CS227313B2 - Method of preparing heterocyclic oxypropanolamine derivatives - Google Patents
Method of preparing heterocyclic oxypropanolamine derivatives Download PDFInfo
- Publication number
- CS227313B2 CS227313B2 CS806605A CS660580A CS227313B2 CS 227313 B2 CS227313 B2 CS 227313B2 CS 806605 A CS806605 A CS 806605A CS 660580 A CS660580 A CS 660580A CS 227313 B2 CS227313 B2 CS 227313B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- propoxy
- hydroxy
- group
- alkyl
- hydrogen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 title description 4
- -1 alkyl radicals Chemical class 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 33
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 150000003254 radicals Chemical class 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 238000003419 tautomerization reaction Methods 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 72
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- LSONXNMNZYBRDE-UHFFFAOYSA-N 2h-benzotriazole;hydrochloride Chemical compound Cl.C1=CC=C2NN=NC2=C1 LSONXNMNZYBRDE-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- QQHDLQDOUOASOX-UHFFFAOYSA-N acetic acid;1h-indazole Chemical compound CC(O)=O.C1=CC=C2C=NNC2=C1 QQHDLQDOUOASOX-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000006308 propyl amino group Chemical group 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RESMEUBPQZEOIP-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(3-ethoxy-4-methoxyphenyl)ethylamino]propan-2-ol Chemical compound C1=C(OC)C(OCC)=CC(CCNCC(O)COC=2C3=CN(CC=4C=CC=CC=4)N=C3C=CC=2)=C1 RESMEUBPQZEOIP-UHFFFAOYSA-N 0.000 description 2
- HVIHMBVIKGDWLD-UHFFFAOYSA-N 1-(2-nitro-6-phenylmethoxyphenyl)ethanol Chemical compound C1=CC=C([N+]([O-])=O)C(C(O)C)=C1OCC1=CC=CC=C1 HVIHMBVIKGDWLD-UHFFFAOYSA-N 0.000 description 2
- PBSZHNXXFIYDBU-UHFFFAOYSA-N 2-methyl-1-nitro-3-phenylmethoxybenzene Chemical compound C1=CC=C([N+]([O-])=O)C(C)=C1OCC1=CC=CC=C1 PBSZHNXXFIYDBU-UHFFFAOYSA-N 0.000 description 2
- IDTQKKVCEKELPJ-UHFFFAOYSA-N 4-(oxiran-2-ylmethoxy)-2,3-dihydroindole-1-carbaldehyde Chemical compound O=CN1CCC2=C1C=CC=C2OCC1CO1 IDTQKKVCEKELPJ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methyl-1h-indole Chemical compound CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IBOYYKXIPLPKBJ-UHFFFAOYSA-N C1=CC=C(C=C1)CCCNCC(COC2=CC=CC3=NN(C=C32)CC4=CC=CC=C4)O Chemical compound C1=CC=C(C=C1)CCCNCC(COC2=CC=CC3=NN(C=C32)CC4=CC=CC=C4)O IBOYYKXIPLPKBJ-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 150000004780 naphthols Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FWWRZKARZBOYSD-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-(3-phenylpropylamino)propan-2-ol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CNCCCC1=CC=CC=C1 FWWRZKARZBOYSD-UHFFFAOYSA-N 0.000 description 1
- NLAUECGJMHDJLM-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1C=NN2 NLAUECGJMHDJLM-UHFFFAOYSA-N 0.000 description 1
- UGVMETBQBJKPAK-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-[2-(2-methoxyphenoxy)propylamino]propan-2-ol Chemical compound COC1=CC=CC=C1OC(C)CNCC(O)COC1=CC=CC2=C1C=NN2 UGVMETBQBJKPAK-UHFFFAOYSA-N 0.000 description 1
- JIRMRZZCVVUEDH-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-(2,3-dihydro-1,4-benzodioxin-3-ylmethylamino)propan-2-ol Chemical compound C1OC2=CC=CC=C2OC1CNCC(O)COC(C1=C2)=CC=CC1=NN2CC1=CC=CC=C1 JIRMRZZCVVUEDH-UHFFFAOYSA-N 0.000 description 1
- JSILGVBTKSVZPF-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-(2-phenoxyethylamino)propan-2-ol Chemical compound C=1C=CC2=NN(CC=3C=CC=CC=3)C=C2C=1OCC(O)CNCCOC1=CC=CC=C1 JSILGVBTKSVZPF-UHFFFAOYSA-N 0.000 description 1
- WVMIMMUQFHJHKL-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-(2-pyridin-4-ylethylamino)propan-2-ol Chemical compound C=1C=CC2=NN(CC=3C=CC=CC=3)C=C2C=1OCC(O)CNCCC1=CC=NC=C1 WVMIMMUQFHJHKL-UHFFFAOYSA-N 0.000 description 1
- YLAVHRZRZDEIOO-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC(C1=C2)=CC=CC1=NN2CC1=CC=CC=C1 YLAVHRZRZDEIOO-UHFFFAOYSA-N 0.000 description 1
- GFZBULYZSUQPIM-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(3,4-dimethoxyphenyl)ethylamino]propan-2-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC(C1=C2)=CC=CC1=NN2CC1=CC=CC=C1 GFZBULYZSUQPIM-UHFFFAOYSA-N 0.000 description 1
- YZOQNFPGNGQRJM-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(3-methoxy-4-phenylmethoxyphenyl)ethylamino]propan-2-ol Chemical compound C=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1CCNCC(O)COC(C1=C2)=CC=CC1=NN2CC1=CC=CC=C1 YZOQNFPGNGQRJM-UHFFFAOYSA-N 0.000 description 1
- XSIJPVDONNXYFJ-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethylamino]-3-(1h-indazol-4-yloxy)propan-2-ol Chemical compound C=1C=C2OCCOC2=CC=1CCNCC(O)COC1=CC=CC2=C1C=NN2 XSIJPVDONNXYFJ-UHFFFAOYSA-N 0.000 description 1
- CSLBGLZSAIFXHL-UHFFFAOYSA-N 1-[2-(2-methoxyphenoxy)ethylamino]-3-[(7-methyl-2h-benzotriazol-4-yl)oxy]propan-2-ol;hydrochloride Chemical compound Cl.COC1=CC=CC=C1OCCNCC(O)COC1=CC=C(C)C2=C1N=NN2 CSLBGLZSAIFXHL-UHFFFAOYSA-N 0.000 description 1
- QXZKJAQQXPODOI-UHFFFAOYSA-N 1-[2-(2-methoxyphenoxy)propylamino]-3-[(6-methyl-1h-indol-4-yl)oxy]propan-2-ol Chemical compound COC1=CC=CC=C1OC(C)CNCC(O)COC1=CC(C)=CC2=C1C=CN2 QXZKJAQQXPODOI-UHFFFAOYSA-N 0.000 description 1
- LAXXKAKEQTVCAJ-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-(1h-indazol-4-yloxy)propan-2-ol;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC2=C1C=NN2 LAXXKAKEQTVCAJ-UHFFFAOYSA-N 0.000 description 1
- JLRCPLRKLJHQQC-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-[[6-(hydroxymethyl)-1h-indol-4-yl]oxy]propan-2-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC(CO)=CC2=C1C=CN2 JLRCPLRKLJHQQC-UHFFFAOYSA-N 0.000 description 1
- LUBHUSKVTINBBJ-UHFFFAOYSA-N 1-[2-(3-ethoxy-4-methoxyphenyl)ethylamino]-3-(1h-indazol-4-yloxy)propan-2-ol Chemical compound C1=C(OC)C(OCC)=CC(CCNCC(O)COC=2C=3C=NNC=3C=CC=2)=C1 LUBHUSKVTINBBJ-UHFFFAOYSA-N 0.000 description 1
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 1
- FARSPAVQUKTXLF-UHFFFAOYSA-N 1h-benzimidazol-1-ium;chloride Chemical compound Cl.C1=CC=C2NC=NC2=C1 FARSPAVQUKTXLF-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- VSNMDLMFNWNGBS-UHFFFAOYSA-N 2-[1-[[2-hydroxy-3-(1h-indazol-4-yloxy)propyl]amino]propan-2-yloxy]phenol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CNCC(C)OC1=CC=CC=C1O VSNMDLMFNWNGBS-UHFFFAOYSA-N 0.000 description 1
- LORPHZRVAQYBNC-UHFFFAOYSA-N 2-[1-[[3-(2-benzylindazol-4-yl)oxy-2-hydroxypropyl]amino]-4-phenylbutan-2-yl]oxyphenol Chemical compound C=1C=CC2=NN(CC=3C=CC=CC=3)C=C2C=1OCC(O)CNCC(OC=1C(=CC=CC=1)O)CCC1=CC=CC=C1 LORPHZRVAQYBNC-UHFFFAOYSA-N 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
- 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 1
- AFUHCMSSWQBYNR-UHFFFAOYSA-N 4-[2-hydroxy-3-[2-(2-methylsulfanylphenoxy)ethylamino]propoxy]-2,3-dihydroindole-1-carbaldehyde Chemical compound CSC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1CCN2C=O AFUHCMSSWQBYNR-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- BHQLLWPWXJFCDP-UHFFFAOYSA-N C(C)(=O)OCC.N1N=CC2=CC=CC=C12 Chemical compound C(C)(=O)OCC.N1N=CC2=CC=CC=C12 BHQLLWPWXJFCDP-UHFFFAOYSA-N 0.000 description 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 1
- ZTWQEYKBIRLFIJ-UHFFFAOYSA-N CCOC(=O)C1=CC2=C(N1)C=C(C=C2OCC(CNCC(C)C3=CC=CC=C3)O)C Chemical compound CCOC(=O)C1=CC2=C(N1)C=C(C=C2OCC(CNCC(C)C3=CC=CC=C3)O)C ZTWQEYKBIRLFIJ-UHFFFAOYSA-N 0.000 description 1
- OZPZQEBXIXOJSX-UHFFFAOYSA-N CCOC(=O)C1=CC2=C(N1)C=C(C=C2OCC(CNCC3COC4=CC=CC=C4O3)O)C Chemical compound CCOC(=O)C1=CC2=C(N1)C=C(C=C2OCC(CNCC3COC4=CC=CC=C4O3)O)C OZPZQEBXIXOJSX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- JVZPRBRILFZTDP-UHFFFAOYSA-N OC(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC2=C1CCN2C=O Chemical compound OC(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC2=C1CCN2C=O JVZPRBRILFZTDP-UHFFFAOYSA-N 0.000 description 1
- GNPBAFWHOVCQHE-UHFFFAOYSA-N OC(=O)C1=CC=CC=C1.C1=CC=C2N(C=O)CCC2=C1 Chemical compound OC(=O)C1=CC=CC=C1.C1=CC=C2N(C=O)CCC2=C1 GNPBAFWHOVCQHE-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- GXRVYWVVJWPPRG-UHFFFAOYSA-N [1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-[1-(2,2-dimethylpropanoyl)indazol-4-yl]oxypropan-2-yl] 2,2-dimethylpropanoate;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCNCC(OC(=O)C(C)(C)C)COC1=CC=CC2=C1C=NN2C(=O)C(C)(C)C GXRVYWVVJWPPRG-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- FMIIDFWFAQDWOD-UHFFFAOYSA-N benzoic acid;4-[2-hydroxy-3-[2-(2-methoxyphenoxy)propylamino]propoxy]-2,3-dihydroindole-1-carbaldehyde Chemical compound OC(=O)C1=CC=CC=C1.COC1=CC=CC=C1OC(C)CNCC(O)COC1=CC=CC2=C1CCN2C=O FMIIDFWFAQDWOD-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011970 concomitant therapy Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000010006 flight Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000003944 halohydrins Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- WLCLBOVXRZPLIW-UHFFFAOYSA-N hydron;1h-indazole;chloride Chemical compound Cl.C1=CC=C2C=NNC2=C1 WLCLBOVXRZPLIW-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- XYDRDTVYCXVUBI-UHFFFAOYSA-N methyl 4-[3-[2-(3,4-dimethoxyphenyl)ethylamino]-2-hydroxypropoxy]-1h-indole-6-carboxylate Chemical compound C=12C=CNC2=CC(C(=O)OC)=CC=1OCC(O)CNCCC1=CC=C(OC)C(OC)=C1 XYDRDTVYCXVUBI-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VRMQWUBVEMLIME-UHFFFAOYSA-N n-[4-[2-[[2-hydroxy-3-(1h-indazol-4-yloxy)propyl]amino]ethoxy]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1OCCNCC(O)COC1=CC=CC2=C1C=NN2 VRMQWUBVEMLIME-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- NARVIWMVBMUEOG-UHFFFAOYSA-N prop-1-en-2-ol Chemical compound CC(O)=C NARVIWMVBMUEOG-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) Způsob přípravy heterocyklických oxypropanolaminových derivátů(54) A process for the preparation of heterocyclic oxypropanolamine derivatives
Vynález se týká způsobu přípravy heterocyklických oxypropenolaminových derivátů obecného vzorce IThe invention relates to a process for the preparation of heterocyclic oxypropenolamine derivatives of the general formula I
OR4 r8 OR 4 r 8
O —CHj—CH —CHj—hl —CH—CH—Z ~^rV R9O —CH3 —CH — CH3 — hl —CH — CH — Z — R in R 9
A r5 ^6 7 R10 ní»A r 5 ^ 6 7 R 10 n »
Rj Rj kdeRj Rj where
Rj znamená vodík, alkylovou skupinu s 1 ež 6 etorny uhlíku, benzylovou skupinu nebo alkenoylovou skupinu s 1 ež 8 atomy uhlíku,R 1 is hydrogen, C 1 -C 6 alkyl, benzyl or C 1 -C 8 alkenoyl,
Rj a R^ které mohou být stejné nebo rozdílné, znamenají vodík, alkylovou skupinu s 1 až 6 etooy uhlíku, hydroxyalkylovou skupinu β 1 ež 4 atomy uhlíku, alkoxykarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku nebo elkenoyloxyelkylovou skupinu s 1 až 8 atomy uhlíku v alkylovýeh zbytcích nebo společně elkylenový zbytek s 3 až 4 atomy uhlíku,R 1 and R 2, which may be the same or different, represent hydrogen, a C 1 -C 6 alkyl group, a C 1 -C 4 hydroxyalkyl group, a C 1 -C 2 alkoxycarbonyl group or a C 1 -C 8 alkyl group. carbon atoms in the alkyl radicals or together an alkylene radical having 3 to 4 carbon atoms,
R^ znamená vodík, alkenoylovou skupinu s 1 až 8 atomy uhlíku nebo benzoylovou skupinu, Rj znamená vodík, alkylovou skupinu s 1 ež 6 atomy uhlíku nebo benzylovou skupinu,R1 is hydrogen, C1-C8 alkenoyl or benzoyl, R1 is hydrogen, C1-C6 alkyl or benzyl,
Rg znamené vodík nebo alkylovou skupinu s 1 až 6 atomy uhlíku,R 8 is hydrogen or C 1 -C 6 alkyl,
Ry znamená vodík, hydroxylovou skupinu nebo alkylovou skupinu s 1 až 6 atomy uhlíku,R y is hydrogen, hydroxyl or C 1 -C 6 alkyl,
Z znamená valenční vazbu, metylenovou skupinu, atom kyslíku nebo síry,Z represents a valence bond, a methylene group, an oxygen or sulfur atom,
Ar znamená fenylový zbytek nebo pyridylový zbytek,Ar is phenyl or pyridyl,
Rg, Rg a R,q, které mohou být stejné nebo rozdílné, znamenají vodík, halogen, hydroxylovou skupinu, alkanoylovou skupinu s 1 až 8 atomy uhlíku, alkylovou skupinu s 1 až 6 atoR 8, R 8 and R 8, which may be the same or different, represent hydrogen, halogen, hydroxyl, C 1 -C 8 alkanoyl, C 1 -C 6 alkyl
2273,32273.3
2273,3 my uhlíku, alkenylovou skupinu se 2 až 6 atomy uhlíku, alkoxyskupinu s 1 až 6 atomy uhlíku, benzyloxyekupinu, allyloxyskupinu, alkylthioskupinu s , až 6 atomy uhlíku, aminokarbonylovou skupinu, aminosulfonylovou skupinu, alkanoylamlnoakupinu β I až 6 atomy uhlíku, nebo Rg a Rg znamenají společně alkylendioxyskupinu s 1 až 2 atomy uhlíku nebo Rg společně s Ry znamená také -CH2-0-skupinu a2273.3 my carbon, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, benzyloxy, allyloxy, C 1 -C 6 alkylthio, aminocarbonyl, aminosulfonyl, C 1 -C 6 alkanoylamino, or R 8 and R 8 together represent C 1 -C 2 alkylenedioxy, or R 8 together with Ry is also -CH 2 -O-and
A znamená skupinu X,-X,, ve které X, představuje metylenový nebo -NR^-zbytek, přičemž R,i značí vodík nebo alkylovou skupinu s 1 až 6 atomy uhlíku, a Xj představuje metylenový zbytek nebo skupinu]] C=Q, přičemž Q znečí kyslík nebo síru, nebo skupinu X2=X2, ve X2 a X2 mohou být stejné nebo rozdílné a značí atom dusíku nebo -ÓR|2-skuplnu, přičemž R,2 představuje vodík, alkylovou nebo alkoxykarbonylovou skupinu s 1 až 6 atomy uhlíku v alkylovém zbytku, přičemž pro případ, Ze X2=X2 představuje -CH=N-skupinu a R, alkylovou skupinu β , až 6 atomy uhlíku nebo benzylovou skupinu, může být tato umístěna vzhledem ke schopnosti tautomerie indezolů také na atomu dusíku pro X2, s pravidlem, že X, nebo X2 je spojen se zbytkem N-R, obecného vzorce I, přičemž pro případ, že Q znamená atom kyslíku nebo X2=X2 -CR,2=CR12- slcup1-nu ® Z valenčnl vazbu, nebo pro případ, že Χ,-Xj představuje -NR,,-Ó=0- skupinu a Z atom kyslíku nebo velenční vazbu, nemohou být bu3 oba zbxtky R2 a Rj současně atom vodíku nebo Ry a Rg musí dohromady tvořit -CHg-O-můstek, a jejich farmakologicky vhodných solí.A represents a group X, -X ,, in which X represents a methylene or -NR6-radical, wherein R1 represents a hydrogen or an alkyl group having 1 to 6 carbon atoms, and Xj represents a methylene radical or a group]] C = Q wherein Q contaminates oxygen or sulfur, or X 2 = X 2 , in X 2 and X 2 may be the same or different and denote a nitrogen atom or -OR 2 | -Skuplnu 2, wherein R 2 represents hydrogen, alkyl or alkoxycarbonyl group having 1 to 6 carbon atoms in the alkyl radical, wherein for the case where X 2 = X 2 represents -CH = N- group and R, an alkyl β, and 6 carbon atoms or a benzyl group, this may also be located on the nitrogen atom for X 2 , with respect to the tautomeric capacity of the indezoles, with the proviso that X or X 2 is linked to the radical NR, of the general formula I; an oxygen atom or X 2 = X 2 -CR 2 = CR 12 - P1- slcu nu ® Z valenčnl bond or in case Χ, -Xj is -NR ,, - 0- = O group and Z is oxygen or The two bonds R @ 2 and R @ 3 cannot both be hydrogen or Ry and R @ 8 together must form a --CH - O - bridge, and their pharmacologically acceptable salts.
Protože mají sloučeniny vzorce I asymetrické atomy uhlíku, jsou déle předmětem vynálezu opticky aktivní formy a racemické směsi těchto sloučenin.Since the compounds of formula I have asymmetric carbon atoms, optically active forms and racemic mixtures of these compounds have long been the subject of the invention.
Sloučeniny vzorce I a jejich farmekologicky vhodné soli mají při nepatrné toxicitě výrazné vasodilatační vlastnosti, které se projevuji v podstatě při snižování krevního tlaku; kromě toho brzdí adrenergické beta-receptory. Sloučeniny podle vynálezu jsou proto vhodné obzvláště k léčeni e profylaxi srdečních a oběhových onemocnění.The compounds of formula I and their pharmacologically acceptable salts have, at low toxicity, significant vasodilatory properties which are manifested essentially by lowering blood pressure; it also inhibits adrenergic beta-receptors. The compounds of the invention are therefore particularly suitable for the treatment and prophylaxis of cardiac and circulatory diseases.
V německých vyložených spisech 19 48 507, 22 30 426, 26 ,9 164, 26 51 574 a 27 00 193 jsou popsány β nárokovány sloučeniny podobné struktury a účinku. Změnou heterocyklické fenolové části β eminopropoxy-postrsnního řetězce bylo docíleno překvepujícího zlepšení účinku.German Offenlegungsschrift 19 48 507, 22 30 426, 26, 9 164, 26 51 574 and 27 00 193 disclose β claimed compounds of similar structure and activity. By altering the heterocyclic phenol moiety of the β-eminopropoxy-post-chain, a surprisingly improved effect was achieved.
Pod alkylovou skupinou substituentů R,, R2, R^, Rg, Rg, Ry, Rg, Rg, H,q a R,2 sa rozumí přímé nebo rozvětvené skupiny s 1 až 6, s výhodou 1 až 4 atomy uhlíku, jako například metyl, etyl, propyl, isopropyl, butyl, isobutyl, tero. butyl nebo n-hexyl. Obzvláště však přichází v úvehu metylová nebo etylové skupině. Alkylenový zbytek případně vytvořený společně substituenty R2 a R-j má 3 až 4, s výhodou 3 atomy uhlíku.The alkyl group of the substituents R 1, R 2 , R 6 , R 8, R 8, R 8, R 8, R 8, H, q and R 12 is understood to mean straight or branched groups having 1 to 6, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tero. butyl or n-hexyl. However, a methyl or ethyl group is particularly preferred. The alkylene radical optionally formed together with R 2 and R 1 has from 3 to 4, preferably 3, carbon atoms.
Hydroxyalkylové skupiny substituentů R2 e R^ obsahují 1 až 4 atomy uhlíku, výhodné je 2-hydroxye tylová e hydroxymetylová skupina.The hydroxyalkyl groups of the substituents R @ 2 and R @ 4 contain from 1 to 4 carbon atoms, a 2-hydroxymethyl or hydroxymethyl group is preferred.
Alkoxyskupiny substituentů Rg, Rg a R,o obsahují 1 ež 6, s výhodou 1 až 4 atomy uhlíku, jako například metoxy-, etoxy-, propoxy-, butoxy- nebo pentoxyskupina. Výhodná je metoxy-, etoxy- a propoxy-skupina.Alkoxy groups Rg, Rg and R, o comprises one EŽ 6, preferably 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or pentoxy. Methoxy, ethoxy and propoxy are preferred.
Alkylthioskupiny substituentů Rg, Rg a R,q jsou skupiny s 1 až 6, s výhodou 1 až 4 atomy uhlíku. Výhodný je metylmerkapto zbytek.The alkylthio groups of substituents R 8, R 8 and R 10 are groups of 1 to 6, preferably 1 to 4 carbon atoms. Methylmercapto residue is preferred.
Alkanoylové skupiny substituentů R,, R^, Rg, Rg e R,q a alkanoylové část alkanoyloxyelkylové skupiny v definici substituentů Rj e Rj a alkanoyleminoskupina substituentů Rg,The alkanoyl groups of the substituents R, R 6, R 8, R 8 and R 8, q and the alkanoyl portion of the alkanoyloxyalkyl group in the definition of the substituents R 3 and R 3 and the alkanoyl amino group of the substituents R 8,
Rg s R,0 obsahují 1 až 8, s výhodou 1 až 5 atomů uhlíku, přičemž jejich alkylové skupiny mohou být přímé, rozvětvené nebo cyklické. Výhodný je formylový, acetylový nebo pivaloylový zbytek.R 8 with R 10 contain 1 to 8, preferably 1 to 5 carbon atoms, wherein their alkyl groups may be straight, branched or cyclic. A formyl, acetyl or pivaloyl residue is preferred.
Jako feitkylendloxy skupina s 1 až 2 atomy uhlíku společně vytvořené substituenty Rg a Rg přichází v úvahu metylen- a etylendioxyskupina.As feitkylendloxy group having 1-2 carbon atoms formed together R g and R g comes into consideration, methylene and ethylenedioxy.
Označení A v obecném vzorci I mé obzvláště význam, že jako heterocykly se rozumí benzimidazolinon-2, benzimidazolinthion-2, benzimidezol, benztriezol, indol, indolin e indazol.The designation A in formula (I) is of particular importance that heterocycles are benzimidazolinone-2, benzimidazolinethion-2, benzimidezole, benztriezole, indole, indoline or indazole.
Pod halogenem se rozumí podle vynálezu fluor, chlor, brom a jod, obzvláště fluor, chlor a brom.Halogen according to the invention is understood to mean fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.
Příprava nových sloučenin obecného vzorce I se vyznačuje tím, že se sloučenina obecného vzorce IX or4 The preparation of the novel compounds of the formula I is characterized in that the compound of the formula IX or 4
(XI) kde R,, Rg, Ry R^, Rj β A mají výše uvedený význam, ného vzorce III nechá reagovat se sloučeninou obec-(XI) wherein R, Rg, Ry, R, R, and R are as defined above, of which Formula III is reacted with
(III) kde Rg, Κγ, Rg, Rg, Η,θ, Z a Ar mají výše uvedený význam, a B představuje reaktivní zbytek, načež se případně provádí redukce, a případně se dodatečně v získané sloučenině obecného vzorce I převede jeden ze zbytků Rj, Rg, Kji Rg, Rgi E,o nebo R^ obvyklým způsobem na jiný definicí definovaný zbytek Rp Rj, Rj, R^, Rg, Rg, Rg, R,q nebo Rj2 θ získané sloučeniny se případně přemění na farmakologicky vhodné soli.(III) wherein Rg, γγ, Rg, Rg, θ, θ, Z and Ar are as defined above, and B is a reactive residue, optionally followed by a reduction, and optionally additionally converting one of the residues in the compound of formula I obtained Ri, Rg, KJI Rg, R gi E o or R ^ in the usual manner on another definition defined radical Rp Ri, Rj, R ^, Rg, Rg, Rg, R, Q or R 2 θ compound obtained is optionally converted into pharmacologically suitable salts.
Reaktivními zbytky B ve sloučeninách obecného vzorce III jsou obzvláště zbytky kyseliny, například kyselin hslogenovodíkových a sulfonovýeh. Obzvláště výhodné jsou chloridy, mesyloxy- a tosyloxy-zbytky.The reactive radicals B in the compounds of the general formula (III) are, in particular, acid radicals, for example hydrogen halide acids and sulfonic acids. Chlorides, mesyloxy and tosyloxy radicals are particularly preferred.
Způsob podle vynálezu se účelně provádí v rozpouštědle inertním ze reakčních podmínek, například ve vodě, metanolu, etanolu, n-butanolu, dioxanu, dimetylformamidu nebo hexaaetyltriaaidu kyseliny fosforečné, případně za přítomnosti činidle vázajícího kyseliny. Reakce se může také provádět smícháním reakčních složek bez rozpouštědla. Reakce probíhá při teplotě místnosti nebo při zahřívání, případně v atmosféře ochranného filmu.The process according to the invention is expediently carried out in a solvent inert from the reaction conditions, for example in water, methanol, ethanol, n-butanol, dioxane, dimethylformamide or hexa-ethyltriaphosphoric acid, optionally in the presence of an acid-binding agent. The reaction can also be carried out by mixing the reactants without solvent. The reaction proceeds at room temperature or with heating, optionally in a protective film atmosphere.
Redukce získaného amidu se s výhodou provádí pomocí komplexních hydridů kovu, například hydridu lithnohlinitého.The reduction of the amide obtained is preferably carried out with complex metal hydrides, for example lithium aluminum hydride.
Výchozí sloučeniny použité ve způsobech podle vynálezu jsou zpravidla sloučeniny známé z literatury. Nové sloučeniny se získají obecně analogicky podle způsobů popsaných pro přípravu těchto známých sloučenin.The starting compounds used in the methods of the invention are generally known from the literature. The novel compounds are generally obtained analogously to the methods described for the preparation of these known compounds.
Aminy obecného vzorce II se mohou získat z příslušných (2,3-epoxypropoxy)-derlvátů reakcí s kapalným amoniakem.The amines of formula (II) can be obtained from the corresponding (2,3-epoxypropoxy) derivatives by reaction with liquid ammonia.
Reaktivní sloučeniny obecného vzorce III například ester kyseliny p-toluensulfonové se připraví zpravidla z příslušných fenolů, naftolů, arylových nebo pyridylových sloučenin reakcí a halogenalkoholy a následující esterifikací kyselinou p-toluensulfonovou.Reactive compounds of formula III, for example p-toluenesulfonic acid ester, are generally prepared from the corresponding phenols, naphthols, aryl or pyridyl compounds by reaction and haloalcohols followed by esterification with p-toluenesulfonic acid.
2273,32273.3
Karbonylové sloučeniny obecného vzorce IV e reaktivní deriváty kyseliny obecného vzorce V se získají například z příslušných fenolů, naftolů, arylových a pyridylových sloučenin reakcí s výhodnými halogenelkylovými sloučeninami.The carbonyl compounds of the formula IV and the reactive acid derivatives of the formula V are obtained, for example, from the corresponding phenols, naphthols, aryl and pyridyl compounds by reaction with preferred haloalkyl compounds.
Jako případně dodatečně prováděné přeměna jednoho ze substituentú R,, Rg, R^, R^, Rg, Hg, Rg, RJ0 nebo R^g ve sloučeninách obecného vzorce I na jiný, definicí definovený zbytek Rp, Rg, R^, R^, Rg, Rg, Rg, R,q nebo R,g přichází například v úvahu dodatečná acylace OH-skupiny na alkanoyloxy, redukce metoxykarbonylové skupiny na hydroxymetylový zbytek, nebo odštěpení beazylové skupiny.As the optionally additionally carried out by conversion of one of the substituents R ,, R₂, R₃, R₅, R₆, Hg, Rg, R J0 or R g in the compounds of formula I into another, be defined by the definition of the radical R p, R₂, R₃, R For example, additional acylation of the OH group to alkanoyloxy, reduction of the methoxycarbonyl group to a hydroxymethyl radical, or cleavage of the beazyl group is possible.
Esterlfikaoe hydroxylové skupiny pro -OR^ se může provádět obvyklým způsobem reakcí s halogenidem nebo anhydridem kyseliny, případně za přítomnosti činidla vázajícího kyselinu, jako například pyridinu nebo trietylaminu.The hydroxyl ester of the -OR 4 group may be carried out in a conventional manner by reaction with an acid halide or anhydride, optionally in the presence of an acid binding agent such as pyridine or triethylamine.
Případně prováděné redukce sloučenin obecného vzorce I, ve kterém Rg a/nebo Rj představuje metoxykarbonylovou skupinu, na sloučeniny vzorce I, ve kterém Rg e/nebo Rg představuje hydroxymetylový nebo metylový substituent, se provédí účelně pomocí komplexních hydridů kovů, jako například hydridu lithno-hlinitého, nebo katalytickou hydrogenací, ze přítomnosti vzácného kovu nebo Raneyove niklu jako katalyzátoru.The possible reduction of compounds of formula I in which Rg and / or Rj represents a methoxycarbonyl group to compounds of formula I in which Rg and / or Rg represents a hydroxymethyl or methyl substituent is conveniently carried out using complex metal hydrides such as lithium hydride aluminum, or catalytic hydrogenation, from the presence of a noble metal or Raney nickel catalyst.
Odštěpení banzylové skupiny pro R, e Rg nebo obsažená v Rg, Rg, R,q se provédí například hydrogenací za přítomnosti vkácného kovu jako katalyzátoru.The cleavage of the banzyl group for R, e Rg or contained in Rg, Rg, R, q is carried out, for example, by hydrogenation in the presence of a volatile metal catalyst.
Pro převedení sloučenin vzorce I na farmakologicky vhodné soli se nechají tyto reagovat s výhodou v organickém rozpouštědle s anorganickou nebo organickou kyselinou, například kyselinou solnou, bromovodikovou, fosforečnou, sírovou, octovou, citrónovou, maleinovou nebo benzoovou.To convert the compounds of formula I into pharmacologically acceptable salts, they are preferably reacted in an organic solvent with an inorganic or organic acid, for example hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, citric, maleic or benzoic acid.
Sloučeniny podle vynálezu vzorce X se mohou získet ve formě racemické směsi. Dělení racemátu na opticky aktivní formy se provédí známými způsoby přes diestereomerní soli.The compounds of the invention of formula X can be obtained in the form of a racemic mixture. The resolution of the racemate into the optically active forms is carried out by known methods via the diesteromeric salts.
Jako aktivní kyseliny ee mohou použít kyselina vinné, jablečná, kafrové a kafrsulfonové.As active acids, ee can be tartaric, malic, camphoric and camphorsulfonic acids.
Pro přípravu léčiv se smíchají sloučeniny vzorce X známým způsobem s vhodnými farmaceutickými nosiči, aromatickými, chuťovými látkami a barvivý a vytvarují se například jako tablety nebo dražé nebo se suspendují nebo rozpustí ze přídavku příslušných pomocných látek ve vodě nebo v oleji, jako například olivovém oleji.For the preparation of medicaments, the compounds of formula X are admixed in a known manner with suitable pharmaceutical carriers, flavoring agents and coloring agents and are shaped, for example, as tablets or dragees or suspended or dissolved from the addition of appropriate excipients in water or oil, such as olive oil.
Nové sloučeniny podle vynálezu vzorce I a jejich soli se mohou aplikovat v kapalné nebo pevné formě enterélně nebo perenterélně. Jako injekční prostředí se s výhodou použije voda, která obsahuje přísady obvyklé v injekčních roztocích jako stabilizační prostředek, látku usnadňující rozpouštění nebo pufr. Takovou přísadou je například vinanový nebo citranový pufr, etanol, komplexotvorné látka (jako etylendiamintetreoctové kyselina a její netoxické soli), vysokomolekulérní polymery (jako kapalný polyetylenoxid) k regulaci viskozity. Jako pevná nosiče přicházejí například v úvahu škroby, lektóza, mannit, metylcelulóza, talek, vysoce dispersní kyselina křemičité, vysokomolekulérní mastné kyseliny (jako kyselina stearové), želatina, agar-agar, fosforečnan vápenatý, stearan hořečnatý, živočišné a rostlinné tuky a pevné vysokomolekulérní polymery (jako polyetylenglykoly). Přípravky vhodné pro orální aplikaci mohou případně obsahovat chuťové látky a sladidla.The novel compounds of the invention of formula I and their salts can be administered in liquid or solid form enterally or perenterally. Preferably, water is used as the injectable medium, which contains additives customary in injection solutions as a stabilizing agent, solubilizer or buffer. Such an additive is, for example, tartrate or citrate buffer, ethanol, a complexing agent (such as ethylenediaminetetreacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) to control viscosity. Suitable solid carriers are, for example, starches, lectose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight. polymers (such as polyethylene glycols). Formulations suitable for oral administration may optionally contain flavoring and sweetening agents.
Podávené dávka závisí na stáří, zdraví a hmotnosti příjemce, závažnosti onemocnění, druhu současně případně prováděných dalších léčení, častých případech léčení a druhu žádaného účinku. Obvykle je denní dávka účinné sloučeniny v rozmezí 0,1 až 50 mg/kg tělesné hmot nostl. Normálně je účinná 0,5 až 40 a s výhodou 1,0 až 20mg/kg/den v jedné nebo více dávkách za den, aby se dosáhlo žádaných výsledků.The dose to be administered depends on the age, health and weight of the recipient, the severity of the disease, the nature of the concomitant therapies being carried out, the frequent cases of treatment and the type of effect desired. Usually, the daily dose of the active compound is in the range of 0.1 to 50 mg / kg body weight. Normally, 0.5 to 40, and preferably 1.0 to 20mg / kg / day is effective in one or more doses per day to achieve the desired results.
227 313227 313
Kromě sloučenin uvedených v nesledujících příkladech jsou v rámci vynálezu dále výhodné nesledující sloučeniny:In addition to the compounds set forth in the following examples, the following are also preferred within the scope of the invention:
4-<2-hydroxy-3-[2-(2,6-dimetoxyf enoxy )etylamino]propoxy>-7~metyl-3-propyl-2-benziaidezólinon4- <2-hydroxy-3- [2- (2,6-dimethoxyphenoxy) ethylamino] propoxy> -7-methyl-3-propyl-2-benziaidezolinone
4-<2-hydroxy-3-f2-(2-ellyloxyfenoxy )etylamino]propoxy> -6-metylindol4- <2-hydroxy-3- [2- (2-ellyloxyphenoxy) ethylamino] propoxy] -6-methylindole
4-<2-hydroxy-3-[2-(2-metylmerkaptofenoxy)etylamino]propoxy)-1-formylindolin4- <2-hydroxy-3- [2- (2-methylmercaptophenoxy) ethylamino] propoxy) -1-formylindoline
4-< 2-hydroxy-3-[2-(2-sulfamoylfen oxy Jetylamino]pr opoxy)indazol4- <2-hydroxy-3- [2- (2-sulfamoylphenoxyethylethylamino) propoxy] indazole
4-<2-hydroxy-3-[2-(3,4-etylěndioxyfenyl) etylamino] propoxy)-indazol4- <2-hydroxy-3- [2- (3,4-ethylenedioxyphenyl) ethylamino] propoxy) indazole
4-<2-hydroxy-3-[2-(3-etoxy-4-metoxyfenyl)etylamino]propoxy)indezol4- <2-hydroxy-3- [2- (3-ethoxy-4-methoxyphenyl) ethylamino] propoxy) indezole
4-<2-hydrcxy-3-[2-( 3,4,5-trimetoxyfenyl)etylamino] propoxy)indazol4- <2-Hydroxy-3- [2- (3,4,5-trimethoxyphenyl) ethylamino] propoxy) indazole
4-<2-hydroxy-3-[2-(3-metoxy-4-hydroxyfenyl)etylamino]propoxy)indazol4- <2-hydroxy-3- [2- (3-methoxy-4-hydroxyphenyl) ethylamino] propoxy) indazole
4-<2-hydroxy-3-[2-(3-hydroxy-4-n-butoxyfenyl)etylamino]propoxy)indazol4- <2-hydroxy-3- [2- (3-hydroxy-4-n-butoxyphenyl) ethylamino] propoxy) indazole
4-<2-hydroxy-3-[2-(3,4-dihydroxyfenylJetylamino]propoxy)indazol4- <2-hydroxy-3- [2- (3,4-dihydroxyphenyl) ethylamino] propoxy) indazole
4-< 2-hy dr oxy- 3-[ 3- (3,4-dioet oxyf enyl) propylamino] propoxy) indazol4- <2-hydroxy-3- [3- (3,4-dioethoxyphenyl) propylamino] propoxy) indazole
4-<2-hydroxy-3-[1 -(3,4-dimetoxyf enyl)propyl-2-amino] propoxy)indazol4- <2-hydroxy-3- [1- (3,4-dimethoxyphenyl) propyl-2-amino] propoxy) indazole
1-metyl-4-<2-hydroxy-3-[2-(3,4-dimetoxyfenyl)etylamin^-pr opoxy)indazol1-methyl-4- <2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamine-4-propoxy] indazole
-me tyl-4-<‘2 -hydr oxy- 3-[ 2- (3,4-di me toxyf enyl) etylamino] pr opoxy)indolin-methyl-4 - (‘2-hydroxy-3- [2- (3,4-methoxyphenyl) ethylamino] propoxy) indoline
4-<2-hydroxy-3-[2-(2-metoxyfenylmerkapto)etylamino]propoxy)-1-formylindolin4- <2-hydroxy-3- [2- (2-methoxyphenylmercapto) ethylamino] propoxy) -1-formylindoline
4-<2-benzoyloxy-3~[2-(3,4-dimetoxyfenyl)etylamino]propoxy)indazol4- <2-Benzoyloxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole
4-<2-hyčroxy-3-[1-(3,4-dihydroxyfenyl)-2-amino-l-propanol]propoxy)-6-metylindol4- <2-hydroxy-3- [1- (3,4-dihydroxyphenyl) -2-amino-1-propanol] propoxy) -6-methylindole
Následující příklady ukazují některé z četných variant přípravy, které se mohou použít k syntéze sloučenin podle vynélezu, aniž by omezovaly rozsah vynálezu.The following examples show some of the numerous preparation variants that can be used to synthesize the compounds of the invention without limiting the scope of the invention.
PřikladlHe did
2-benzyl~4-[2~hydroxy-3-/ 3-fenyl-propylamino/-propoxy] indazol2-Benzyl-4- [2-hydroxy-3- (3-phenyl-propylamino) -propoxy] -indazole
7,5 g-benzyl-4-/3-emino-2-hydroxy-propoxy/-indazolu, 5,3 g 3-fenylpropylbroaidu a 5,2 g uhličitanu draselného se míchají 24 hodiny při 55 °C v 50 ml dimetylformamidu. Anorganické soli se odsají, produkt se rozpustí ve zředěném hydroxidu sodném a metylenchloridu, suěí se e čistí se chromatograficky na silikagelu se směsí octan-metanol-trietylamin v poměru 100:10:1 jako eluens. Po zahuštění čistých frakcí se získá 4,7 g (45 % teorie) žádané sloučeniny jeko bezbarvý olej.7.5 g of benzyl-4- (3-emino-2-hydroxy-propoxy) -indazole, 5.3 g of 3-phenylpropylbroaid and 5.2 g of potassium carbonate are stirred for 24 hours at 55 DEG C. in 50 ml of dimethylformamide. The inorganic salts are filtered off with suction, the product is dissolved in dilute sodium hydroxide and methylene chloride, dried and purified by chromatography on silica gel with a 100: 10: 1 acetate / methanol / triethylamine mixture as eluent. Concentration of the pure fractions gave 4.7 g (45%) of the title compound as a colorless oil.
4-[2-hydroxy-3-/3-fenyl-propylamino/-propoxyjindazol4- [2-hydroxy-3- (3-phenyl-propylamino) -propoxy] indazole
4,7 g 2-benzyl-4-[2-hydroxy-3-/3-fenylpropylamino/-propoxy]indazolu se hydrogenuje v 70 ml metanolu a 5 ml koncentrované kyseliny chlorovodíkové za přítomnosti 1 g 10% palédia na uhlí.4.7 g of 2-benzyl-4- [2-hydroxy-3- (3-phenylpropylamino) propoxy] indazole are hydrogenated in 70 ml of methanol and 5 ml of concentrated hydrochloric acid in the presence of 1 g of 10% palladium on carbon.
Po odsátí se zahustí, zalaklizuje louhem sodným a extrahuje se metylenchloridem. Po zahuštění se rozetře s éterem a překrystaluje z octanu, přičemž se získá 2,1 g (57 % teorie) žádané sloučeniny jako bezbarvé krystaly, teplot® tání 123 °C.After aspiration, it is concentrated, made alkaline with sodium hydroxide solution and extracted with methylene chloride. After concentration, it is triturated with ether and recrystallized from acetate to give 2.1 g (57% of theory) of the title compound as colorless crystals, m.p. 123 ° C.
Příklad 2Example 2
4-[2~hydroxy-3-(2-fenoxy-propylaaino)propoxy]-6-metylindol-p-chlorbenzoát g 4-[2-hydroxy-3-(2-fenoxy-N-benzyl-propylemino)-propoxy]-6-metylindolu se hydrogenuje ve 200 ml metanolu a 5 ml trietylaminu při teplotě místnosti a 0,1 MPa tlaku vodíku za použití ? g 104 paládia na uhlí, filtruje se, zahustí se, zbytek ae rozpustí v 50 ml octanu a přidá se vypočítané množství kyseliny p-chlorbenzoové, Po odsátí a překrystalovéní sc získá 4,3 g 4-[2-hydroxy-3-(2-fenoxypropylamíno)propoxy]-6-metylindol-p-chlorbenzoétu o teplotě tání. 134 až 136 °C (42 % teorie).4- [2-hydroxy-3- (2-phenoxy-propylaaino) propoxy] -6-methylindole-p-chlorobenzoate 4- [2-hydroxy-3- (2-phenoxy-N-benzyl-propylemino) -propoxy] The 6-methylindole is hydrogenated in 200 ml of methanol and 5 ml of triethylamine at room temperature and 1 bar of hydrogen pressure using? 104 g of palladium on carbon, filtered, concentrated, the residue is dissolved in 50 ml of acetate and the calculated amount of p-chlorobenzoic acid is added. After suction and recrystallization, 4.3 g of 4- [2-hydroxy-3- (2) are obtained. (phenoxypropylamino) propoxy] -6-methylindole-p-chlorobenzoate, m.p. 134-136 ° C (42% of theory).
Příklad 3Example 3
Analogickým způsobem) jek popsáno v příkladu 2, ee získá:In an analogous manner) as described in Example 2, ee obtains:
OznačeníDesignation
Výtěžek Teplote tání °C % teorie (rozpouštědlo)Yield Melting point ° C% of theory (solvent)
Příklad 4Example 4
4-<2-hydroxy-3-(2-(3,4-dimetoxy-fenyl)etylamino]propoxy)-6-hydroxymetylindol4- <2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino] propoxy) -6-hydroxymethylindole
K suspenzi 2,3g hydridu lithno-hlinitého v 50 ml absolutního tetrahydrofuranu se přikape roztok 5,0 g 4-(2-hydroxy-3-(2-(3,4-dimetoxyfenyl)etylemino]propoxy^-6-metoxykerbonylindolu ve 150 ml ebsolutního tetrahydrofuranu, míchá se 12 hodin při teplotě místnosti, za chlazení se rozloží roztokem chloridu sodného a ION hydroxidem sodným, filtruje se, promyje se tetrehydrofuranem a zahustí se. Zbytek se čistí na silikegelovém sloupci směsi metylenehloridu/metenol 9:1. Báze se vysráží éterem a odsaje se. Získá se 2,4 g 4-^2-hydroxy-3-(2-( 3,4-dimetoxyfenyl)etylamino] propoxy>-6-hydroxymetylindolu o teplotě slinuti 60 °C (51 % teorie).To a suspension of lithium aluminum hydride (2.3 g) in absolute tetrahydrofuran (50 ml) was added dropwise a solution of 4- (2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylemino) propoxy) -6-methoxycarbonylindole (5.0 g) in 150 ml. ml of ebsolute tetrahydrofuran, stirred at room temperature for 12 hours, quenched with sodium chloride solution and 10N sodium hydroxide solution with cooling, filtered, washed with tetrahydrofuran and concentrated. The residue was purified on a silica gel column with methylene chloride / methylene 9: 1. It is precipitated with ether and filtered off with suction to give 2.4 g of 4- (2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propoxy) -6-hydroxymethylindole, sintering temperature of 60 ° C (51% of theory). .
Příklad 5Example 5
4-/2-hydroxy-3-(2-( 3,4-dimetoxyfenyl)etylamino] propoxy^indazol4- / 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole
19,1 g 2-benzyl-4-(2-hydroxy-3-(2-(3,4-dime toxyf enyl) etylemino] pr opoxy} indezolu se hydrogenuje v 700 ml metanolu a 22,4 ml koncentrované kyseliny chlorovodíkové za přítomnosti 2 g 10% paládia na uhlí. Po odsáti se zahustí, rozpustí ve vodě, zelkalizuje se hydroxidem sodným a extrahuje se metylenchloridem. Organická féze se zahustí, rozetře se s éterem a odsaje se. Získá se 9,1 g žádané sloučeniny o teplotě tání 118 až ,19 °C (59% teorie).19.1 g of 2-benzyl-4- (2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylemino] propoxy} indezole) are hydrogenated in 700 ml of methanol and 22.4 ml of concentrated hydrochloric acid, After concentration by suction, it is concentrated, dissolved in water, made alkaline with sodium hydroxide solution and extracted with methylene chloride, and the organic phase is concentrated, triturated with ether and filtered off with suction to give 9.1 g of the desired compound. mp 118-119 ° C (59% of theory).
Rozpuštěním v etanolu a přídavkem éterického roztoku kyseliny chlorovodíkové se získá hydrochlorid o teplotě tání ,57 až 159 °C.Dissolution in ethanol and addition of ethereal hydrochloric acid gave the hydrochloride, m.p. 57-159 ° C.
2273122731
Analogickým způsobem, jak popsáno výše, se získá:In an analogous manner as described above, it is obtained:
OznačeníDesignation
Výtěžek Teplota tání °C (rozpouštědlo)Yield Melting point ° C (solvent)
a) 4-<2-hydroxy-3-[2-(2-hydroxyfenoxy)etylamino]propoxy)indazol z 41a) 4- <2-hydroxy-3- [2- (2-hydroxyphenoxy) ethylamino] propoxy) indazole from 41
2-benzyl-4-(2-hydróxy-3-[2-(2-benzyloxy-f enoxy )etylaminójpropoxy)indazolu2-Benzyl-4- (2-hydroxy-3- [2- (2-benzyloxy-phenoxy) -ethylamino-propoxy) -indazole
b) 4-[2-hydroxy-3-(2-fenoxyetylamino)propoxy! indazol z 88b) 4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy; indazole from 88
2-benzyl-4-[2-hydr oxy-3-(2-fenoxyetylamino) propoxy ]-indazolu2-Benzyl-4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] indazole
c) 4-{2-hydroxy-3-[2-(2-matoxyfenoxy)etylamino] propoxy)indazol z 32c) 4- {2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino] propoxy) indazole from 32
2-benzyl-4-(2-hydroxy-3-(2-(2-metoxyfenoxy) etylamino) propoxy) indazolu2-Benzyl-4- (2-hydroxy-3- (2- (2-methoxyphenoxy) ethylamino) propoxy) indazole
d) 4-{2-hydroxy-3-[2-(2-metoxyfenoxy)propylaminóT propoxy) indazol z 58d) 4- {2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy) indazole from 58
2-benzyl-4-(2-hydroxy-3-[2-(2-metoxyfenoxy)propylemino] propoxy)indazolu2-Benzyl-4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylemino] propoxy) indazole
e) 4-{2-hydroxy-3-[2-(4-pyridyl)etylamino)propoxy)indazolu z 72e) 4- {2-hydroxy-3- [2- (4-pyridyl) ethylamino) propoxy) indazole of 72
2-benzyl-4-(2-hydroxy-3-[2-(4-pyridyl) etylamino] propoxy)indezolu2-Benzyl-4- (2-hydroxy-3- [2- (4-pyridyl) ethylamino] propoxy) indazole
f) 4-[2-hydr oxy-3- (benzo[b)-1,4-dioxan-2-yl-metylaminQ)pr opoxý]indazol z r __ 54f) 4- [2-hydroxy-3- (benzo [b) -1,4-dioxan-2-yl-metylaminQ) PR propoxy] indazole of r __ 54
2-benzyl-4-[2-hydroxy-3-(benzo[bJ-1,4-dioxan-2-yl-metylamino)propoxy]indazolu2-Benzyl-4- [2-hydroxy-3- (benzo [b] -1,4-dioxan-2-ylmethylamino) propoxy] indazole
g) 4-('2-hydroxy-3-[2-(2-hydroxyfenoxy)propylamino] propoxy)indazol(g) 4- (2-hydroxy-3- [2- (2-hydroxyphenoxy) propylamino] propoxy) indazole
2-benzyl-4-(2-hydroxy-3-[2-(2-hydroxyfenoxy)-N-benzylpropylamíno] propoxy)indazolu2-Benzyl-4- (2-hydroxy-3- [2- (2-hydroxyphenoxy) -N-benzylpropylamino] propoxy) indazole
h) 4-(2-hydroxy-3-[2-(4-acetamidofenoxy) etylamino] propoxy)indazol z _49h) 4- (2-hydroxy-3- [2- (4-acetamidophenoxy) ethylamino] propoxy) indazole from _49
2-benzyl-4-(2-hydroxy-3-[2-(4-acetamidof enoxy)-N-benzyle tyl amino] propoxy) indazolu2-Benzyl-4- (2-hydroxy-3- [2- (4-acetamidophenoxy) -N-benzylsyl amino] propoxy) indazole
i) 4-(2-hydroxy-3-[2-(3,4-etylendi oxyfenyl)etylamino] propoxy) indazol z 59i) 4- (2-hydroxy-3- [2- (3,4-ethylenedioxyphenyl) ethylamino] propoxy) indazole from 59
2-benzyl-4-(2-hydroxy-3-[2-(3-etoxy-4-metoxyfenyl) etylamino] propoxy) indazolu2-Benzyl-4- (2-hydroxy-3- [2- (3-ethoxy-4-methoxyphenyl) ethylamino] propoxy) indazole
j) 4-(2-hydroxy-3-[2-(3-etoxy-4-metoxyfenyl)etylamino] propoxy)indazol z 73j) 4- (2-hydroxy-3- [2- (3-ethoxy-4-methoxyphenyl) ethylamino] propoxy) indazole from 73
2-benzyl-r4-(2-hydroxy-3-[2-( 3-etoxy-4-metoxyf enyl) etylamino] propoxy)-indazolu2-Benzyl-4- (2-hydroxy-3- [2- (3-ethoxy-4-methoxyphenyl) ethylamino] propoxy) indazole
k) 4-{2-hydroxy-3-[2-(3,4,5-trlmetoxyfenyl)etylamino] propoxy)indazol z 63k) 4- {2-hydroxy-3- [2- (3,4,5-trimethylphenyl) ethylamino] propoxy) indazole from 63
2~benzyl-4-(2-hydroxy-3- [2-(3,4,5-trirae t oxyf enyl )etylamino]pr o poxy)ind a z olu2-Benzyl-4- (2-hydroxy-3- [2- (3,4,5-triaxyphenyl) ethylamino] propoxy) indole
l) 4-(2-hydr oxy- 3- [2 - (4-hy dr oxy- 3-me t oxyfenyl)etylamin6l propoxy)indazol z 57l) 4- (2-hydroxy-3- [2- (4-hydroxy-3-methoxyphenyl) ethylamino-6-propoxy) indazole from 57
2-benzyl-4-(2-hydroxy-3- [2-(4-benzyloxy- 3-me t oxyf enyl) e tyl amino] propoxy) indazolu2-Benzyl-4- (2-hydroxy-3- [2- (4-benzyloxy-3-methoxyphenyl) ethyl amino] propoxy) indazole
137 až 139 (isopropanol)137 to 139 (isopropanol)
134 až 135 (octěn)134 to 135 (vinegar)
106 až 107 (octan)106 to 107 (acetate)
127 ež 128 (octan)127 to 128 (acetate)
123 ež 125 (octan)123 to 125 (acetate)
142 až 143 (octan) až 95 (octan)142 to 143 (acetate) to 95 (acetate)
130 až 133 (etanol/voda)130 to 133 (ethanol / water)
125 až 126 (octan)125 to 126 (acetate)
118 ®Ž 119 (octan)118 ®Ž 119 (acetate)
171 až 172 (octan)171-172 (acetate)
139 až 141 (i sopropanol/octan) pokračování139-141 (also sopropanol / acetate) continued
Příklad 6Example 6
1-piveloyl-4-/2-piveloyloxy-3-[2-(3,4-dimetoxyfenyl)etylamino]propoxy)indazol-hydrochlorid1-piveloyl-4- / 2-piveloyloxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole hydrochloride
Srnče 4,2 g 4-/2-hydroxy-3-[2-(3,4-dimetoxyfenyl)etylamino] propoxy)indazol-hydrochloridu, 4,2 ml anhydridu kyseliny plvalová a 35 ml kyseliny pivelové se míchá 50 ež 60 hodin při 75 °C. Získané pevné hmota se míchá s ligroinem, odsaje se a promyje llgroinem. Získá se 4,1 g žádané sloučeniny o teplotě tání 155 až 158 °C (69 % teorie).4.2 g of 4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole hydrochloride, 4.2 ml of plicic anhydride and 35 ml of pivelic acid are stirred for 50 to 60 hours at 75 ° C. The solid obtained is stirred with ligroin, filtered off with suction and washed with ilgroin. 4.1 g of the desired compound of melting point 155 DEG-158 DEG C. (69% of theory) are obtained.
Příklad 7Example 7
4-/2-plvaloyloxy-3-[2-(3,4-dimetoxyfenyl)etylamino] propoxy) indazol4- / 2-plvaloyloxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole
4,0 g 1-pivaloyl-4-<2-pivaloyloxy-3-[2-(3,4-dimetoxyfenyl)etylamino] propoxý>indazol-hydrochloridu se zahřívá 2,5 hodiny pod zpětným chladičem se 150 ml isopropyleminu. Zahusti se, rozpustí se v éteru, třepe se s IN hydroxidem sodným, a organické fáze se čistí chromatografický na sllikagelovém sloupci (eluenss metylenchlorid : octan etylnatý=,:1). Získé se 2,7 g žádané sloučeniny jeko olej (85 * teorie).4.0 g of 1-pivaloyl-4- [2-pivaloyloxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy] indazole hydrochloride was refluxed for 2.5 hours with 150 ml of isopropylemine. Concentrate, dissolve in ether, shake with 1N sodium hydroxide, and purify the organic phases by column chromatography (eluents methylene chloride: ethyl acetate = 1: 1). 2.7 g of the desired compound are obtained as an oil (85%).
Příklad 8Example 8
4-/2-hydroxy-3-[2-(2-metoxyfenoxy)propylamino] propoxy>1-formylindolin-benzoát4- / 2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy> 1-formylindoline benzoate
6,7 g 4-(2-hydroxy-3-[2-(2-metoxyfenoxy)-N-benzylpropylemino]propoxy)- 1-f ormylindolinu se hydrógenuje ve 250 ml metanolu a 20 ml trietylaminu při teplotě místnosti a 0,1 MPa tlaku vodíku a 2 g 10* peládie ne uhlí, filtruje se, zahustí se a zbytek se rozpustí v 50 ml octanu a přidá se ekvivalentní množství kyseliny benzoová. Po odsátí se získé 2,1 g 4-/2-hydroxy-3-[2-(2-metoxyfenoxy)propylamino]propoxy)-1-formylindolin-benzoátu o teplotě tání 131 až 133 °C (31 » teorie).6.7 g of 4- (2-hydroxy-3- [2- (2-methoxyphenoxy) -N-benzylpropylemino] propoxy) -1-formylindoline are hydrogenated in 250 ml of methanol and 20 ml of triethylamine at room temperature and 0.1 MPa of hydrogen pressure and 2 g of 10% Pd / C, filtered, concentrated and the residue was dissolved in 50 ml of acetate and an equivalent amount of benzoic acid was added. After aspiration, 2.1 g of 4- [2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy] -1-formylindoline benzoate, m.p. 131 DEG-133 DEG C. (31 DEG), are obtained.
Příklad 9Example 9
Analogickým způsobem, jak popsáno v příkladu 6, se získá:In an analogous manner to that described in Example 6:
Výchozí létky potřebné pro příprevu předchozích sloučenin se připraví následujícím způsobem:The starting flights needed to prepare the preceding compounds are prepared as follows:
4-(2,3-epoxypr opoxy)-1-f ormylindolin4- (2,3-epoxypropoxy) -1-formylindoline
48,6 g 2-benzyloxy-6-nitrotoluenu se rozpustí ve 670 ml dimetylformamidu a přidá se 29,9 g paraformaldehydu e potom se přikepe 200 ml 1 N roztoku terč. butylótu draselného.48.6 g of 2-benzyloxy-6-nitrotoluene are dissolved in 670 ml of dimethylformamide and 29.9 g of paraformaldehyde are added and then added dropwise with 200 ml of a 1 N solution of tert. of potassium butyl ion.
Po hodinovém míchání při teplotě místnosti se rozmíchá ve 3 1 ledové vody a extrahuje se éterem. Éterová fáze se suší síranem sodným a zahustí se ve vakuu. Získá se 62 g 2-benzyloxy-6-nitrofenyletanolu, který se použije jako surový produkt v následujícím stupríi.After stirring at room temperature for 1 hour, it is stirred in 3 l of ice-water and extracted with ether. The ether phase was dried over sodium sulfate and concentrated in vacuo. 62 g of 2-benzyloxy-6-nitrophenylethanol are obtained, which is used as a crude product in the following step.
g 2-benzyloxy-6-nitrofenyletanolu se rozpustí v 500 ml bezvodého pyridinu a ze chlazení se přidá při cca 10 °C 47,7 g p-toluensulfonylchloridu. Teplota se nechá zvýšit na teplotu místnosti a míchá se cca 10 hodin až do úplné reakce. Reakční roztok se vmíchá do ledové vody. Po odsátí, promytí vodou e sušení se získají 74 g 2-(2-benzyloxy)-6-nitrofenyl)etylesteru kyseliny p-toluensulfonové o teplotě tání 96 až 98 °C (86 % teorie, vztaženo na 2-benzyloxy-6-nitrotoluen).g of 2-benzyloxy-6-nitrophenylethanol is dissolved in 500 ml of anhydrous pyridine and from cooling at about 10 DEG C. 47.7 g of p-toluenesulfonyl chloride are added. The temperature was allowed to rise to room temperature and stirred for about 10 hours until complete reaction. The reaction solution is stirred into ice water. After suctioning off, washing with water and drying, 74 g of p-toluenesulfonic acid 2- (2-benzyloxy) -6-nitrophenyl) ethyl ester of melting point 96 DEG-98 DEG C. (86% of theory, based on 2-benzyloxy-6-nitrotoluene) are obtained. ).
g 2-(2-benzyloxy-6-nitrofenyl)-etylesteru kyseliny p-toluensulfonové se rozpustí ve 2 1 etylenglykolmonometylesteru, přidá se 5 g 10% paládia na aktivním uhlí a hydrogenuje se při teplotě místnosti a 0,1 MPa tlaku vodíku. Po odstranění katalyzátoru se zehustí a zbytek se formyluje směsí 227 ml anhydridů kyseliny octové a 91 ml kyseliny mravenčí (podle C. Ví. Huffmanna, J. org. Chem. 23, 727 /1958/). Po reakci se rozloží ledovou 4 vodou a extrahuje se octanem. Organické féze se neutralizuje, suší síranem sodným e odpaří se ve vakuu. Zbytek se smíchá s 320 ml epichlorhydrinu a přidá se 173 ml 2N roztoku metylátu sodného. Po mícháni přes noc se zahustí e zbytek se rozpustí ve vodě e octanu.g of p-toluenesulfonic acid 2- (2-benzyloxy-6-nitrophenyl) ethyl ester is dissolved in 2 l of ethylene glycol monomethyl ester, 5 g of 10% palladium on charcoal are added and hydrogenated at room temperature and 1 bar of hydrogen pressure. After removal of the catalyst, it is concentrated and the residue is formulated with a mixture of 227 ml of acetic anhydride and 91 ml of formic acid (according to C. Vi. Huffmann, J. org. Chem. 23, 727 (1958)). After the reaction was quenched with ice water and extracted 4 with ethyl acetate. The organic phase was neutralized, dried over sodium sulfate and evaporated in vacuo. The residue is mixed with 320 ml of epichlorohydrin and 173 ml of 2N sodium methylate solution are added. After stirring overnight, it is concentrated and the residue is dissolved in water and acetate.
Z octenového zbytku se získá po rozetření s isopropylelkoholem a odsátím 15,8 g 4-(2,3-epoxy-propoxy)-1-formylindolinu o teplotě tání 88 až 89 °C (42 % teorie).15.8 g of 4- (2,3-epoxy-propoxy) -1-formylindoline, m.p. 88 DEG-89 DEG C. (42% of theory), are obtained from the vinegar residue after trituration with isopropyl alcohol and suction.
Příklad 10Example 10
Byly připraveny teblety:Teblets were prepared:
Každá tableta obsahuje 10 mg 4-(2-hydroxy-3-|]2-(2-metoxyfenoxy)etylaraino propoxy}-7-metyl-2-benzimidazolinon-hydrochloridu. Tablety byly připraveny podle následujícího složení:Each tablet contains 10 mg of 4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethylaraino propoxy} -7-methyl-2-benzimidazolinone hydrochloride) The tablets were prepared according to the following composition:
4-{2-hydroxy-3-[2-(2-metoxyfenoxy )etylemino] propoxy)-7-metyl-2-benzimidazolinon-hydrochlorid 10 g laktóza 80 g škrob stearan hořečnatý • 29 g ' &4- {2-hydroxy-3- [2- (2-methoxyphenoxy) ethylemino] propoxy) -7-methyl-2-benzimidazolinone hydrochloride 10 g lactose 80 g starch magnesium stearate • 29 g '&
2273,3 ,02273.3, 0
Předchozí sloučenina se jemně rozmělní e smíchá se s Laktózou a škrobem. Smšs se obvyklým způsobem granuluje. Ke granulátu se přidá steeren hořečnatý a směs se lisuje ne 1 000 tablet o hmotnosti 0,12 g.The preceding compound is finely divided and mixed with Lactose and starch. The mixture is granulated in the usual manner. Magnesium steerene is added to the granulate and the mixture is compressed into 1000 tablets weighing 0.12 g.
Způsobem podle vynálezu se připraví:The process according to the invention provides:
4-(2-hydroxy-3-[2-(2-metoxyfenoxy)propylemino] propoxy)-7-metyl-2-benzimidazolln-hydrochlorid, t. t. 228 až 230 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylemino] propoxy) -7-methyl-2-benzimidazoline hydrochloride, mp 228-230 ° C.
4-Q2-hydroxy-3-(3,4-dimetoxyfenetylemino)propoxy]-7-metyl-2-benzimidazolinon-hydrochlorid, t. t. 204 ež 206 °C.4-Q2-hydroxy-3- (3,4-dimethoxyphenethylemino) propoxy] -7-methyl-2-benzimidazolinone hydrochloride, m.p. 204 DEG-206 DEG.
4-{2-hydroxy-3-p-(2-hydroxyf enoxy Jetylemino] propoxy)-7-metyl-2-benzimidezolinon-hydrochlorid, t. t. 262 až 263 °C.4- {2-hydroxy-3-p- (2-hydroxyphenoxy-Jetylemino] propoxy) -7-methyl-2-benzimidezolinone hydrochloride, m.p. 262-263 ° C.
6.7- diraetyl-4-(2-hydroxy-3-[2-(2-metylfenoxy)etylemino]propoxy)-2-benzimldezolinon-hydro chlorid, 273 ež 274 °C.6.7- di-ethyl-4- (2-hydroxy-3- [2- (2-methylphenoxy) ethylemino] propoxy) -2-benzimldezolinone hydrochloride, 273-274 ° C.
4-(2-hydroxy-3-[2-(2-metoxyfenoxy)etylemino] propoxý)-7-metyl-2-benzimidazolinon-hydrochlorid, t. t. 202 až 203 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethylemino] propoxy) -7-methyl-2-benzimidazolinone hydrochloride, m.p. 202-203 ° C.
4- [2-hydroxy-3-(2-fenoxyetylamino)propoxy]-7-metyl-2-bemzimidazolinon-hydrochlorid1 t. t. 231 až 233 °C.4- [2-hydroxy-3- (2-Phenoxyethylamino) propoxy] -7-methyl-2-one hydrochloride bemzimidazolinon mp 231-233 ° C.
4-p-hydroxy-3-(2-fenoxyetylemíno)propoxyJ-6-metyl-2-benzimidazollnon-hydrochlorid, t. t. 250 až 252 °C.4-p-hydroxy-3- (2-phenoxyethylmino) propoxy] -6-methyl-2-benzimidazolone hydrochloride, m.p. 250-252 ° C.
4-<2-hydroxy-3-p-(2-metoxyfenoxy)etylamino] propoxy)-6-metyl-2-benzimidezolinon-hydrochlorid, t. t. 2,3 až 215 °C,4- <2-hydroxy-3-β- (2-methoxyphenoxy) ethylamino] propoxy) -6-methyl-2-benzimidezolinone hydrochloride, m.p. 2.3-215 ° C,
4-|]2-hyóroxy-3-( 3,4-dimetoxyfenetylemino)propoxy]-6-metyl-2-benzimidazolinon-hydrochlorid, t. t. 260 ež 262 °C.4- | 2-Hydroxy-3- (3,4-dimethoxyphenethylemino) propoxy] -6-methyl-2-benzimidazolinone hydrochloride, m.p. 260-262 ° C.
4-(2-hydroxy-3-[2-(2-metoxyfenoxy)-propylemino] propoxy)-7-metyl-benzimidazol-hydrochlorid, t. t. ,03 ež ,05 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propyllemino] propoxy) -7-methylbenzimidazole hydrochloride, m.p.
4-[2-hydroxy-3-(3,4-dimetoxyfenetylemino).propoxy]benzimidezol-hydrochlorid, t. t. 255 až 256 °C.4- [2-hydroxy-3- (3,4-dimethoxyphenethylemino) propoxy] benzimidezole hydrochloride, m.p. 255-256 ° C.
4-[p-hydroxy-3- (3,4-dimetoxyf enetylemino) propoxy] -7-metyl-benzimidezolhydrochlorid, t. t. 254 až 256 °C.4- [p-hydroxy-3- (3,4-dimethoxyphenethylemino) propoxy] -7-methylbenzimidezole hydrochloride, mp 254-256 ° C.
4-(2-hydroxy-J-[2-(2-hydroxyfenoxy)etylamino]propoxy>-7-metylbenzimidazol-hydrochlorid, t. t. 229 až 231 °C.4- (2-hydroxy-1- [2- (2-hydroxyphenoxy) ethylamino] propoxy] -7-methylbenzimidazole hydrochloride, m.p. 229-231 ° C.
6.7- dimetyl-4-/2-hydroxy-3-[2-(2-metylf enoxy Jety lamino] propoxy)benzimidezol-hydrochlorid, t. t. 106 až 109 °C.6.7-Dimethyl-4- [2-hydroxy-3- [2- (2-methylphenoxy) ethylamino] propoxy] benzimidezole hydrochloride, m.p. 106-109 ° C.
4-(2-hydroxy-3-[2-(2-metoxyfenoxyJetylamino]propoxy) -7-metyl-benzimidazol-hydrochlorid, t. t. 2,9 až 221 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino] propoxy) -7-methylbenzimidazole hydrochloride, m.p. 2.9-221 ° C.
4-p-hydroxy-3-p-(2-raetoxyfenoxy)etylemino]propoxy)benzimidazol-hydrochlorid, t. t. 1,5 až 1,8 °C.4-p-hydroxy-3-p- (2-methoxyethoxyphenoxy) ethylemino] propoxy) benzimidazole hydrochloride, m.p. 1.5-1.8 ° C.
4-[2-hyčroxy-3-(4-fenyl-2-butylemino)propoxy]benzimidezolhydroehlorid, t. t. eraorf. 4~C2-hydroxy-3-benzo [b] -1,4-dioxen-2-ylmetylemino)propoxy]benzimidezol-hydrochlorid,4- [2-hydroxy-3- (4-phenyl-2-butylemino) propoxy] benzimidezol hydrochloride, m.p. 4-C 2 -hydroxy-3-benzo [b] -1,4-dioxen-2-ylmethylemino) propoxy] benzimidezole hydrochloride,
t. t. ,05 ež 107 °C.mp, 05 to 107 ° C.
4-(2-hydroxy-3-[2-£2-metoxyfenoxy)propylamino]propoxy)benzimidezol-hydrochlorid, t. t. 115 až 118 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy) benzimidezole hydrochloride, m.p. 115-118 ° C.
4-[2-hydroxy-3-(3,4-dimetoxyfenetylemino)propoxy]-2,7-dimetylbenzimidezol-hydrochlorid, t. t. 167 ež 169 °C.4- [2-hydroxy-3- (3,4-dimethoxyphenethylemino) propoxy] -2,7-dimethylbenzimidezole hydrochloride, m.p. 167-169 ° C.
4-(2-hydroxy-3-[2-(2-propoxyfenoxy)etylemino] propoxy)-2,7-dimetylbenzimidezol-hydrochlorid, t. t. 143 ež 145 °C.4- (2-hydroxy-3- [2- (2-propoxyphenoxy) ethylemino] propoxy) -2,7-dimethylbenzimidezole hydrochloride, m.p. 143-145 ° C.
4-(2-hydroxy-3-[2-(2-metoxy-4-metylfenoxy)etylemino]propoxy)-2,7-dimetylbenzimidazol-hydrochlorič, t. t. 165 ež 167 °C.4- (2-hydroxy-3- [2- (2-methoxy-4-methylphenoxy) ethylemino] propoxy) -2,7-dimethylbenzimidazole hydrochloride, m.p. 165-167 ° C.
4-[2-hydroxy-3-(3,4-dimetoxyfenetylsmino)propoxy]benzotriazol-hydrochlorid, t. t. 123 až 124 °C.4- [2-hydroxy-3- (3,4-dimethoxyphenethylsmino) propoxy] benzotriazole hydrochloride, m.p. 123-124 ° C.
4-[2-hydroxy-3-(3,4-dimetoxyfenetylsmino)propoxy]-7-metylbenzotriazol-hydrochlorid, t. t. 184 až 186 °C.4- [2-hydroxy-3- (3,4-dimethoxyphenethylsmino) propoxy] -7-methylbenzotriazole hydrochloride, m.p. 184-186 ° C.
4-{2-hydroxy-3-r_2-í2-metoxyfenoxy)etyl8<flino]propoxy)benzotriazol-hydrochlorid, t. t. 113 ež 115 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethyl (flino) propoxy) benzotriazole hydrochloride, m.p. 113-115 ° C.
4-Č2-hydroxy-3-[2-(2-metoxyfenoxy)etylamino]propoxy>-7-metylbenzotriazol-hydrochlorid,4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino] propoxy) -7-methylbenzotriazole hydrochloride,
t. t. 109 až 111 °C.mp 109-111 ° C.
4-(2-hydroxy-3-[2-(2-hydroxyfenoxy)etyl8minojpropoxy)benzotriazol-hydrochlorid,4- (2-hydroxy-3- [2- (2-hydroxyphenoxy) ethyl8mino-propoxy) benzotriazole hydrochloride,
t. t. 200 až 203 °C.mp 200-203 ° C.
4-[2-hydroxy-3-(2-metoxy-fenetylemino)propoxy]benzotriazol-hydrochlorid, t. t. 82 až 85 °C.4- [2-hydroxy-3- (2-methoxyphenethylemino) propoxy] benzotriazole hydrochloride, m.p. 82-85 ° C.
4-(2-hydroxy-3-[2-(2-allyloxyfenoxy)propylamino3propoxy^benzotriazol-hydrochlorid, t. t. 143 až 145 °C.4- (2-hydroxy-3- [2- (2-allyloxyphenoxy) propylamino) propoxy] benzotriazole hydrochloride, m.p. 143-145 ° C.
4-[2-hydroxy-3-( 3,4-dimetoxyfenetylaniino)propoxyJ-2-benzimidezolinthion-hydrochlorid, t. t. ,08 až 110 °C.4- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -2-benzimidezolinthione hydrochloride, m.p. 08-110 ° C.
4-(2-hydroxy-3-[2-(2-metoxyfenoxy)propylamino] propoxy)-7-metyl-2-benzimidezolinthion-benzoét, t. t. 169 až 170 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy) -7-methyl-2-benzimidezolinthione benzoate, m.p. 169-170 ° C.
4-(2-hydroxy-3-[2-(2-hydroxyfenoxy)etyl8mino3propoxy>-6,7-eyklopenteno-2-benzimiaazollnon-hydrochlorid, t. t. ,45 až ,55 °C.4- (2-hydroxy-3- [2- (2-hydroxyphenoxy) ethyl] amino-3-propoxy) -6,7-cyclopenteno-2-benzimidazolinone hydrochloride, m.p. 45-55 ° C.
4-^3-[2-(3,4-dlmetoxyfenyl)etylamlno]-2-hydroxypropoxy^-6,7-cyklopenteno-2-benzimidazolinon-hydrochlorid, t. t. ,93 až 195 °C.4- [3- (2- (3,4-dimethoxyphenyl) ethylamino) -2-hydroxypropoxy] -6,7-cyclopenteno-2-benzimidazolinone hydrochloride, m.p. 93-195 ° C.
4-[2-hydroxy-3-(2-fenoxypropylamino)propoxy]-6,7-cyklopenteno-2-benzimidezollnon-hydrochlorid, t. t. 261 až 263 °C.4- [2-hydroxy-3- (2-phenoxypropylamino) propoxy] -6,7-cyclopenteno-2-benzimidezolone hydrochloride, m.p. 261-263 ° C.
4-(2-hydroxy-3-[2-(2-hydroxy-fenoxy)etylemino3 propoxy>-6,7-cyklopenteno-benzimidazol, t. t. 182 až ,83 °C.4- (2-hydroxy-3- [2- (2-hydroxy-phenoxy) ethyl) amino] propoxy-6,7-cyclopentenobenzimidazole, m.p. 182 DEG-83 DEG.
4-(2-hydroxy-3-[(1-metyl-3-fenyl)propylamino3propoxy>-6-inetylindol-benzoót, t. t. 119 až ,22 °C.4- (2-hydroxy-3 - [(1-methyl-3-phenyl) propylamino-3-propoxy] -6-ethylindole benzoate, m.p. 119 DEG-22 DEG.
4-č2-hydroxy-3-[2-(3,4-dioetoxyfenyl)etylamino3propoxy^-6-metylindolinbenzoát, t. t. ,47 až ,48 °C.4- [2-hydroxy-3- [2- (3,4-dioethoxyphenyl) ethylamino] propoxy-6-methylindoline benzoate, m.p. 47-48 ° C.
4-Č2-hydroxy-3-L2-(2-pyridinyl)etylemino]propoxy>-6-metylÍndol-dl-p-nitroberizoét, t. t. ,46 °C.4- (2-Hydroxy-3-L2- (2-pyridinyl) ethylemino] propoxy) -6-methylindole-d1-p-nitroberizoate, m.p. 46 ° C.
4-[2-hýdroxy-3-(2-fenoxyetylemino)propoxy]-6-metyl-indolbenzoét, t. t. ,23 až ,25 °C. 4-^2-hydroxy-3-[(1-metyl-2-fenyl)etylamino3propoxy>-6-metylindol-benzoét, t. t. ,25 až 128 °C.4- [2-hydroxy-3- (2-phenoxyethylemino) propoxy] -6-methyl-indole benzoate, m.p. 23-225 ° C. 4- [2-hydroxy-3 - [(1-methyl-2-phenyl) ethylamino-3-propoxy] -6-methylindole benzoate, m.p. 25-128 ° C.
4-(2-hydroxy-3-[2-(2-metoxyfenoxy)etylamino3 propoxý>-6-metylindol, t. t. 123 až ,25 °C. 4-č2-hydroxy-3-[2-(4-karbemidofenoxy)etylemino]propoxy)-6-metylindol, t. t. 128 až ,30 °C. 4- [2-hydroxy-3-(benzo[b]-1,4-dioxen-2-yl-matylemino)propoxy]-6-metylindol-p-chlorbenzoét, t. t. ,68 až 170 °C.4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino) propoxy] -6-methylindole, mp 123 DEG -25 DEG C. 4- (2-hydroxy-3- [2- (4-carbemidophenoxy) ethylemino) Propoxy) -6-methylindole, mp 128 DEG -30 DEG. 4- [2-hydroxy-3- (benzo [b] -1,4-dioxen-2-ylmethylamino) propoxy] -6-methylindole-p-chlorobenzoate, m.p. 68-170 ° C.
4-[2-hydroxy-3-(2-fenoxy-N-benzylpropylemino)propoxy3-6-metylindol.4- [2-hydroxy-3- (2-phenoxy-N-benzylpropylemino) propoxy] -6-methylindole.
4-(2-hydroxy-3-[2-(3,4-dimetoxyfenyl)etylamino]propoxy)-6-metoxykarbonylindol, t. t. 145 až ,47 °C.4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) -6-methoxycarbonylindole, m.p. 145 DEG-47 DEG.
4-^2-hydroxy-3-[2-(2-allyloxyfenoxy)etylamino3propoxy>-6-metyllndol, t. t. ,25 °C. 2-etoxykerbonyl-4-[2-hydroxy-3-(2-fenylpropylamino)propoxy]-6-metyllndol, t. t. 127 °C. 2-etoxykarbonyl-4-(2-hydroxy-3-[(,-metyl-3-f enyl )propylaoiino]propoxy)-6-iaetylindol,4- [2-hydroxy-3- [2- (2-allyloxyphenoxy) ethylamino] propoxy] -6-methylindole, m.p. 25 [deg.] C. 2-Ethoxycarbonyl-4- [2-hydroxy-3- (2-phenylpropylamino) propoxy] -6-methylindole, mp 127 ° C. 2-ethoxycarbonyl-4- (2-hydroxy-3 - [(, - methyl-3-phenyl) propylamino] propoxy) -6-ethylindole,
t. t. 133 až ,34 °C.mp 133-34 ° C.
2-etoxykarbonyl-4-(2-hydroxy-3-[2-(2-pyridinyl)etylamino]propoxy^-6-metylindol-benzoát, t. t. 129 až 13, °C.2-Ethoxycarbonyl-4- (2-hydroxy-3- [2- (2-pyridinyl) ethylamino] propoxy-6-methylindole benzoate, mp 129-13 ° C.
2-etoxykerbonyl-4-č2-hydroxy-3-[2-(4-pyridinyl)etylaminoJpropoxy^-6-metylindol, t. t. ,33 až 134 °C.2-ethoxycarbonyl-4- [2-hydroxy-3- [2- (4-pyridinyl) ethylamino] propoxy-6-methylindole, m.p. 33-134 ° C.
2-etoxykarbonyl-4-[2-hydroxy-3-(2-fenoxyetylamino)propoxy]-6-metylindol-benzoát, t. t. 147 °C.2-ethoxycarbonyl-4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] -6-methylindole benzoate, m.p. 147 ° C.
2-e toxykarbonyl-4-{2-hydr oxy-3-Γ( 1 -metyl-2-f enoxy)etylamino3 propoxy^-6-metylindol-benzoét, t. t. ,35 až 137 °C.2-ethoxycarbonyl-4- {2-hydroxy-3-Γ (1-methyl-2-phenoxy) ethylamino-3-propoxy-6-methylindole-benzoate, m.p. 35-137 ° C.
2-etoxykarbonyl-4-{2-hydroxy-3-[2-(2-metoxyfenoxy)etylamino3 propoxy^-6-metylindol, t. t. ,45 až ,47 °C.2-ethoxycarbonyl-4- {2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino] propoxy-6-methylindole, m.p. 45-47 ° C.
2-etoxykarbonyl-4-{2-hydroxy-3-[2-(4-karbamidofenoxy)etyletnino3 propoxy^-6-metylindol-aoetét, t. t. 160 až ,65 °C.2-ethoxycarbonyl-4- {2-hydroxy-3- [2- (4-carbamidophenoxy) ethylethino-3-propoxy-6-methylindole-o-acetate, m.p. 160-65 ° C.
2-etoxykarbonyl-4-[2-hydroxy-3-(benzo [b]-1,4-dioxan-2-yl-metylamino)propoxy]-6-metyltndol, t. t. 135 až 137 °C.2-ethoxycarbonyl-4- [2-hydroxy-3- (benzo [b] -1,4-dioxan-2-ylmethylamino) propoxy] -6-methylindole, mp 135-137 ° C.
4-[2-hydroxy-3-(3-fenylpropylemino)propoxy]ind8Zol, t. t. 122 až 124 °C.4- [2-hydroxy-3- (3-phenylpropylemino) propoxy] indole, m.p. 122-124 ° C.
2273)32273) 3
4-C2-hydroxy-3-[.( 1-metyl-2-fenoxy)etylamino]propoxy)indazol, t. t. 175 až 177 °C. 2-benzyl-4-f2-hydroxy-3-[2-(3,4-dimetoxyfenyl)etylamino]propoxy)indazol, t. t. 101 až4-C2-hydroxy-3 - [(1-methyl-2-phenoxy) ethylamino] propoxy) indazole, m.p. 175-177 ° C. 2-Benzyl-4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole, m.p.
102 °C.102 ° C.
2-benzyl-4-f2-hydroxy-3-[2-(2-benzyloxyfenoxy)etylemino]propoxy)indazol, t. t. 81 ež 03 °C.2-Benzyl-4- (2-hydroxy-3- [2- (2-benzyloxyphenoxy) ethylemino] propoxy) indazole, m.p. 81 DEG-03 DEG C .;
2-benzyl-4-(2-hydroxy-3-[2-(3,4-etylendioxyfenyl)etylemino]propoxy)lndazol, t. t. 165 až ,68 °C.2-Benzyl-4- (2-hydroxy-3- [2- (3,4-ethylenedioxyphenyl) ethylemino] propoxy) indazole, m.p. 165-68 ° C.
4-f2-hydroxy-3-[2-(3,4-dimetoxyfenyl)etylamino]propoxy)-1-formylindolin -benzoát, t. t. ,36 až 138 °C.4- [2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy] -1-formylindoline benzoate, m.p. 36-138 ° C.
4-(2-hydroxy-3-[2-(4-fluorfenoxy)etylemino]propoxy)-1-formylindolin-benzoát, t. t. 12, až 123 °C.4- (2-hydroxy-3- [2- (4-fluorophenoxy) ethylemino] propoxy) -1-formylindoline benzoate, m.p. 12-123 ° C.
4-f2-hydroxy-3-[2-(2-metoxyfenoxy)etyiamino]propoxy)-1-formylindolinbenzoét, t. t. 78 až 79 °C.4- [2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino] propoxy] -1-formylindoline benzoate, m.p. 78-79 ° C.
4-[2-taydroxy-3-(2-fenyletylamino)propoxy]-1-formylindolin, t. t. ,2, až 123 °C. 4-f2-hydroxy-3-[2-(2-ehlorfenoxy)etylemino]propoxy)-1~formylindolin, t. t. ,04 až 107 °C. 4-f2-hydroxy-3-[2-(2-metylmerkaptofenoxy)etylamino]propoxy)-,- formylindolin, t. t. 129 ež 130 °C.4- [2-Tetroxy-3- (2-phenylethylamino) propoxy] -1-formylindoline, m.p. 2-123 ° C. 4- (2-hydroxy-3- [2- (2-chlorophenoxy) ethylemino] propoxy) -1-formylindoline, m.p. 04-107 ° C. 4- (2-hydroxy-3- [2- (2-methylmercaptophenoxy) ethylamino] propoxy) -1-formylindoline, mp 129-130 ° C.
4-(2-hydroxy-3-[2-(2~8llylfenoxy)-etylamino]propoxy)indazol, t. t. ,25 až ,26 °C. 4-(,2-hydroxy-3-[2-{2-ellyloxyfenoxy)etylamlnoJpropoxy)indazol, t. t. 137 až ,39 °C.4- (2-hydroxy-3- [2- (2- (8-llyl-phenoxy) -ethylamino] -propoxy) -indazole, mp 25-25 ° C. 4- (2-hydroxy-3- [2- {2-ellyloxyfenoxy) etylamlnoJpropoxy) indazole, mp 137 DEG, 39 DEG.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS806605A CS227313B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792905877 DE2905877A1 (en) | 1979-02-16 | 1979-02-16 | NEW AMINOPROPANOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| CS801055A CS227305B2 (en) | 1979-02-16 | 1980-02-15 | Method of preparing heterocyclic oxypropanolamine derivatives |
| CS806605A CS227313B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS227313B2 true CS227313B2 (en) | 1984-04-16 |
Family
ID=25745373
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS806605A CS227313B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
| CS806604A CS227312B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
| CS814336A CS227327B2 (en) | 1979-02-16 | 1981-06-10 | Method of preparing heterocyclic oxypropanolamine derivatives |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS806604A CS227312B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
| CS814336A CS227327B2 (en) | 1979-02-16 | 1981-06-10 | Method of preparing heterocyclic oxypropanolamine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CS (3) | CS227313B2 (en) |
-
1980
- 1980-09-30 CS CS806605A patent/CS227313B2/en unknown
- 1980-09-30 CS CS806604A patent/CS227312B2/en unknown
-
1981
- 1981-06-10 CS CS814336A patent/CS227327B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS227327B2 (en) | 1984-04-16 |
| CS227312B2 (en) | 1984-04-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI80681C (en) | FOERFARANDE FOER FRAMSTAELLNING AV ARYLOXIPROPANOLAMINER ANVAENDBARA FOER AVVAERJNING OCH FOEREBYGGANDE AV HJAERT- OCH BLODKAERLSSJUKDOMAR. | |
| EP0079545B1 (en) | Benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containing the same | |
| US4346093A (en) | Heterocyclic oxypropanolamine compounds and pharmaceutical compositions | |
| BG60428B2 (en) | Benzimidazoles, method for their preparation and medicaments containing them | |
| US4234584A (en) | Substituted phenylpiperazine derivatives | |
| JPS6339875A (en) | Pyrimidine derivative | |
| US4171365A (en) | Antiviral aryloxyalkylpyrazoles | |
| KR100388568B1 (en) | Pyrimidinyl pyrazole derivatives and salts thereof and antitumor agents containing the same | |
| JPH0272158A (en) | Isoindolinone derivatives, their production methods and drugs containing them | |
| HU184238B (en) | Process for preparing piperidino-propyl-derivatives and pharmaceutical compositions containing thereof | |
| KR900003277B1 (en) | Method for preparing piperazine derivatives | |
| US5120736A (en) | 4-methyl-5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazole derivatives their method of preparation and the pharmaceutical compositions in which they are present | |
| CA1207774A (en) | 1-phenylindazol-3-one compounds, a method of preparing them and pharmaceutical compositions containing these compounds | |
| CS227313B2 (en) | Method of preparing heterocyclic oxypropanolamine derivatives | |
| EP1423378B1 (en) | Aminopyrrole compounds as antiinflammatory agents | |
| JPH0375542B2 (en) | ||
| US5110816A (en) | 3-[2-(4-arylpiperazin-1-yl)ethoxy]-p-cymene, the method of preparing and composition thereof | |
| JPH0372221B2 (en) | ||
| CZ280445B6 (en) | Dihydropyrimidothiazine derivatives, process of their preparation and pharmaceutical compositions containing thereof | |
| EP0034752B1 (en) | Phenoxyalkane derivative and processes for preparing same | |
| JPH0386871A (en) | Substituted 2-imino-3- alkylbenzothiazolines | |
| US5322846A (en) | 4-methylthiazole derivatives, their methods of preparation and the pharmaceutical compositions in which they are present | |
| FR2551753A2 (en) | 1,2,3-Benzotriazin-4-ones, process for preparing them and medicinal products containing them | |
| HU189775B (en) | Process for preparing nitriles substituted with a heterocyclic group | |
| CA1210763A (en) | 1,5-diphenyl-pyrazolin-3-one compounds, process and intermediates for preparation thereof and pharmaceutical compositions containing them |