-(3-amino-2-hydroksy-propoksy)-benzimidazol-2-on og 21,2 g natriumkarbonat i 100 ml dioksan, som omrøres under tilbakeløpskoking under en nitrogenatmosfære, lar man det iløpet av 30 timer tildryppe en oppløsning av 22 g 4-hydroksy-fenoksyetylbromid i 200 ml dioksan. Man lar det etterreagere i 5 timer, frasuger uorganiske salter, inndamper filtratet under nedsatt trykk, opptar den gjenblivende olje i aceton og blander med en eterisk klorhydrogenoppløsning. Man får således 4-/3-/<2>- (4-hydroksyfenoksy)-etylamino_7-2-hydroksy-propoksy_7-benzimidazol-2-on-hydroklorid, som smelter ved 206-208°C. To a suspension of 22.4 g of 4-(3-amino-2-hydroxy-propoxy)-benzimidazol-2-one and 21.2 g of sodium carbonate in 100 ml of dioxane, which is stirred under reflux under a nitrogen atmosphere, is allowed to flow of 30 hours drip a solution of 22 g of 4-hydroxyphenoxyethyl bromide in 200 ml of dioxane. It is left to react for 5 hours, inorganic salts are sucked off, the filtrate is evaporated under reduced pressure, the remaining oil is taken up in acetone and mixed with an ethereal hydrogen chloride solution. Thus, 4-/3-/<2>-(4-hydroxyphenoxy)-ethylamino_7-2-hydroxy-propoxy_7-benzimidazol-2-one hydrochloride is obtained, which melts at 206-208°C.
Eksempel 2Example 2
5,2 g 4-/3-/N-benzyl-N-/2-(4-benzyloksyfenoksy)-etyl7~aminQ7-2-hydroksypropoksy7-benzimidazol-2-on hydrogeneres i 200 ml etanol over 0,5 g 5%-palladium-på-kull-katalysator ved 20-25°C under normaltrykk. Etter avslutning av hydrogenopptaket fra-suges fra katalysatoren og filtratet inndampes. Fra det dannede inndampningsresiduum tilberedes etter oppløsning! en aceton-metanol-blanding ved tilsetning av eterisk klorhydrogenoppløsning på vanlig måte hydrokloridet. Man får således 4-/3-/2-(4-hydroksy-fenoksy) -et<y>iamino_<7->2-hydroksypropoksy_7-benzimidazol-2-on-hydro-klorid, som smelter ved 206-208°C. 5.2 g of 4-/3-/N-benzyl-N-/2-(4-benzyloxyphenoxy)-ethyl7~amineQ7-2-hydroxypropoxy7-benzimidazol-2-one is hydrogenated in 200 ml of ethanol over 0.5 g of 5% -palladium-on-charcoal catalyst at 20-25°C under normal pressure. After completion of the hydrogen absorption, suction is taken from the catalyst and the filtrate is evaporated. From the formed evaporation residue is prepared after dissolution! an acetone-methanol mixture by adding ethereal hydrogen chloride solution in the usual way to the hydrochloride. One thus obtains 4-/3-/2-(4-hydroxy-phenoxy)-eth<y>iamino_<7->2-hydroxypropoxy_7-benzimidazol-2-one-hydrochloride, which melts at 206-208°C .
Utgangsstoffet kan fremstilles som følger:The starting material can be prepared as follows:
En blanding av 3,09 g 4-(2,3-epoksypropoksy)-benzimi-dazol-2-on, 4,9 9 g benzylaminoetoksyfenyl-4-benzyleter og 50 ml isopropanol oppvarmes 2 timer under omrøring og tilbakeløp til koking. Man får en klar oppløsning, som inndampes under nedsatt trykk. Residuet gir fra en eddiksyreetylester-eter-blanding 4-/3- (N-benzyl-N-/2- (4-benzyloksyfenoksy) -etyl7-amino7-2-hydroksy-propoksy7~benzimidazol-2-on, som smelter ved 108-109°C. A mixture of 3.09 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one, 4.99 g of benzylaminoethoxyphenyl-4-benzyl ether and 50 ml of isopropanol is heated for 2 hours with stirring and refluxed to boiling. A clear solution is obtained, which is evaporated under reduced pressure. The residue gives from an acetic acid ethyl ester-ether mixture 4-/3-(N-benzyl-N-/2-(4-benzyloxyphenoxy)-ethyl7-amino7-2-hydroxy-propoxy7~benzimidazol-2-one, which melts at 108 -109°C.
E ksempel 3Example 3
I en destillasjonsapparatur oppvarmes en suspensjon av 22,4 g 4-(3-amino-2-hydroksypropoksy)-benzimidazol-2-on og 20 g 4-hydroksyfenoksyeddiksyremetylester i 200 ml xylen under om-røring til koking, idet det påsees at temperaturen i destillasjons-hodet ikke stigerover 100°C. Derved destillerer den ved reaksjonen frigjorte metanol langsomt over. Etter 24 timer økes temperaturen således at xylen destillerer over. Destillasjonsresiduet 4-/3-/2-(4-hydroksyfenoksy)-acetamido7-2-hydroksypropoksy7-benz-imidazol-2-on oppløses i absolutt tetrahydrofuran og dryppes langsomt til en omrørt suspensjon av 7,6 g litiumaluminiumhydrid i 200 ml absolutt tetrahydrofuran. Deretter oppvarmer man reaksjonsblandingen enda 5 timer under omrøring og tilbakeløp, avkjøler deretter til 0°C og spalter residuet ved tildrypping av 80 ml In a distillation apparatus, a suspension of 22.4 g of 4-(3-amino-2-hydroxypropoxy)-benzimidazol-2-one and 20 g of 4-hydroxyphenoxyacetic acid methyl ester in 200 ml of xylene is heated with stirring to boiling, it being ensured that the temperature in the distillation head does not rise above 100°C. Thereby, the methanol liberated by the reaction slowly distills over. After 24 hours, the temperature is increased so that the xylene distills over. The distillation residue 4-/3-/2-(4-hydroxyphenoxy)-acetamido7-2-hydroxypropoxy7-benz-imidazol-2-one is dissolved in absolute tetrahydrofuran and slowly added dropwise to a stirred suspension of 7.6 g of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran . The reaction mixture is then heated for a further 5 hours with stirring and reflux, then cooled to 0°C and the residue is split by dropwise addition of 80 ml
12-n. klorhydrogensyre ved en temperatur på 0-5°G. Derpå innfører man 70 g -Seignette-salJt og innstiller reaksjonsblandingen ved tilsetning av konsentrert ammoniakkoppløsning på pH 9-10. Reaksjons-oppløsningen foreligger nu som tofase-blanding. Den organiske 12-n. hydrochloric acid at a temperature of 0-5°G. 70 g of Seignette salt are then introduced and the reaction mixture is adjusted by adding concentrated ammonia solution to pH 9-10. The reaction solution is now available as a two-phase mixture. The organic
fase adskilles, €ørkes over natriumsulfat, og inndampes under nedsatt trykk. Det gjenblivende rå4-/3-/2-(4-hydroksy-fenoksy)-e.tylaminq7-2-hydroksypropoksy7-benzimidazol-2-on gir med saltsyre hydrokloridet som etter omkrystalliséring fra aceton smelter ved 206-208°C. phase is separated, €dried over sodium sulfate, and evaporated under reduced pressure. The remaining crude 4-/3-/2-(4-hydroxy-phenoxy)-ethylamineq7-2-hydroxypropoxy7-benzimidazol-2-one gives with hydrochloric acid the hydrochloride which, after recrystallization from acetone, melts at 206-208°C.
Det som utgangsmateriale anvendte 4-(3-amino-2-hydroksy-propoksy)-benzimidazol-2-on kan fremstilles som følger: a) 3,3 g 4-(2,3-epoksypropoksy)-benzimidazol-2-on og 11,8 g benzylamin oppvarmes i 80 ml isopropanol i 5 timer under tilbakeløp til koking. Deretter avdestilleres under nedsatt trykk oppløsningsmidlet samt overskytende benzylamin og den gjenblivende olje tørkes ved 90°C/0,001 torr i 2 timer. Den består av 4-(3-benzylamino-2-hydroksy-propoksy)-benzimidazol-2-on, som.fåes i krystaller fra vann som etter tørking ved 60°C/1 torr i 18 timer smelter ved 203-205°C- • ^ • The 4-(3-amino-2-hydroxy-propoxy)-benzimidazol-2-one used as starting material can be prepared as follows: a) 3.3 g of 4-(2,3-epoxypropoxy)-benzimidazol-2-one and 11.8 g of benzylamine are heated in 80 ml of isopropanol for 5 hours under reflux until boiling. The solvent and excess benzylamine are then distilled off under reduced pressure and the remaining oil is dried at 90°C/0.001 torr for 2 hours. It consists of 4-(3-benzylamino-2-hydroxy-propoxy)-benzimidazol-2-one, which is obtained in crystals from water which, after drying at 60°C/1 torr for 18 hours, melts at 203-205°C - • ^ •
Hydrokloridet smelter ved 231-232°C under spaltning. The hydrochloride melts at 231-232°C during decomposition.
b) En oppløsning av 15,5 g 4-(3-benzylamino-2-hydroksy-propoksy)-benzimidazol-2-on i 160 ml metanol blandes med 1,6 g b) A solution of 15.5 g of 4-(3-benzylamino-2-hydroxy-propoxy)-benzimidazol-2-one in 160 ml of methanol is mixed with 1.6 g
5%-palladium-på-kull-katalysator og hydrogeneres til opptak av den beregnede hydrogenmengde. Etter filtrering fra. katalysatoren og avdestillering av oppløsningsmidlet får man 4-(3-amino-2-hydrok-sypropoksy)-benzimidazol-2-on, som etter omkrystallisering smelter fra etanol ved 188-190°C. 5% palladium-on-charcoal catalyst and hydrogenated to absorb the calculated amount of hydrogen. After filtering from. the catalyst and distilling off the solvent gives 4-(3-amino-2-hydroxy-cypropoxy)-benzimidazol-2-one, which after recrystallization melts from ethanol at 188-190°C.
Hydrokloridet smelter ved 232-239°C.The hydrochloride melts at 232-239°C.
Eksempel 4Example 4
9,5 g 4-_/3-/N-benzyl-N-/2-(2-benzyloksyf enoksy)-etyl7-amino7-2-hydroksypropoksy_7-benzimidazol-2-on oppløses under tilsetning av 18 ml l-n. metanolisk klorhydrogensyre i 100 ml metanol og hydrogeneres deretter over 1,0 g. 5%-palladium-på-kull-katalysator ved 2 0-25°C under normalt trykk. Etter avslutning av hydrogenopptak fortynner man med metanol-vann-blanding (1:1, v/v) inntil det utfelte produkt er oppløst. Derpå frafiltrerer man katalysatoren og inndamper filtratet. Fra det dannede inn-dampningsresidu får man.etter omkrystallisering fra varmt vann 4-/3-/2-(2-hydroksyfenoksy)-etylaminq/-2-hydroksypropoksy7-benz-imidazol-2-on-hydroklorid, som smelter ved 256-257°C. 9.5 g of 4-_/3-/N-benzyl-N-/2-(2-benzyloxyphenoxy)-ethyl7-amino7-2-hydroxypropoxy_7-benzimidazol-2-one are dissolved while adding 18 ml of l-n. methanolic hydrochloric acid in 100 ml methanol and then hydrogenated over 1.0 g. 5% palladium-on-charcoal catalyst at 20-25°C under normal pressure. After completion of hydrogen uptake, dilute with a methanol-water mixture (1:1, v/v) until the precipitated product is dissolved. The catalyst is then filtered off and the filtrate is evaporated. From the evaporation residue formed, after recrystallization from hot water, 4-/3-/2-(2-hydroxyphenoxy)-ethylamineq/-2-hydroxypropoxy7-benz-imidazol-2-one hydrochloride is obtained, which melts at 256 257°C.
Utgangsstoffet kan. fremstilles som følger:The starting material can produced as follows:
En blanding av 6,86 g 4-(2>3-epoksypropoksy)-benz-imidazol-2-on, 11,1 g benzylaminoetoksyfenyl-2-benzyleter og 150 ml isopropanol oppvarmes 3 timer under omrøring og tilbake-løpskoking. Deretter avdestilleres oppløsningsmidlet under nedsatt trykk og residuet opptas i varm metanol. Ved avkjøling ut-krystalliserer 4-/3-/N-benzyl-N- (2-benzyloksyf enoksy) -etyl7-amino_7-2-hydroksypropoksy_7-benzimidazol-2-on, som smelter ved 152-153°C. A mixture of 6.86 g of 4-(2>3-epoxypropoxy)-benz-imidazol-2-one, 11.1 g of benzylaminoethoxyphenyl-2-benzyl ether and 150 ml of isopropanol is heated for 3 hours while stirring and refluxing. The solvent is then distilled off under reduced pressure and the residue is taken up in hot methanol. On cooling, 4-(3-(N-benzyl-N-(2-benzyloxyphenoxy)-ethyl7-amino_7-2-hydroxypropoxy_7-benzimidazol-2-one) crystallizes out, which melts at 152-153°C.
Eksempel 5Example 5
Tabletter inneholdende 0,00 2 g 4-/3-/2-(4-hydroksyf enoksy) -etylamino/-2-hydroksy-propoksy_7-benzimidazol-2-on-hydro-klorid.fremstilles som følger: Tablets containing 0.00 2 g of 4-[3-(2-(4-hydroxyphenoxy)-ethylamino]-2-hydroxy-propoxy_7-benzimidazol-2-one-hydrochloride. are prepared as follows:
Sammen s e t n ing (for 1000 tabletter): 4-/3-/2- (4-hydroksyf enoksy) -etylaminq7-2-hydroksypropoksy_7-benz- Composition (for 1000 tablets): 4-/3-/2-(4-hydroxyphenoxy)-ethylamineq7-2-hydroxypropoxy_7-benz-
4-/3-/2-(4-hydroksyfenoksy)-etylamino7-2-hydroksy-propoksy_7-benzimidazol-2-on-hydroklorid 'blandes med melkesukker, en del av maisstivelsen og med kolloidal kis.elsyre og. blandingen drives gjennom en sikt. En ytterligere del av maisstivelsen forklistres med fem ganger vannmengden på vannbad.og pulver-blandingen knas med dette klister, inntil det oppstår en svak plastisk masse. Denne trykkes gjennom en sikt av ca. 3 mm maske-vidde, tørkes og det tørre granulat drives igjen gjennom en sikt. Derpå tilblandes resterende maisstivelse, talkum og magnesium-steårat og den dannede blanding presses til tabletter av 0,100 g vekt (med bruddrille). 4-/3-/2-(4-Hydroxyphenoxy)-ethylamino7-2-hydroxy-propoxy_7-benzimidazol-2-one hydrochloride is mixed with milk sugar, part of the corn starch and with colloidal silicic acid and. the mixture is passed through a sieve. A further part of the cornstarch is pasted with five times the amount of water in a water bath, and the powder mixture is crushed with this paste, until a weak plastic mass is formed. This is printed through a sieve of approx. 3 mm mesh width, is dried and the dry granules are run through a sieve again. The remaining cornstarch, talc and magnesium stearate are then mixed in and the resulting mixture is pressed into tablets of 0.100 g weight (with a crushing drill).
På analog måte kan andre forbindelser med formel I eller deres farmasøytisk godtagbare, ikke-toksiske syreaddisjonssalter, f. eks. 4-/3-/2- ( 2-hydroksyf enoksy) -etylamiho_7-2-hydroksy-propoksy7-benz-imidazol-2-on-hydroklorid anvendes som virksomme stoffer i de omtalte tabletter. Analogously, other compounds of formula I or their pharmaceutically acceptable, non-toxic acid addition salts, e.g. 4-/3-/2-(2-Hydroxyphenoxy)-ethylamiho_7-2-hydroxy-propoxy7-benz-imidazol-2-one hydrochloride is used as active substance in the mentioned tablets.
Claims (5)
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CH145078 | 1978-02-09 | ||
CH559478 | 1978-05-23 |
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EP (1) | EP0003758A1 (en) |
JP (1) | JPS54117475A (en) |
AU (1) | AU4410279A (en) |
DD (1) | DD141926A6 (en) |
DK (1) | DK52179A (en) |
FI (1) | FI790397A (en) |
GB (1) | GB2014146A (en) |
GR (1) | GR72461B (en) |
IE (1) | IE790237L (en) |
IL (1) | IL56617A0 (en) |
NO (1) | NO790409L (en) |
PL (1) | PL213252A3 (en) |
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DE2905877A1 (en) * | 1979-02-16 | 1980-08-28 | Boehringer Mannheim Gmbh | NEW AMINOPROPANOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
DK187880A (en) | 1979-05-04 | 1980-11-05 | Continental Pharma | PROCEDURE FOR THE PREPARATION OF PHENYL TYLAMINE DERIVATIVES |
JPH09502166A (en) * | 1993-07-31 | 1997-03-04 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 2-Benzoheterocyclyloxy or thiopropanolamine derivatives having adrenergic receptor agonist activity |
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CH486442A (en) * | 1963-07-30 | 1970-02-28 | Ici Ltd | Process for the preparation of new heterocyclic derivatives |
GB1058822A (en) * | 1963-07-30 | 1967-02-15 | Ici Ltd | 3-amino-2-hydroxypropoxy heterocyclic derivatives |
CH624395A5 (en) * | 1976-01-08 | 1981-07-31 | Ciba Geigy Ag | |
NZ187066A (en) * | 1977-05-03 | 1981-02-11 | Hoffmann La Roche | 4-(3-substitutedamino-2-hydroxypropoxy)-benzimidazolidin-2-(ones or thiones) |
GB1595316A (en) * | 1977-05-03 | 1981-08-12 | Roche Products Ltd | 4-(3-amino-2-hydroxy-propoxy)-benzimidazole derivatives and pharmaceutical compositions containing them |
-
1979
- 1979-01-31 EP EP79100273A patent/EP0003758A1/en not_active Withdrawn
- 1979-02-07 FI FI790397A patent/FI790397A/en unknown
- 1979-02-07 IL IL56617A patent/IL56617A0/en unknown
- 1979-02-07 GR GR58288A patent/GR72461B/el unknown
- 1979-02-07 PL PL21325279A patent/PL213252A3/xx unknown
- 1979-02-08 AU AU44102/79A patent/AU4410279A/en not_active Abandoned
- 1979-02-08 DD DD79210909A patent/DD141926A6/en unknown
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- 1979-02-08 DK DK52179A patent/DK52179A/en unknown
- 1979-02-08 NO NO790409A patent/NO790409L/en unknown
- 1979-02-08 GB GB7904509A patent/GB2014146A/en not_active Withdrawn
- 1979-02-09 JP JP1346479A patent/JPS54117475A/en active Pending
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PL213252A3 (en) | 1980-03-24 |
EP0003758A1 (en) | 1979-09-05 |
DK52179A (en) | 1979-08-10 |
GB2014146A (en) | 1979-08-22 |
AU4410279A (en) | 1979-08-16 |
FI790397A (en) | 1979-08-10 |
IE790237L (en) | 1979-08-09 |
GR72461B (en) | 1983-11-10 |
DD141926A6 (en) | 1980-05-28 |
IL56617A0 (en) | 1979-05-31 |
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