CS227327B2 - Method of preparing heterocyclic oxypropanolamine derivatives - Google Patents
Method of preparing heterocyclic oxypropanolamine derivatives Download PDFInfo
- Publication number
- CS227327B2 CS227327B2 CS814336A CS433681A CS227327B2 CS 227327 B2 CS227327 B2 CS 227327B2 CS 814336 A CS814336 A CS 814336A CS 433681 A CS433681 A CS 433681A CS 227327 B2 CS227327 B2 CS 227327B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- propoxy
- hydroxy
- group
- alkyl
- hydrogen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 4
- -1 alkanoyloxyalkyl carbon Chemical compound 0.000 claims description 103
- 150000001875 compounds Chemical class 0.000 claims description 35
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 238000003419 tautomerization reaction Methods 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 125000006308 propyl amino group Chemical group 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 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 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- MQTYQCAVOMQEFJ-UHFFFAOYSA-N benzene;trihydrochloride Chemical compound Cl.Cl.Cl.C1=CC=CC=C1 MQTYQCAVOMQEFJ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000005042 acyloxymethyl group Chemical group 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- LSONXNMNZYBRDE-UHFFFAOYSA-N 2h-benzotriazole;hydrochloride Chemical compound Cl.C1=CC=C2NN=NC2=C1 LSONXNMNZYBRDE-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- MNFOMRNZIGGTCE-UHFFFAOYSA-N 3-propoxybenzene-1,2-diamine Chemical class CCCOC1=CC=CC(N)=C1N MNFOMRNZIGGTCE-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- WLCLBOVXRZPLIW-UHFFFAOYSA-N hydron;1h-indazole;chloride Chemical compound Cl.C1=CC=C2C=NNC2=C1 WLCLBOVXRZPLIW-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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
- FARSPAVQUKTXLF-UHFFFAOYSA-N 1h-benzimidazol-1-ium;chloride Chemical compound Cl.C1=CC=C2NC=NC2=C1 FARSPAVQUKTXLF-UHFFFAOYSA-N 0.000 description 2
- NMGLVHXJOMBIJW-UHFFFAOYSA-N 1h-benzimidazole;dihydrochloride Chemical compound Cl.Cl.C1=CC=C2NC=NC2=C1 NMGLVHXJOMBIJW-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
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-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
- 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
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000004685 alkoxythiocarbonyl group Chemical group 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000003245 coal Substances 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
- 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
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 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
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 235000010288 sodium nitrite Nutrition 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
- 238000011282 treatment Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RCLWWZAAOXOPIC-UHFFFAOYSA-N 1-(1H-benzimidazol-4-yloxy)-3-(2-phenoxyethylamino)propan-2-ol Chemical compound OC(COC1=CC=CC=2N=CNC21)CNCCOC2=CC=CC=C2 RCLWWZAAOXOPIC-UHFFFAOYSA-N 0.000 description 1
- MBKNQTJPJVWJLH-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-(2-phenoxyethylamino)propan-2-ol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CNCCOC1=CC=CC=C1 MBKNQTJPJVWJLH-UHFFFAOYSA-N 0.000 description 1
- OSNMJMGGUPTOPL-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-(2-pyridin-2-yloxyethylamino)propan-2-ol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CNCCOC1=CC=CC=N1 OSNMJMGGUPTOPL-UHFFFAOYSA-N 0.000 description 1
- SZILDPPAVJCZLU-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-[2-(3,4,5-trimethoxyphenyl)ethylamino]propan-2-ol Chemical compound COC1=C(OC)C(OC)=CC(CCNCC(O)COC=2C=3C=NNC=3C=CC=2)=C1 SZILDPPAVJCZLU-UHFFFAOYSA-N 0.000 description 1
- QZZMEWDTCNUGDZ-UHFFFAOYSA-N 1-(2,3-diamino-4-methylphenoxy)-3-[2-(2-methoxyphenoxy)propylamino]propan-2-ol;trihydrochloride Chemical compound Cl.Cl.Cl.COC1=CC=CC=C1OC(C)CNCC(O)COC1=CC=C(C)C(N)=C1N QZZMEWDTCNUGDZ-UHFFFAOYSA-N 0.000 description 1
- LJRARSWFDJHIML-UHFFFAOYSA-N 1-(2,3-diamino-4-methylphenoxy)-3-[2-(3,4-dimethoxyphenyl)ethylamino]propan-2-ol;trihydrochloride Chemical compound Cl.Cl.Cl.C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=C(C)C(N)=C1N LJRARSWFDJHIML-UHFFFAOYSA-N 0.000 description 1
- ORXJXUJYZGDSCC-UHFFFAOYSA-N 1-(2,3-diaminophenoxy)-3-[2-(3,4-dimethoxyphenyl)ethylamino]propan-2-ol;trihydrochloride Chemical compound Cl.Cl.Cl.C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC(N)=C1N ORXJXUJYZGDSCC-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
- ZTNXEXWWUSJNSP-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-(2-pyridin-2-yloxyethylamino)propan-2-ol Chemical compound C(C1=CC=CC=C1)N1N=C2C=CC=C(C2=C1)OCC(CNCCOC1=NC=CC=C1)O ZTNXEXWWUSJNSP-UHFFFAOYSA-N 0.000 description 1
- LPPFBZOPJJVGMG-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(3,4,5-trimethoxyphenyl)ethylamino]propan-2-ol Chemical compound COC1=C(OC)C(OC)=CC(CCNCC(O)COC=2C3=CN(CC=4C=CC=CC=4)N=C3C=CC=2)=C1 LPPFBZOPJJVGMG-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
- XNZRTKHTMRWYJC-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-(1h-indazol-4-yloxy)propan-2-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC2=C1C=NN2 XNZRTKHTMRWYJC-UHFFFAOYSA-N 0.000 description 1
- QXMJHLJKXRTLOT-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-[(7-methyl-3H-benzimidazol-4-yl)oxy]propan-2-ol hydrochloride Chemical compound Cl.OC(COC1=CC=C(C=2N=CNC21)C)CNCCC2=CC(=C(C=C2)OC)OC QXMJHLJKXRTLOT-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
- DKUPQELYRFUSRF-UHFFFAOYSA-N 1-[3-(3,4-dimethoxyphenyl)propylamino]-3-(1h-indazol-4-yloxy)propan-2-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCCNCC(O)COC1=CC=CC2=C1C=NN2 DKUPQELYRFUSRF-UHFFFAOYSA-N 0.000 description 1
- RTTYVSYSJKDAAF-UHFFFAOYSA-N 1-[[2-(2-methoxyphenoxy)-4-phenylbutyl]amino]-3-[(6-methyl-1H-indol-4-yl)oxy]propan-2-ol Chemical compound OC(COC1=C2C=CNC2=CC(=C1)C)CNCC(CCC1=CC=CC=C1)OC1=C(C=CC=C1)OC RTTYVSYSJKDAAF-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-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
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- FYDMBYXBQYEOEL-UHFFFAOYSA-N 2,3-dihydro-1h-indene;hydrochloride Chemical compound Cl.C1=CC=C2CCCC2=C1 FYDMBYXBQYEOEL-UHFFFAOYSA-N 0.000 description 1
- XQRIIZNTOKFIBU-UHFFFAOYSA-N 2-[(4-methyl-2,3-dinitrophenoxy)methyl]oxirane Chemical compound [O-][N+](=O)C1=C([N+]([O-])=O)C(C)=CC=C1OCC1OC1 XQRIIZNTOKFIBU-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- BWJTZPAFYJUIRZ-UHFFFAOYSA-N 4-[2-[[2-hydroxy-3-(1h-indazol-4-yloxy)propyl]amino]ethyl]benzene-1,2-diol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CNCCC1=CC=C(O)C(O)=C1 BWJTZPAFYJUIRZ-UHFFFAOYSA-N 0.000 description 1
- BXQBVXUYLKBZNR-UHFFFAOYSA-N 4-[2-hydroxy-3-[[2-(2-methoxyphenoxy)-4-phenylbutyl]amino]propoxy]-2,3-dihydroindole-1-carbaldehyde Chemical compound COC1=CC=CC=C1OC(CNCC(O)COC=1C=2CCN(C=2C=CC=1)C=O)CCC1=CC=CC=C1 BXQBVXUYLKBZNR-UHFFFAOYSA-N 0.000 description 1
- FGSCADUOTWRPOQ-UHFFFAOYSA-N 4-[2-hydroxy-3-[[3-phenyl-2-(2-phenylmethoxyphenoxy)propyl]amino]propoxy]-2,3-dihydroindole-1-carbaldehyde Chemical compound OC(COC1=C2CCN(C2=CC=C1)C=O)CNCC(OC1=C(C=CC=C1)OCC1=CC=CC=C1)CC1=CC=CC=C1 FGSCADUOTWRPOQ-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
- FJGVOKJWZAPZHK-UHFFFAOYSA-N 4-chlorobenzoic acid;1-[(6-methyl-1h-indol-4-yl)oxy]-3-(2-phenoxypropylamino)propan-2-ol Chemical compound OC(=O)C1=CC=C(Cl)C=C1.C=1C(C)=CC=2NC=CC=2C=1OCC(O)CNCC(C)OC1=CC=CC=C1 FJGVOKJWZAPZHK-UHFFFAOYSA-N 0.000 description 1
- DUPJEKYVVIGXEJ-UHFFFAOYSA-N 4-propylbenzenesulfonic acid Chemical compound CCCC1=CC=C(S(O)(=O)=O)C=C1 DUPJEKYVVIGXEJ-UHFFFAOYSA-N 0.000 description 1
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methylindole Natural products CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- GRUMNPDGYIYWDF-UHFFFAOYSA-N Cl.COC1=CC(C)=CC=C1OCCNCC(O)COC1=CC=C(C)C2=C1NC(C)=N2 Chemical compound Cl.COC1=CC(C)=CC=C1OCCNCC(O)COC1=CC=C(C)C2=C1NC(C)=N2 GRUMNPDGYIYWDF-UHFFFAOYSA-N 0.000 description 1
- PIGIGZZVVQOFHT-UHFFFAOYSA-N Cl.Cl.Cl.COC1=CC=CC=C1OC(C)CNCC(O)COC1=CC=CC(N)=C1N Chemical compound Cl.Cl.Cl.COC1=CC=CC=C1OC(C)CNCC(O)COC1=CC=CC(N)=C1N PIGIGZZVVQOFHT-UHFFFAOYSA-N 0.000 description 1
- QQXIWCADJQMUDD-UHFFFAOYSA-N Cl.Cl.Cl.NC1=CC=CC(OCC(O)CNCCOC=2C=CC=CC=2)=C1N Chemical compound Cl.Cl.Cl.NC1=CC=CC(OCC(O)CNCCOC=2C=CC=CC=2)=C1N QQXIWCADJQMUDD-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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-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
- 229930195725 Mannitol Natural products 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 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
- JWZZONRKUKDSKD-UHFFFAOYSA-N [1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-(1h-indazol-4-yloxy)propan-2-yl] 2,2-dimethylpropanoate Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(OC(=O)C(C)(C)C)COC1=CC=CC2=C1C=NN2 JWZZONRKUKDSKD-UHFFFAOYSA-N 0.000 description 1
- KBSLSQPBMNMUBH-UHFFFAOYSA-N acetic acid 4-[2-hydroxy-3-[2-(2-hydroxyphenoxy)ethylamino]propoxy]-2,3-dihydroindole-1-carbaldehyde Chemical compound CC(O)=O.C=1C=CC=2N(C=O)CCC=2C=1OCC(O)CNCCOC1=CC=CC=C1O KBSLSQPBMNMUBH-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- QQHDLQDOUOASOX-UHFFFAOYSA-N acetic acid;1h-indazole Chemical compound CC(O)=O.C1=CC=C2C=NNC2=C1 QQHDLQDOUOASOX-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
- 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
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005333 aroyloxy group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 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
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000011970 concomitant therapy Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000004985 diamines Chemical class 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
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 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
- 238000001914 filtration Methods 0.000 description 1
- 235000003599 food sweetener 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
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- YKCAEQUWYQHAPP-UHFFFAOYSA-N n-benzyl-2-(3,4-dimethoxyphenyl)ethanamine Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC1=CC=CC=C1 YKCAEQUWYQHAPP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 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
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000010898 silica gel chromatography 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 229930195735 unsaturated hydrocarbon Natural products 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
Vynález se týká způsobu přípravy heterocyklických oxypropanolaminových derivátů obecného vzorce IThe invention relates to a process for the preparation of heterocyclic oxypropanolamine derivatives of the general formula I
kdewhere
R, znamená vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, benzylovou skupinu nebo alkanoylovou skupinu s 1 až 8 atomy uhlíku,R 1 is hydrogen, C 1 -C 6 alkyl, benzyl or C 1 -C 8 alkanoyl,
Rg a Rj, které mohou být stejné nebo rozdílné, znamenají vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, hydroxyalkylovou skupinu s 1 až 4 atomy uhlíku, alkoxykarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku nebo alkanoyloxyalkylovou skupinu s 1 až 8 atomy uhlíku v alkylových zbytcích nebo společně alkylenový zbytek s 3 až 4 atomy uhlíku,R 8 and R 8, which may be the same or different, are hydrogen, C 1 -C 6 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 2 alkoxycarbonyl or C 1 -C 8 alkanoyloxyalkyl carbon atoms in the alkyl radicals or together an alkylene radical having 3 to 4 carbon atoms,
R^ znamená vodík, alkanoylovou skupinu s 1 až 8 atomy uhlíku nebo benzoylovou skupinuR @ 1 is hydrogen, C1 -C8 alkanoyl or benzoyl
Rj znamená vodík, alkylovou skupinu s 1 až 6 atomy uhlíku nebo benzylovou skupinu,R 1 is hydrogen, C 1 -C 6 alkyl or benzyl,
Rg znamená 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, metylénovou skupinu, atom kyslíku nebo síry,Z is 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, R10, 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 atomy uhlíku, alkenylovou skupinu se 2 až 6 atomy uhlíku, alkoxyskupinu s 1 až 6 atomy uhlíku allyloxyskupinu, alkylthioskupinu s 1 až 6 atomy uhlíku, aminokarbonylovou skupinu, aminosulfonylovou skupinu, alkanoylaminoskupinu s 1 až 8 atomy uhlíku, nebo Rg a Rg znamenají společně alkylendioxyskupinu s 1 až 2 atomy uhlíku nebo Rg společně s Ry znamená také -CHg-O-skupinu aR 8, R 8, R 10 , which may be the same or different, are hydrogen, halogen, hydroxyl, C 1 -C 8 alkanoyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, alkoxy C 1 -C 6 allyloxy, C 1 -C 6 alkylthio, aminocarbonyl, aminosulfonyl, C 1 -C 8 alkanoylamino, or R 8 and R 8 together represent C 1 -C 2 alkylenedioxy, or R 8 together with R 8 also means -CHg-O-group a
A znamená skupinu X2=Y2, ve které Xg a Yg mohou být stejné nebo rozdílné a značí atom dusíku nebo =CR12-skupinu, přičemž R, 2 představuje vodík,'alkylovou skupinu sl až 6 atomy uhlíku nebo alkoxykarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku, při čemž pro případ, že ^2=^2 P^e<ístavuje -CH=N-skupinu a R, alkylovou skupinu s 1 až 6 atomy uhlíku, může být tato umístěna vzhledem ke schopnosti tautomerie indazolů také na atomu dusíku pro Y2, a jejich farmakologicky vhodných solí.A represents a group X 2 = Y 2 in which X g and Y g may be the same or different and represent a nitrogen atom or a = CR 12 group, wherein R 2 represents hydrogen, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxycarbonyl group 2 carbon atoms in the alkyl moiety, wherein in case 2 ^ 2 = ^ P ^ e <ístavuje -CH = N-group and R is alkyl having 1 to 6 carbon atoms, this may be positioned with respect to the ability of tautomerism indazoles also on the nitrogen atom for Y 2, and their pharmacologically acceptable salts.
Protože mají sloučeniny vzorce I asymetrické atomy uhlíku, spadají do rozsahu 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 thereof are within the scope of the invention.
Sloučeniny vzorce I a jejich farmakologicky 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 léčení a profylaxi srdečních a oběhových onemocnění.The compounds of formula (I) and their pharmacologically acceptable salts have, at low toxicity, significant vasodilatory properties, which manifest themselves essentially in the lowering of blood pressure, and in addition inhibit the 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 19 164, 26 51 574 aIn German patents 19 48 507, 22 30 426, 26 19 164, 26 51 574 a
00 193 jsou popsány a nárokovány sloučeniny podobné struktury a účinku. Změnou heterocyklické fenolové části a aminopropoxy-postranního řetězce bylo docíleno překvapujícího zlepšení účinku.Compounds of similar structure and activity are described and claimed. By altering the heterocyclic phenol moiety and the aminopropoxy side chain, a surprising improvement was achieved.
Pod alkylovou skupinou substituentú R,, R2, R^, Rg, Rg, R-j, Rg, Rg, R10, R, 1 a R12 se rozumí přímé nebo rozvětvené skupiny s 1 až 6, s výhodou 1 až 4 atomy uhlíku, jako například metyl, etyl, propyl, isopropyl, butyl, isobutyl, terč.butyl nebo n-hexyl. Obzvláště věak přichází v úvahu metylová nebo etylová skupina. Alkylenový zbytek případně vytvořený společně substituenty R2 a Rj mé 3 až 4, s výhodou 3 atomy uhlíku.The alkyl group of R 1, R 2 , R 6 , R 8, R 8, R 8, R 8, R 9 , R 10 , R 11 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, tert-butyl or n-hexyl. Especially methyl or ethyl is particularly suitable. The alkylene radical optionally formed together by R 2 and R 3 has from 3 to 4, preferably 3, carbon atoms.
Pod alkenylovou skupinou se rozumí nenasycené uhlovodíkové zbytky s 1 až 6 atomy uhlí ku, obzvláště allylový a metylvinylový zbytek.The alkenyl group means unsaturated hydrocarbon radicals having 1 to 6 carbon atoms, in particular an allyl and methylvinyl radical.
Hydroxyalkylové skupiny substituentú R2 a Rj obsahují 1 až 4 atomy uhlíku, výhodné je 2-hydroxyetylová a hydroxymetylová skupina.The hydroxyalkyl groups of R 2 and R 1 contain from 1 to 4 carbon atoms, preferably 2-hydroxyethyl and hydroxymethyl groups.
Alkoxyskupiny substituentú Rg, Rg a R^ obsahují 1 až 6 s výhodou 1 až 4 atomy uhlíku jako například metoxy-, etoxy-, a propoxyskupinu.The alkoxy groups of substituents R 8, R 8 and R 8 contain 1 to 6, preferably 1 to 4, carbon atoms such as methoxy, ethoxy, and propoxy.
Jako alkoxykarbonylové skupiny substituentú Rg, Rj a R,2 přicházejí obzvláště v úvahu metoxykarbonylové a etoxykarbonylové skupiny.As the alkoxycarbonyl groups Rg, Ri and R 2 are in particular the methoxy- and ethoxycarbonyl.
Alkyl thi o skupiny substituentú Rg, Rg a R^ jsou skupiny s 1 až 6, s výhodou 1 až 4 atomy uhlíku. Výhodný je metylmerkaptozbytek.Alkyl thio groups of substituents R 8, R 8 and R 6 are groups having 1 to 6, preferably 1 to 4, carbon atoms. Methyl mercapto is preferred.
Alkanoylové skupiny substituentú R1, R^, Rg, Rg, R10 a alkanoylové část alkanoyloxy3 alkylové skupiny v definici substituentů Rg a R-j a alkanoylaminoskupina substituentů Rg,The alkanoyl groups of the substituents R @ 1 , R @ 1 , R @ 8, R @ 8, R @ 10 and the alkanoyl moiety of the alkanoyloxy3 alkyl group in the definition of R @ 8 and R @ 11 and the alkanoylamino group of R @ 8;
Rg a Rjθ 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. Jako alkanoyloxyalkylové skupiny jsou obzvláště výhodné alkanoyloxymetylové skupiny.R 8 and R 10 contain from 1 to 8, preferably 1 to 5, carbon atoms, the alkyl groups of which may be straight, branched or cyclic. A formyl, acetyl or pivaloyl residue is preferred. Particularly preferred alkanoyloxyalkyl groups are alkanoyloxymethyl groups.
Pod aroylovou skupinou v definici substituentu R^ se s výhodou rozumí benzoylová skupina, která může být jednou nebo vícenásobně substituované halogenem, alkylovou skupinou s 1 až 4 atomy uhlíku nebo alkoxyskupinou s 1 až 4 atomy uhlíku.The aroyl group in the definition of the substituent R1 is preferably a benzoyl group which may be mono- or polysubstituted by halogen, a C1-C4 alkyl group or a C1-C4 alkoxy group.
Pod aralkylovou skupinou v definici substituentů R, a Rg a pod aralkoxyskupinou v definici substituentů Rg, Rg a R,θ se rozumí zbytky, které mají jako arylovou část fenylový nebo naftylový zbytek a jako alkylovou část přímý nebo rozvětvený nasycený uhlovodíkový řetězec s 1 až 4 atomy uhlíku. Obzvláště výhodný je benzylový zbytek.Aralkyl in the definition of the substituents R, Rg and aralkoxy in the definition of the substituents Rg, Rg and R, θ are those which have a phenyl or naphthyl radical as an aryl moiety and a straight or branched saturated hydrocarbon chain having from 1 to 4 as the alkyl moiety carbon atoms. Particularly preferred is a benzyl residue.
Jako alkylendioxyskupina společně vytvořené substituenty Rg a Rg přichází s výhodou v úvahu metylén- a etylándioxyskupina.Suitable alkylenedioxy groups Rg and Rg together are preferably methylene and ethylenedioxy groups.
Označení A v obecném vzorci I má zvláště takový význam, že jako heterocykly se rozumí benzimidazolinon-2, benzimidazolinthion-2, benzimidazol, benztriazol, indol, indolin a indazol.In particular, the designation A in formula I is such that heterocycles are benzimidazolinone-2, benzimidazolinethion-2, benzimidazole, benztriazole, indole, indoline and indazole.
Pod halogenem se rozumí podle vynálezu fluor, chlor, brom, jod, obzvláště fluor, chlor a brom.Halogen according to the invention is understood to mean fluorine, chlorine, bromine, iodine, especially fluorine, chlorine and bromine.
Způsob přípravy sloučenin obecného vzorce I se vyznačuje tím, že se nechá reagovat sloučenina obecného vzorce IIA process for the preparation of compounds of the formula I is characterized by reacting a compound of the formula II
(II) kde R1, Rg, Rj, R^, Rg, Rg, R?, Rg, Rg, R1o, Z a Ar mají výše uvedený význam a X představuje HX2, ee sloučeninou obecného vzorce III(II) wherein R 1 , R 8, R 8, R 8, R 8, R 9, R 8, R 8, R 8, R 10 , R 10 , Z and Ar are as defined above and X is HX 2 ee
(III) kde Yg má výše uvedený význam, znamená atom vodíku, hydroxylovou skupinu nebo reaktivní zbytek jako chlor, nebo brom, aminoskupinu, imidazolylovou skupinu, alkoxyskupinu s 1 až 6 atomy uhlíku, fenoxyskupinu, merkaptoskupinu a alkoxythiokarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku, a Lg' znamená atom vodíku nebo reaktivní zbytek jako chlor nebo brom, aminoskupinu, imidazolylovou skupinu, alkoxyskupinu s 1 až 6 atomy uhlíku, fenoxy skupinu, merkaptoskupinu a alkoxythiokarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku a L^ znamená atom vodíku nebo dohromady s Lg' atom kyslíku, a vzniklý produkt se cyklizuje, a případně se dodatečně v získané sloučenině obecného vzorce I převede jeden ze zbytků R,, Rg, Rj, R^, Rg, Rg, Rg, R^q, nebo R12 obvyklým způsobem na jiný definicí definovaný zbytek R,, Rg, R^, R^, Rg, Rg, Rg, R1o nebo R12 a získané sloučeniny se případně přemění na farmakologicky vhodné soli.(III) wherein Yg is as defined above, represents a hydrogen atom, a hydroxyl group or a reactive radical such as chlorine or bromine, amino, imidazolyl, alkoxy of 1 to 6 carbon atoms, phenoxy, mercapto and alkoxythiocarbonyl of 1 to 2 carbon atoms in an alkyl radical, and Lg 'represents a hydrogen atom or a reactive radical such as chlorine or bromine, amino, imidazolyl, alkoxy of 1 to 6 carbon atoms, phenoxy, mercapto and alkoxythiocarbonyl of 1 to 2 carbon atoms in the alkyl radical and L 1'; represents a hydrogen atom or, together with Lg ', an oxygen atom, and the product is cyclized, and optionally one of the radicals R @ 1, R @ 8, R @ 8, R @ 8, R @ 8, R @ 8, R @ 8 or R 12 in the usual manner on another definition defined a radical R ,, R₂, R₃, R₅, R₆, Rg, Rg, R 1o or R 12 and the compound obtained is optionally converted into pharmacologically acceptable salts.
Jako sloučeniny obecného vzorce III přicházejí např. v úvahu karboxylové kyseliny, jako kyselina mravenčí nebo kyselina octová, estery kyseliny karboxylové nebo také halogenidy karboxylové kyseliny. Sloučeniny vzorce III se mohou vSak také připravit in šitu z jiných látek v reakční směsi, např. anorganický dusitan ve vodném roztoku minerální kyseliny, nízký alkylový ester kyseliny dusité v organickém rozpouštědle.Suitable compounds of the formula III are, for example, carboxylic acids, such as formic acid or acetic acid, carboxylic acid esters or carboxylic acid halides. However, the compounds of formula III may also be prepared in situ from other materials in the reaction mixture, e.g., inorganic nitrite in an aqueous mineral acid solution, a low alkyl nitrite of nitrous acid in an organic solvent.
Způsob podle vynálezu se účelně provádí v rozpouštědle inertním za reakčních podmínek, např. vodě, metanolu, etanolu, n-butanolu, dioxanu, dimetylformsmidu nebo hexametyltriamidu kyseliny fosforečné, případně za přítomnosti činidla vázajícího kyselinu. 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 conveniently carried out in a solvent inert under the reaction conditions, e.g. water, methanol, ethanol, n-butanol, dioxane, dimethylformsmide or hexamethyltriophosphoric triamide, optionally in the presence of an acid binder. 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.
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.
Jako případně dodatečně prováděná přeměna jednoho ze substituentů R,, Rg, Rg, R41 Rj, Rg, Rg, R,0 nebo R,g ve sloučeninách obecného vzorce I na jiný, definicí definovaný zbytek R,, Rg, Rp Rp Rg, Rg, Rg, Rjq nebo R,2 přichází např. v úvahu dodatečná aeylaee OH-skupiny na alkanoyloxy- nebo aroyloxyskupinu, redukce alkoxykarbonylové ekupiny na hydroxymetylový zbytek, hydrolýza alkanoyloxymetylová skupiny na hydroxymetylový zbytek, redukce alkanoyloxymetylová skupiny na metylové substituenty nebo odštěpení benzylové ekupiny.The conversion of one of the substituents R, Rg, Rg, R41, Rj, Rg, Rg, Rg, R, O or R, g in the compounds of formula I into an optionally defined radical R, Rg, Rp Rp Rg, Rg , Rg, Rjq or R, 2 are, for example, additional aeylaee OH groups to alkanoyloxy or aroyloxy, reduction of alkoxycarbonyl to hydroxymethyl, hydrolysis of alkanoyloxymethyl to hydroxymethyl, reduction of alkanoyloxymethyl to methyl substituents or cleavage of benzyl.
Esterifikace hydroxylové skupiny pro -OR^ se může provádět obvyklým způsobem reakcí s halogenidem nebo anhydridem kyseliny, případně za přítomnosti činidla vázajícího kyselinu, jako např. pyridinu nebo trietylaminu.The esterification of the hydroxyl group for -OR 6 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 Rg představuje alkoxykarbonylovou nebo alkanoyloxymetylovou skupinu, na sloučeniny vzorce I, ve kterém Rg a/nebo Rg představuje hydroxymetylový nebo metylový substituent, ae provádí účelně pomoci komplexnlxh hydridů kovu, jako např. hydridu lithno-hlinitáho, nebo katalytickou hydrogenací za přítomnosti vzácného kovu nebo Raneyova niklu jako katalyzátoru.The optional reduction of compounds of formula I in which Rg and / or Rg represents an alkoxycarbonyl or alkanoyloxymethyl group to compounds of formula I in which Rg and / or Rg represents a hydroxymethyl or methyl substituent is conveniently carried out with complex metal hydrides such as e.g. lithium aluminum hydride, or by catalytic hydrogenation in the presence of a noble metal or Raney nickel catalyst.
Hydrolýza álkanoyloxymetylových skupin Rg a/nebo Rg ve sloučeninách obecného vzorce I na hydroxymetylová zbytky Rg a/nebo Rg se může provádět známým způsobem v Kyselám nebo alkalickém prostředí.The hydrolysis of the alkanoyloxymethyl groups Rg and / or Rg in the compounds of the formula I to the hydroxymethyl radicals Rg and / or Rg can be carried out in known manner in acids or alkaline medium.
Odštěpení benzylové skupiny pro R, a Rg nebo obsažené v Rg, Rg a R^ q se provádí např. hydrogenací za přítomnosti vzácného kovu jako katalyzátoru.The cleavage of the benzyl group for R 1 and R 8 or contained in R 8, R 8 and R 10 is carried out, for example, by hydrogenation in the presence of a noble metal catalyst.
Pro převedení sloučenin vzorce I na farmakologicky vhodná soli se nechají tyto reagovat s výhodou v organickém rozpouštědle s anorganickou nebo organickou kyselinou, např. kyselinou solnou, bromovodíkovou, 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, e.g. hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, citric, maleic or benzoic acids.
Sloučeniny podle vynálezu vzorce I se mohou získat ve formě racemické směsi. Děleni racemátu na opticky aktivní formy se provádí známými způsoby přes disstersomsrní soli.The compounds of the invention of formula I 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 dissteromide salts.
Jako aktivní kyseliny se mohou použít kyselina vinná, jablečná, kafrová a kafrsulfonová.Tartaric, malic, camphoric and camphorsulfonic acids can be used as active acids.
Pro přípravu léčiv se smíchají sloučeniny vzorce I známým způsobem s vhodnými farmaceutickými nosiči, aromatickými, chulovými látkami a barvivý a vytvarují se např. jako tablety nebo dražé nebo se suspendují nebo rozpustí za přídavku přísluSnýeh pomocných látek ve vodě nebo oleji, jako např. olivovém oleji.For the preparation of medicaments, the compounds of the formula I are admixed in a known manner with suitable pharmaceutical carriers, flavoring agents and coloring agents and are formed, for example, as tablets or dragees or suspended or dissolved in water or oil, for example with olive oil. .
Nové sloučeniny podle vynálezu vzorce I a jejich soli sa mohou aplikovat v kapalná nebo pevné formě ehterálně nebo parenterálně. 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 např. vinanový nebo citrónový pufr, etanol, komplexotvorná látka (jako etyléndiamintetraoctová kyselina 8 její netoxické soli), vysokomolekulární polymery (jako kapalný polyetylénoxid) k regulaci viskozity. Jako pevné nosiče přicházejí např. v úvahu Škroby, laktóza, mannlt, raetylcelulóza, talek, vysoce disperzní kyselina křemičitá, vysokomolekulární mastné kyseliny (jako kyselina stearo vá), želatina, agar-agar, fosforečnan vápenatý, stearan hořečnatý, živočišné a rostlinné tuky a pevné vysokomolekulární polymery (jako polyetylénglykoly). Přípravky vhodné pro orální aplikaci mohou případně obsahovat chutové látky a sladidla.The novel compounds of the invention of the formula I and their salts can be applied in liquid or solid form ethereal or parenteral. 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 lemon buffer, ethanol, a complexing agent (such as ethylenediaminetetraacetic acid 8 of its non-toxic salt), high molecular weight polymers (such as liquid polyethylene oxide) to control viscosity. Suitable solid carriers are, for example, starches, lactose, 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.
Podávaná 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 hmotnosti. Normálně je účinné 0,5 až 40 a s výhodou 1,0 až 20 mg/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, the frequent 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 20 mg / kg / day in one or more doses per day is effective to achieve the desired results.
Kromě sloučenin uvedených v následujících příkladech jsou v rámci vynélezu déle výhodné následující sloučeniny:In addition to the compounds exemplified in the following examples, the following compounds are preferred within the scope of the invention:
4- 2-hydroxy-3- 2-/2,6-dimetoxy-fenoxy/etylamino propoxy -7-metyl-3-propyl™2-benzimidazolinon4- 2-hydroxy-3- 2- (2,6-dimethoxy-phenoxy) ethylamino-propoxy-7-methyl-3-propyl ™ 2-benzimidazolinone
4-{2-hydroxy-3-j2-/2-allyloxyfenoxy/etylaminoJpropoxy) -6-metylindol4- (2-hydroxy-3- [2- (2-allyloxyphenoxy) 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-sulfamylfenoxy/etylamino]propoxy)indazol4- {2-hydroxy-3- [2- (2-sulfamylphenoxy / ethylamino] propoxy) indazole
4-^2-hydroxy-3-[2-/3,4-etyléndioxyfenyl/etylamino]propoxy) indazol4- (2-hydroxy-3- [2- (3,4-ethylenedioxyphenyl) ethylamino] propoxy) indazole
4-^2-hydroxy-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-dihydroxyfenyl/etylamino]propoxy)indazol4- (2-hydroxy-3- [2- (3,4-dihydroxyphenyl) ethylamino] propoxy) indazole
4-(2-hydroxy-3-[3-/3,4-dimetoxyfenyl/propylamino] propoxy)indazol4- (2-hydroxy-3- [3- (3,4-dimethoxyphenyl) propylamino] propoxy) indazole
4- (2-hydroxy-3-[2-/3-etoxy-4-metoxyfenyl/etylamino]propoxy)indazol4- (2-hydroxy-3- [2- / 3-ethoxy-4-methoxyphenyl / ethylamino] propoxy) indazole
4- (2-hy droxy-3·?· [ 1 -/3,4-dimetoxyfenyl/propyl-2~amino] propoxy^ indazol4- (2-Hydroxy-3R, [1- (3,4-dimethoxyphenyl) propyl-2-amino] propoxy) indazole
1-metyl-4-{2-hydroxy-3-[2-/3,4-dimetoxyf enyl/etylamino] propoxy)indazol1-Methyl-4- {2-hydroxy-3- [2- (3,4-dimethoxyphenyl / ethylamino] propoxy) indazole
1-metyl-4-(2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etylamino]propoxy)indolin1-Methyl-4- (2-hydroxy-3- [2- / 3,4-dimethoxyphenyl / 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-dimetoxyf enyl/etylamino] propoxy) indazol4- (2-Benzoyloxy-3- [2- / 3,4-dimethoxyphenyl / ethylamino] propoxy) indazole
4-(2-hydroxy-3-[i-/3,4-dihydroxyfenyl/-2-amino-1-propanol]propoxyý-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
4- (2-hydroxy-3- [2-/2-metoxyfenoxy/propylamino] propoxy^-7-metyl-benzimidazol-hydrochlorid4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy-7-methylbenzimidazole hydrochloride
14,7 g 2,3-diamino-1-^2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino]propoxy^-4-mety1-benzen-trihydrochloridu se vaří 3 hodiny pod zpětným chladičem v 80 ml kyseliny mravenčí. Zjasní se aktivním uhlím a zahustí se do sucha. Vzniklá formylové sloučenina se zmýdelní za varu v 50 ml 2N kyseliny chlorovodíkové. Po zahuštění do sucha se zbytek překrystaluje z 50 ml etanolu za přídavku aktivního uhlí. Získá se 5,6 g (41 % teorie) žádané sloučeniny o teplotě tání 103 až 105 °C.14.7 g of 2,3-diamino-1- [2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy] -4-methylbenzene trihydrochloride are refluxed in 80 ml of acid for 3 hours. ant. It is brightened with activated carbon and concentrated to dryness. The resulting formyl compound is saponified by boiling in 50 ml of 2N hydrochloric acid. After concentration to dryness, the residue is recrystallized from 50 ml of ethanol with the addition of activated carbon. 5.6 g (41% of theory) of the title compound of melting point 103 DEG-105 DEG C. are obtained.
Příklad 2Example 2
Analogicky podle příkladu 1 se získá z kyseliny mravenčí a příslušně substituovaného 1-propoxy-2,3-diaminobenzenového derivátu:Analogously to Example 1, the following is obtained from formic acid and an appropriately substituted 1-propoxy-2,3-diaminobenzene derivative:
OznačeníDesignation
Výtěžek Teplota tání °C % teorie (rozpouštědlo)Yield Melting point ° C% of theory (solvent)
a) 4-[2-hydroxy-3-/3,4-dimetoxyfenetylamino/propoxy]benzimidazol-hýdroohlorid z 50(a) 4- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] benzimidazole dihydrochloride of 50
2.3- diamino-1-[2-hydroxy-3-/3,4-dimetoxyfenetylamino/propoxy]benzen trihydroohloridu2,3-diamino-1- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] benzene trihydro chloride
b) 4- [2-hydroxy-3-/3,4-dimetoxyfenetylamino/propoxy]-7-metyl-benzimidazol-hydrochlorid 20 zb) 4- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -7-methylbenzimidazole hydrochloride 20 z
2.3- di amino-1- [2-hydroxy-3-/3,4-dimetoxyfenetylamino/propoxy]-4-metyl-benzen-trihydrochloridu2,3-diamino-1- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -4-methylbenzene trihydrochloride
o) 4-(2-hydroxy-3-[2-/2-hydroxyfenoxy/etylamino]propoxy) -7-metyl-benzimidazol-hydrochlorid z . 92o) 4- (2-hydroxy-3- [2- (2-hydroxyphenoxy / ethylamino) propoxy) -7-methylbenzimidazole hydrochloride z. 92
2,3-di amino-1 -(2-hydroxy-3-[2-/2-hydroxyfenoxy/etylamino]propoxy)-4-metylbenzen-trihydrochloridu2,3-di amino-1- (2-hydroxy-3- [2- / 2-hydroxyphenoxy / ethylamino] propoxy) -4-methylbenzene trihydrochloride
d) 6,7-dimetyl-4-(2-hydroxy-3-[2-/2-metylfenoxy/etylamino]propoxy)benzimidazol-hýdroohlorid z 17d) 6,7-dimethyl-4- (2-hydroxy-3- [2- (2-methylphenoxy / ethylamino) propoxy) benzimidazole dihydrochloride of 17
2,3-diamino-4,5-dimetyl-1-(2-hydroxy-3-[2-/2-metylfenoxy/etylamino]propoxy)benzen-trihydrochloridu2,3-diamino-4,5-dimethyl-1- (2-hydroxy-3- [2- (2-methylphenoxy / ethylamino) propoxy) benzene trihydrochloride
e) 4-(2-hydroxy-3-[2-/2-metoxyfenoxy/etylaraino]propoxy)-7-metyl-benzimidazol-hydrochlorid z 62e) 4- (2-hydroxy-3- [2- / 2-methoxyphenoxy / ethylaraino] propoxy) -7-methylbenzimidazole hydrochloride of 62
2,3-diamino-l-(2-hydroxy-3- [2-/2-metoxyfenoxy/etylamino]propoxy)-4-metylbenzen-trihydroohloridu2,3-diamino-1- (2-hydroxy-3- [2- / 2-methoxyphenoxy / ethylamino] propoxy) -4-methylbenzene-trihydro chloride
f) 4- (2-hydroxy-3- [2-/2-metoxyfenoxy/etylamino] propoxy)benzimidazol-hýdroohlorid z 17f) 4- (2-Hydroxy-3- [2- (2-methoxyphenoxy / ethylamino) propoxy) benzimidazole dihydrochloride from 17
2,3-di amino-1-{2-hydroxy-3-[2-/2-metoxyfenoxy/etylamino]propoxy)benzen-trihydrochloridu2,3-diamino-1- {2-hydroxy-3- [2- (2-methoxyphenoxy / ethylamino] propoxy) benzene trihydrochloride
255 až 256 (etanol)255 to 256 (ethanol)
254 až 256 (etanol/voda)254 to 256 (ethanol / water)
229 až 231 (voda)229 to 231 (water)
106 až 109 (etanol/octan)106 to 109 (ethanol / acetate)
219 až 221 (etanol/metanol)219 to 221 (ethanol / methanol)
115 až 118 (etanol)115 to 118 (ethanol)
g) 4-[2-hydroxy-3-/4-fenyl-2-butylamino/propoxy]benzimidazol-hýdroohlorid z 77 amorf.g) 4- [2-hydroxy-3- (4-phenyl-2-butylamino) propoxy] benzimidazole dihydrochloride from 77 amorph.
2,3-di amino-1- [2-hydroxy-3-/4-fenyl-2-butylamino/propoxy]benzen-trihydroohloridu pokračování tabulky2,3-diamino-1- [2-hydroxy-3- (4-phenyl-2-butylamino) propoxy] benzene trihydro chloride
Výtěžek Teplota tání °C % teorie (rozpouštědlo)Yield Melting point ° C% of theory (solvent)
OznačeniDesignation
h) 4-(2-hydroxy-3-/2-fenoxyetylamino/propoxy)benzimidazol-hydrochlorid _ 10 amorf.h) 4- (2-hydroxy-3- (2-phenoxyethylamino) propoxy) benzimidazole hydrochloride-10 amorph.
ZOF
2,3-diamino-1- (2-hydroxy-3-/2-fenoxyetylamino/propoxy) benzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- (2-phenoxyethylamino) propoxy) benzene trihydrochloride
i) 4- (2-hydroxy-3-benzo[b] -1,4-dioxan-2-yl-metylamino/propoxy)benzimidazol-hydrochlorid z 19(i) 4- (2-hydroxy-3-benzo [b] -1,4-dioxan-2-ylmethylamino / propoxy) benzimidazole hydrochloride from 19
2.3- diamino-1-(2-hydroxy-3-/benzo[b] -1 ,4-dioxan-2-yl-metylamino/propoxy)benzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- / benzo [b] -1,4-dioxan-2-ylmethylamino / propoxy) benzene trihydrochloride
j) 4-(2-hydroxy-3- [2-/2-metoxyfenoxy/propylamino] propoxy)benzimidazol-hydrochlorid z 59j) 4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) benzimidazole hydrochloride of 59
2.3- diamino-1- (2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino]propoxy)benzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) benzene trihydrochloride
105 až 107 (isopropanol/metanol)105 to 107 (isopropanol / methanol)
115 až 118 (etanol)115 to 118 (ethanol)
Příklad 3Example 3
4- [2-hydroxy-3-/3,4-dimetoxy-fenetylamino/propoxy]-2,7-dimetyl-benzimidazol-hydrochlorid4- [2-hydroxy-3- (3,4-dimethoxy-phenethylamino / propoxy) -2,7-dimethyl-benzimidazole hydrochloride
14,6 g 2,3-diaaino-1-[2-hydroxy-3-/3,4-dimetoxyfenetylamino/propoxy]-4-metylbenzen-trihydrochloridu se zahřívá 3 hodiny pod zpětným chladičem v 50 ml ledové kyseliny octové Zjasní se aktivním uhlím a úplně se zahustí. Zbytek se vaří 2 hodiny pod zpětným chladičem ve 40 ml 2H kyseliny solné a zahustí se do sucha. Čistí se na silikagelovém sloupci směsi chloroform/metanol 8:2 jako eluens a krystaluje ze 100 ml etanolu 2,2 g (19 % teorie) žádané sloučeniny o teplotě tání 167 až 169 °C.14.6 g of 2,3-diaaino-1- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -4-methylbenzene trihydrochloride are heated under reflux in 50 ml of glacial acetic acid for 3 hours. coal and thicken completely. The residue was refluxed in 40 ml of 2H hydrochloric acid for 2 hours and concentrated to dryness. Purified on a silica gel column with chloroform / methanol 8: 2 as eluent and crystallized from 100 ml of ethanol. 2.2 g (19% of theory) of the title compound, m.p. 167-169 ° C.
Diamin použitý jako výchozí látka se získá následujícím způsobem.The diamine used as starting material is obtained as follows.
26,0 g N-benzyl-3,4-dimetoxy-fenetylaminu a 24,3 g 2,3-dinitro-1-/2,3-epoxy-propoxy/-4-metylbenzenu se vaří 4 hodiny pod zpětným chladičem ve 300 ml etanolu. Reakční směs se zředí 300 ml etanolu a hydrogenuje se při 50 °C a tlaku 3 MPa za použití 7,0 g 10% paládia na uhlí. Katalyzátor se odstraní, okyselí se 211 kyselinou chlorovodíkovou a po zahuštění se získá amorfní diaminová sůl.26.0 g of N-benzyl-3,4-dimethoxyphenethylamine and 24.3 g of 2,3-dinitro-1- (2,3-epoxy-propoxy) -4-methylbenzene are refluxed for 4 hours at 300 ° C. ml of ethanol. The reaction mixture was diluted with 300 mL of ethanol and hydrogenated at 50 ° C and 3 MPa using 7.0 g of 10% palladium on carbon. The catalyst was removed, acidified with 211 hydrochloric acid and concentrated to give the amorphous diamine salt.
Příklad 4Example 4
Analogicky podle příkladu 3 se získá z kyseliny octové a příslužného substituovaného 1-propoxy-2,3-diaminobenzenového derivátu:Analogously to Example 3, the following is obtained from acetic acid and the corresponding substituted 1-propoxy-2,3-diaminobenzene derivative:
OznačeníDesignation
a) 4-(2-hydřoxy-3-[2-/2-propoxyfenoxy/etylamino]propoxy)-2,7-dimetyl-benzimidazol-hydrochlorid z 44a) 4- (2-Hydroxy-3- [2- (2-propoxyphenoxy / ethylamino) propoxy) -2,7-dimethyl-benzimidazole hydrochloride from 44
2,3-diamino-4-metyl-1- (2-hydroxy-3-[2-/2-propoxy-f enoxy/etylamino] propoxy)benzen-trihydrochloridu2,3-diamino-4-methyl-1- (2-hydroxy-3- [2- / 2-propoxy-phenoxy / ethylamino] propoxy) benzene trihydrochloride
143 až 145 (alkohol/octan)143 to 145 (alcohol / acetate)
Výtěžek Teplota tání °C % teorie (rozpouštědlo) pokračování tabulkyYield Melting point ° C% of theory (solvent) continued table
pokračování tabulkycontinued table
Výtěžek Teplota tání °C % teorie (rozpouštědlo)Yield Melting point ° C% of theory (solvent)
OznačeníDesignation
d) 4-(2-hydroxy-3-[2-/2-hydroxyfenoxy/etylamino]propoxy)benzotriazol-hydrochlorid z 14d) 4- (2-hydroxy-3- [2- / 2-hydroxyphenoxy / ethylamino] propoxy) benzotriazole hydrochloride from 14
2,3-diamino-1- (2-hy droxy-3-[2-/2-hydroxyfenoxy/etylamino]propoxy)benzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- / 2-hydroxyphenoxy / ethylamino] propoxy) benzene trihydrochloride
200 až 203 (etanol/metanol)200 to 203 (ethanol / methanol)
e) 4-[2-hydroxy-3-/2-metoxy-fenetylamino/propoxy]benzotriazol-hydrochlorid ze) 4- [2-hydroxy-3- (2-methoxy-phenethylamino / propoxy) -benzotriazole hydrochloride
2,3-diamino-1 -[2-hydroxy-3-/2-metoxy-fenetyl -amino/propoxy]benzen-trihydrochloridu2,3-diamino-1- [2-hydroxy-3- (2-methoxy-phenethyl-amino / propoxy) -benzene trihydrochloride
f) 4-(2-hydroxy-3-[2-/2-metoxy-fenoxy/propylaminojpropoxy)benzotriazol-hydrochlorid z 62 amorfníf) 4- (2-hydroxy-3- [2- (2-methoxy-phenoxy / propylamino) propoxy) benzotriazole hydrochloride of 62 amorphous
2,3-diamino-1 - (2-hydroxy-3- [2-/2-metoxy-f enoxy/propylamino] propoxy)benzen-trihydrochloridu . 82 až 85 (alkohol/octan)2,3-diamino-1- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy) benzene trihydrochloride. 82 to 85 (alcohol / acetate)
g) 4-(2-hydroxy-3- [2-/2-allyloxyfenoxy/propylamino]propoxy)benzotriazol-hydrochlorid , g až ,^g 2 (etanol/octan)g) 4- (2-hydroxy-3- [2- / 2-allyloxyfenoxy / propylamino] propoxy) benzotriazole hydrochloride, and g, g ^ 2 (ethanol / ethyl acetate)
2,3-diamino-1-(2-hydroxy-3- [2-/2-allyloxyfenoxy/propylamino]propoxy)benzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- / 2-allyloxyphenoxy / propylamino] propoxy) benzene trihydrochloride
Příklad 7Example 7
4- (2-hydroxy-3- [2-hydroxy-fenoxy/etylamino]propoxy)-6,7-cyklopenteno-benzimidazol4- (2-hydroxy-3- [2-hydroxy-phenoxy / ethylamino] propoxy) -6,7-cyclopenteno-benzimidazole
Směs 4,1 g (0,01 molu) 4,5-diamino-6-(2-hydroxy-3-[2-/2-hydroxy-fenoxy/etylaminoJpropoxy)indan-hydrochloridu a 35 ml formamidu se zahřívá 40 minut pod zpětným tokem, zahustí se, přidá se voda, extrahuje se metylénchloridem, extrakt se zahustí a roztírá se s octanem. Získá se 1,3 g žádané sloučeniny (34 % teorie) o teplotě táni 182 až 183 °C).A mixture of 4.1 g (0.01 mol) of 4,5-diamino-6- (2-hydroxy-3- [2- / 2-hydroxy-phenoxy / ethylamino] propoxy) indane hydrochloride and 35 ml of formamide is heated for 40 minutes under reflux, concentrate, add water, extract with methylene chloride, concentrate the extract and triturate with acetate. 1.3 g of the desired compound are obtained (34% of theory), melting point 182 DEG-183 DEG C.).
Přiklad 8Example 8
4-[2-hydroxy-3-/2-fenoxy-propylamino/propoxy]-6-metylindol-p-chlorbenzoát g 4- [2-hydroxy-3-/2-fenoxy-N-benzyl-propylamino/propoxy]-6-metylindolu se hydrogenuje ve 200 ml metanolu a 5 ml trietylaminu při teplotě místnosti a 0,1 MPa tlaku vodíku za použiti 2 g 10% paládia na uhlí, filtruje se, zahustí se, zbytek se rozpustí v 50 ml octanu a přidá se vypočítané množství kyseliny p-chlorbenzoové. Po odsátí a překryštelováni se získá 4,3 g 4-[2-hydroxy-3-/2-fenoxy-propylamino/propoxy]-6-metylindol-p-chlorbenzoátu o teplotě tání 134 až 136 °C (42 % teorie).4- [2-hydroxy-3- (2-phenoxy-propylamino / propoxy) -6-methylindole-p-chlorobenzoate g 4- [2-hydroxy-3- / 2-phenoxy-N-benzyl-propylamino / propoxy] - 6-methylindole is hydrogenated in 200 ml of methanol and 5 ml of triethylamine at room temperature and 1 bar of hydrogen pressure using 2 g of 10% palladium on carbon, filtered, concentrated, the residue is dissolved in 50 ml of acetate and the calculated amount of p-chlorobenzoic acid. After suctioning and recrystallization, 4.3 g of 4- [2-hydroxy-3- (2-phenoxy-propylamino) -propoxy] -6-methyl-indole-p-chloro-benzoate are obtained, m.p. 134-136 ° C (42% of theory).
227327 10227327 10
Příklad 9Example 9
Příklad 10Example 10
4- (2-hydroxy-3- [2-/3,4-dimetoxyf enyl/etylamino] propoxy) -6-hydroxymetylindol4- (2-hydroxy-3- [2- / 3,4-dimethoxyphenyl / ethylamino] propoxy) -6-hydroxymethylindole
K suspenzi 2,3 g hydridu lithno-hlinitého v 50 ml absolutního tetrahydrofuranu se přikape roztok 5,0 g 4-(2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etylamino]propoxy)6-metoxykarbonylindolu ve 150 ml absolutního tetrahydrofuranu, míchá se 12 hodin při teplotě místnosti, za chlazení se rozloží roztokem chloridu sodného a 10N hydroxidem sodným, filtruje se, promyje se tetrahydrofuranem a zahustí se. Zbytek se čistí na silikagelovém sloupci směsí metylénchloridu/metanol 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 slinutí 60 °C (51 % teorie).To a suspension of 2.3 g lithium aluminum hydride in 50 ml absolute tetrahydrofuran was added dropwise a solution of 5.0 g of 4- (2-hydroxy-3- [2- / 3,4-dimethoxyphenyl / ethylamino] propoxy) 6-methoxycarbonylindole in 150 ml. ml of absolute tetrahydrofuran, stirred for 12 hours at room temperature, quenched with brine and 10N sodium hydroxide with cooling, filtered, washed with tetrahydrofuran and concentrated. The residue was purified on a silica gel column with methylene chloride / methanol 9: 1. The base is precipitated with ether and filtered off with suction. 2.4 g of 4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) 6-hydroxymethylindole of sintering temperature of 60 DEG C. (51% of theory) are obtained.
PřikladliThey did
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-dimetoxyfenyl)etylemino]propoxy)indazolu se hydrogenuje v 700 ml metanolu a 22,4 ml koncentrované kyseliny chlorovodíkové za přítomnosti 2 g 10% palédia na uhlí. Po odsátí se zahustí, rozpustí se ve vodě, zalkalizuje se hydroxidem sodným a extrahuje se metylénchloridem. Organická fáze se zahustí, rozetře se s éterem a odsaje se. Získá se 9,1 g žádané sloučeniny o teplotě tání 118 až 119 °C (59 % teorie).19.1 g of 2-benzyl-4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylemino] propoxy) indazole is hydrogenated in 700 ml of methanol and 22.4 ml of concentrated hydrochloric acid in the presence of 2 g 10% palladium on coal. After suction, the mixture is concentrated, dissolved in water, basified with sodium hydroxide and extracted with methylene chloride. The organic phase is concentrated, triturated with ether and filtered off with suction. 9.1 g of the desired compound of melting point 118 DEG-119 DEG C. (59% of theory) are obtained.
Rozpuštěním v etanolu a přídavkem éteriekého roztoku kyseliny chlorovodíkové se získá hydrochlorid o teplotě tání 157 až 159 °C. Analogickým způsobem, jak popsáno výěe, se získá:Dissolution in ethanol and addition of ethereal hydrochloric acid gave the hydrochloride, m.p. 157-159 ° C. In an analogous manner as described above, it is obtained:
Výtěžek Teplota tání °C % teorie (rozpouštědlo) pokračování tabulkyYield Melting point ° C% of theory (solvent) continued table
OznačeníDesignation
Příklad 12Example 12
1-pivaloyl-4-(2-pivalyloxy-3- [2-/3,4-dimetoxyfenyl/etylamino]propoxy)indazol-hydrochlorid1-Pivaloyl-4- (2-pivalyloxy-3- [2- / 3,4-dimethoxyphenyl / ethylamino] propoxy) indazole hydrochloride
Směs 4,2 g 4-^2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etylamino]propoxy)indazol-hydrochloridu (příprava viz příklad 11), 4,2 ml anhydridu kyseliny pivalové a 35 ml kyseliny pivalové se míchá 50 až 60 hodin při 75 °C. Získaná pevná hmota se míchá s ligroinem, odsaje se a promyje ligroinem. Získá.se 4,1 g žádané sloučeniny o teplotě táni 155 až 158 °C (69 % teorie).A mixture of 4.2 g of 4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl / ethylamino) propoxy) indazole hydrochloride (preparation see Example 11), 4.2 ml of pivalic anhydride and 35 ml of pivalic acid is stirred at 75 ° C for 50 to 60 hours. The solid obtained is stirred with ligroin, filtered off with suction and washed with ligroin. 4.1 g of the title compound of melting point 155 DEG-158 DEG C. (69% of theory) are obtained.
Příklad 13Example 13
4-^2-pivaloyloxy-3- [2-/3,4-dimetoxyfenyl/etylamino]propoxy)indazol4- (2-pivaloyloxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole
4,0 g 1-pivaloyl-4-(2.-pivaloyloxy-3-[2-/3-dimetoxyfenyl/etylamino]propoxy)indazol-hydrochloridu (příprava viz příklad 12) se zahřívá 2,5 hodiny pod zpětným chladičem se 150 ml isopropylaminu. Zahustí se, rozpustí se v éteru, třepe se s IN hydroxidem sodným, a organická fáze se čistí ohromatograficky na silikagelovém sloupci (eluens, metylén chlorid : octan 1:1). Získá se 2,7 g žádané sloučeniny jako olej (85 % teorie).4.0 g of 1-pivaloyl-4- (2.-pivaloyloxy-3- [2- (3-dimethoxyphenyl / ethylamino) propoxy) indazole hydrochloride (preparation see Example 12) was heated at reflux for 150 hours. ml of isopropylamine. Concentrate, dissolve in ether, shake with 1N sodium hydroxide, and purify the organic phase by silica gel column chromatography (eluent, methylene chloride: acetate 1: 1). 2.7 g of the desired compound are obtained as an oil (85% of theory).
Příklad 14Example 14
4- ^2-hydroxy-3-[.2-/2-metoxyfenoxy/propylamino] propoxy) -,-formylindolinbenzoát4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) -, - formylindoline benzoate
6,7 g 4-^2-hydroxy-3-[2-/2-metoxyfenoxy/-N-benzylpropylamino]propoxy)-1-formylindoli nu se hydrogenuje ve 250 ml metanolu a 20 ml trietylaminu při teplotě místnosti a 0,1 KPa tlaku vodíku za použití 2 g 10% paládia na uhlí, filtruje se, zahustí se a zbytek se rozpustí v 50 ml octanu a přidá se ekvivalentní množství kyseliny benzoové. Po odsátí se zís ká 2,1 g 4-{2-hydroxy-3-[2-/2-metoxyfenoxy/propylamiho]propoxy)-1-formylindolinbenzoátu o teplotě tání 131 až ,33 °C (31 % teorie).6.7 g of 4- (2-hydroxy-3- [2- (2-methoxyphenoxy) -N-benzylpropylamino] propoxy) -1-formylindoline are hydrogenated in 250 ml of methanol and 20 ml of triethylamine at room temperature and 0.1 ml. To the hydrogen pressure, using 2 g of 10% palladium on carbon, filter, concentrate and dissolve the residue in 50 ml of acetate and add an equivalent amount of benzoic acid. After suctioning, 2.1 g of 4- {2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy] -1-formylindoline benzoate are obtained, m.p. 131 DEG-33 DEG C. (31% of theory).
Příklad 15Example 15
Analogickým způsobem, jak popsáno v příkladu 14, se získá:In an analogous manner to that described in Example 14, one obtains:
Výchozí látky potřebné pro přípravu předchozích sloučenin se připraví následujícím způsobem:The starting materials needed to prepare the foregoing compounds are prepared as follows:
4-/2.3-epoxvproDQxv/-1 -formyllndolin4- (2,3-epoxylproDQxv) -1-formylindoline
48,6 g 2-benzyloxy-6-nitrotoluenu se rozpustí ve 670 ml dimetylformamidu a přidá se 29,9 g paraformaldehydu a potom se přikape 200 ml ,N roztoku terc.butylátu draselného. Po hodinovém míchání při teplotě místnosti se rozmíchá ve 3 1 ledová 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 stupni.48.6 g of 2-benzyloxy-6-nitrotoluene are dissolved in 670 ml of dimethylformamide and 29.9 g of paraformaldehyde are added, followed by the dropwise addition of 200 ml of a N solution of potassium tert-butylate. 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 product is used as crude in the next step.
g 2-benzyloxy-6-nitrofenyletanolu se rozpustí v 500 ml bezvodého pyridinu a za 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 a sušení se získá 74 g 2-/2-benzyloxy/-6-nitrofenyl/etylesteru kyseliny p-toluensulfonová 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, while cooling, 47.7 g of p-toluenesulfonyl chloride are added at about 10 ° C. The temperature is 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, washing with water and drying, 74 g of 2- (2-benzyloxy) -6-nitrophenyl) ethyl p-toluenesulfonic acid 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 etylénglykolmonometylesteru, přidá se 5 g 10% paládia na aktivním uhlí a hydrogenuje se při teplotě místnosti a 0,1 KPa tlaku vodíku. Po odstranění katalyzátoru ae zahustí a zbytek se formyluje směsí 227 ml anhydridu kyseliny octové a 91 ml Kyseliny mravenčí (podle C. W. Huffmanna, J. org. Chem. 23, 727 /1958/). Fo reakci se rozloží ledovou vodou a extrahuje se octanem. Organické féze ae neutralizuje, suěí síranem sodným a odpaří se ve vakuu. Zbytek ae smíchá s 320 ml epichlorhydrinu a přidá se 173 ml 2N roztoku metylátu sodného. Po mícháni přes noc se zahustí a zbytek se rozpustí ve vodě a octanu. Z octanového zbytku aa získá po rozetření s isopropylalkoholem a odsátím 15,8 g 4-/2,3-epoxypropoxy/-1-fornylindolinu o teplotě tání 88 až 89 °C (42 % teorie).g of 2- (2-benzyloxy-6-nitrophenyl) ethyl p-toluenesulfonic 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 0.1 KPa of hydrogen pressure. After removal of the catalyst and concentration, the residue is formulated with a mixture of 227 ml of acetic anhydride and 91 ml of formic acid (according to C. W. Huffmann, J. org. Chem. 23, 727 (1958)). The reaction was quenched with ice water and extracted with acetate. The organic phases are neutralized, dried over sodium sulphate and evaporated in vacuo. The residue ae is mixed with 320 ml of epichlorohydrin and 173 ml of 2N sodium methylate solution are added. After stirring overnight, it was concentrated and the residue was dissolved in water and acetate. From the acetate residue aa, after trituration with isopropyl alcohol and suction, 15.8 g of 4- (2,3-epoxypropoxy) -1-fornylindoline of melting point 88 DEG-89 DEG C. (42% of theory) are obtained.
Příklad 16Example 16
Byly připraveny tablety:Tablets were prepared:
Každá tableta obsahuje 10 mg 4-(2-hydroxy-3-t2-/2-metoxyfenoxy/etylamino propoxy -7-metyl-2-benzimidezolinon-hydrochloridu. Tablety byly připraveny podle následujícího složení :Each tablet contains 10 mg of 4- (2-hydroxy-3- t 2/2-methoxyphenoxy / propoxy ethylamino -7-methyl-2-benzimidezolinon hydrochloride. Tablets were prepared according to the following composition:
4-{2-hydroxy-3- [2-/2-metoxyfenoxy/etylamino] propoxy}-7-metyl-2-benzimidazolinon-hydroehlorid 10 g laktóza 80 g Škrob 29 g stearan hořečnatý 1 g4- {2-hydroxy-3- [2- / 2-methoxyphenoxy / ethylamino] propoxy} -7-methyl-2-benzimidazolinone hydrochloride 10 g lactose 80 g Starch 29 g magnesium stearate 1 g
Předchozí sloučenina se jemně rozmělní a smíchá se s 1aktózou a Škrobem. Směs se obvyklým způsobem granuluje. Ke granulátu se přidá stearan hořečnatý a směs se lisuje na 1 000 tablet o hmotnosti 0,12 g.The preceding compound is finely pulverized and mixed with 1actose and starch. The mixture is granulated in the usual manner. Magnesium stearate was added to the granulate and the mixture was compressed into 1000 tablets weighing 0.12 g.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS814336A CS227327B2 (en) | 1979-02-16 | 1981-06-10 | 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 |
| CS814336A CS227327B2 (en) | 1979-02-16 | 1981-06-10 | Method of preparing heterocyclic oxypropanolamine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS227327B2 true CS227327B2 (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 Before (2)
| 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 |
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 |
|---|---|
| CS227313B2 (en) | 1984-04-16 |
| CS227312B2 (en) | 1984-04-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4346093A (en) | Heterocyclic oxypropanolamine compounds and pharmaceutical compositions | |
| US4430343A (en) | Benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containing the same | |
| JP2738932B2 (en) | New benzimidazole derivatives active as antiulcer agents | |
| US4059621A (en) | Substituted benzamido propanolamines | |
| JPS6339875A (en) | Pyrimidine derivative | |
| DE69119013T2 (en) | Benzene, pyridine, pyrimidine derivative | |
| JPS5839673A (en) | Novel piperazinone, manufacture and cerebral function improver | |
| HRP930508A2 (en) | Difenilpropilamina process for the preparation of the novel enylpropylamine derivatives | |
| US4404384A (en) | O-[3-(4-Substituted-piperazin-1-yl)-2-hydroxypropyl]-hydroxylamines | |
| IE47139B1 (en) | 4-substituted-pyrazoles | |
| US4288442A (en) | Inhibiting adrenergic β-receptors with piperidinopropyl derivatives | |
| US4086353A (en) | Certain azolinylamino (azolidinylimino) indazoles | |
| EP0034116A2 (en) | N-(3-phenoxy-2-hydroxypropyl)benzimidazole-1-alkanamines | |
| CA1208643A (en) | 1,5-diphenyl-pyrazolin-3-one compounds, process and intermediates for preparation thereof and pharmaceutical compositions containing them | |
| US4537975A (en) | 1-Phenylindazol-3-one compounds | |
| CS227327B2 (en) | Method of preparing heterocyclic oxypropanolamine derivatives | |
| US4746661A (en) | Phenylpiperazine propyloxyquinolinones and methods for sedating and inhibiting aggression in livestock therewith | |
| US4479962A (en) | Indazoloxypropanolamine derivatives and use in combating, and for the prophylaxis of, cardiac and circulatory diseases | |
| US4087541A (en) | 2-(Aralkylaminoalkyl)phthalimidines | |
| CA2458808A1 (en) | Aminopyrrole compounds as antiinflammatory agents | |
| US4038407A (en) | Benzisothiazoline-1,1-dioxide derivatives, compositions and methods | |
| US5110816A (en) | 3-[2-(4-arylpiperazin-1-yl)ethoxy]-p-cymene, the method of preparing and composition thereof | |
| US4153711A (en) | 3-(3H-Pyrazol-3-one)-2-(disubstituted aminomethyl)indoles and pharmaceutical preparations | |
| US4160092A (en) | Quinazolinone oxides and their use as intermediates for pharmaceutical agents | |
| FR2551753A2 (en) | 1,2,3-Benzotriazin-4-ones, process for preparing them and medicinal products containing them |