CS227312B2 - Method of preparing heterocyclic oxypropanolamine derivatives - Google Patents
Method of preparing heterocyclic oxypropanolamine derivatives Download PDFInfo
- Publication number
- CS227312B2 CS227312B2 CS806604A CS660480A CS227312B2 CS 227312 B2 CS227312 B2 CS 227312B2 CS 806604 A CS806604 A CS 806604A CS 660480 A CS660480 A CS 660480A CS 227312 B2 CS227312 B2 CS 227312B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- propoxy
- hydroxy
- carbon atoms
- hydrogen
- group
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 4
- -1 amino, imidazolyl Chemical group 0.000 claims description 99
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004685 alkoxythiocarbonyl group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000005041 acyloxyalkyl 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
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 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 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 104
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 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 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 125000006308 propyl amino group Chemical group 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 4
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- MQTYQCAVOMQEFJ-UHFFFAOYSA-N benzene;trihydrochloride Chemical compound Cl.Cl.Cl.C1=CC=CC=C1 MQTYQCAVOMQEFJ-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYDMBYXBQYEOEL-UHFFFAOYSA-N 2,3-dihydro-1h-indene;hydrochloride Chemical compound Cl.C1=CC=C2CCCC2=C1 FYDMBYXBQYEOEL-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 125000005042 acyloxymethyl group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003610 charcoal Substances 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
- 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
- 239000008101 lactose Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000011282 treatment Methods 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
- 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
- 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 2
- JLLQXDVIQDVETJ-UHFFFAOYSA-N 4-nitro-6-(oxiran-2-ylmethoxy)-2,3-dihydro-1h-inden-5-amine Chemical compound C1=C2CCCC2=C([N+]([O-])=O)C(N)=C1OCC1CO1 JLLQXDVIQDVETJ-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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-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
- 239000000654 additive Substances 0.000 description 2
- 125000003277 amino 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
- 239000000872 buffer Substances 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
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 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
- 150000004820 halides Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 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
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 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
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- VXJHIRSMFQUIOU-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-(2-pyridin-4-ylethylamino)propan-2-ol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CNCCC1=CC=NC=C1 VXJHIRSMFQUIOU-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
- HDKZATQLGBCKGX-UHFFFAOYSA-N 1-(2,3-diamino-4-methylphenoxy)-3-[2-(3,4-dimethoxyphenyl)ethylamino]propan-2-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=C(C)C(N)=C1N HDKZATQLGBCKGX-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
- CDGZXOPYYJJFDF-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethylamino]propan-2-ol Chemical compound C=1C=C2OCCOC2=CC=1CCNCC(O)COC(C1=C2)=CC=CC1=NN2CC1=CC=CC=C1 CDGZXOPYYJJFDF-UHFFFAOYSA-N 0.000 description 1
- MBIRTCWMCVXLHZ-UHFFFAOYSA-N 1-(2-benzylindazol-4-yl)oxy-3-[2-(2-methoxyphenoxy)propylamino]propan-2-ol Chemical compound COC1=CC=CC=C1OC(C)CNCC(O)COC(C1=C2)=CC=CC1=NN2CC1=CC=CC=C1 MBIRTCWMCVXLHZ-UHFFFAOYSA-N 0.000 description 1
- SFNAQQQOVQLMOK-UHFFFAOYSA-N 1-[(6,7-diamino-2,3-dihydro-1H-inden-5-yl)oxy]-3-[2-(3,4-dimethoxyphenyl)ethylamino]propan-2-ol hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCNCC(O)COC(C(=C1N)N)=CC2=C1CCC2 SFNAQQQOVQLMOK-UHFFFAOYSA-N 0.000 description 1
- LNCIABKZRSOYPQ-UHFFFAOYSA-N 1-[(6,7-diamino-2,3-dihydro-1h-inden-5-yl)oxy]-3-(2-phenoxypropylamino)propan-2-ol;hydrochloride Chemical compound Cl.C=1C=2CCCC=2C(N)=C(N)C=1OCC(O)CNCC(C)OC1=CC=CC=C1 LNCIABKZRSOYPQ-UHFFFAOYSA-N 0.000 description 1
- FNLPDAMBRSRPRC-UHFFFAOYSA-N 1-[(6-methyl-1h-indol-4-yl)oxy]-3-[(2-phenoxy-4-phenylbutyl)amino]propan-2-ol Chemical compound C=12C=CNC2=CC(C)=CC=1OCC(O)CNCC(OC=1C=CC=CC=1)CCC1=CC=CC=C1 FNLPDAMBRSRPRC-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
- 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
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-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
- 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
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 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
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- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
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- 239000005711 Benzoic acid Substances 0.000 description 1
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- 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
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- YRQQAXUMUDNQEW-UHFFFAOYSA-N benzoic acid;1-[3-(3,4-dimethoxyphenyl)propylamino]-3-(1h-indazol-4-yloxy)propan-2-ol Chemical compound OC(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CCCNCC(O)COC1=CC=CC2=C1C=NN2 YRQQAXUMUDNQEW-UHFFFAOYSA-N 0.000 description 1
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- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
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- 230000036772 blood pressure Effects 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
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- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
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- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
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- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 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
- 235000001055 magnesium Nutrition 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 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
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká způsobů přípravy heterocyklických oxypropanolaminových derivátů obecného vzorce IThe invention relates to processes 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,R1 is hydrogen, C1-C6 alkyl, benzyl or C1-C8 alkanoyl,
R2 a R^, které mohou být stejné nebo rozdílné, znamenají vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, hydroxyelkylovou skupinu s 1 až 4 atomy uhlíku, alkoxykarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku nebo elkanoyloxyalkylovou skupinu s 1 až 8 atomy uhlíku v alkylových zbytcích nebo společně alkylenový zbytek se 3 ež 4 atomy uhlíku,R 2 and R, which may be identical or different, represent hydrogen, alkyl having 1 to 6 carbon atoms, hydroxyelkylovou group having 1 to 4 carbon atoms, alkoxycarbonyl having 1-2 carbon atoms in the alkyl moiety or elkanoyloxyalkylovou group 1 up to 8 carbon atoms in the alkyl radicals or together an alkylene radical having from 3 to 4 carbon atoms,
R^ znamená vodík, alkanoylovou skupinu s 1 ež 8 atomy uhlíku nebo benzoylovou skupinu,R1 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 ež 6 atomy uhlíku,R 8 is hydrogen or C 1 -C 6 alkyl,
Ηγ znamená vodík, hydroxylovou skupinu nebo alkylovou skupinu s 1 až 6 atomy uhlíku,Ηγ represents hydrogen, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms,
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 a R,o které mohou být stejné nebo rozdílné, znamenají vodík, halogen, hydroxylovouR g, R g and R, which may be identical or different, represent hydrogen, halogen, hydroxy,
227312.227312.
skupinu, alkenoylovou skupinu s 1 až 8 atomy uhlíku, alkylovou skupinu s 1 až 6 atomy uhlíku, alkenylovou skupinu β 1 ež 6 atomy uhlíku, alkoxyskupinu s 1 ež 6 atomy uhlíku, benzyloxyskupinu, allyloxyskuplnu, alkyltbioskupinu a 1 ež 6 atomy uhlíku, aminokarbonylovou skupinu, eainoaulfonylovou skupinu, alkenoylaminoskupinu s 1 až 8 atomy uhlíku, nebo Rg a Rg znamenají společně elkylendioxyskupinu s 1 až 2 atomy uhlíku nebo Rg společně s R? znamená taká -CHg-O-skupinu eC 1 -C 8 alkenoyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, benzyloxy, allyloxy, C 1 -C 6 alkylthio, C 1 -C 6 aminocarbonyl or C 1 -C 8 alkenoylamino, or R 8 and R 8 together represent C 1 -C 2 alkylenedioxy or R 8 together with R 6; represents such a -CHg-O-group e
A znamená skupinu Χ,-ϊ,, ve která X, představuje metylenový nebo -NR,,-zbytek, přičemžA represents a group Χ, -ϊ ,, in which X, represents a methylene or -NR ,, - residue, wherein
R, , značí vodík nebo alkylovou skupinu s 1 až 6 atomy uhlíku, a Y, představuje metylénový zbytek nebo skupinu /c=>Q, přičemž Q značí kyslík nebo síru, přičemž pro případ, že Q znamená atom kyslíku a Z valenční vazbu, nebo pro případ, že Χ,-ϊ, představuje -NR,,-C=O-akupinu a Z atom kyslíku nebo valenční vazbu nemohou být buS obe zbytky Rg e Rj současně atom vodíku nebo R? e Rg musí dohromady tvořit -CHg-O-můstek, a jejich farmakologicky vhodných solí.R1 is hydrogen or C1-C6alkyl, and Y is methylene or (c => Q), wherein Q is oxygen or sulfur, and when Q is oxygen and Z is a valence bond, or in case Χ, -ϊ, represents -NR ,, - C = O- and Z is an oxygen atom or a valence bond, either Rg and Rj cannot be hydrogen or R? Rg must together form a -CHg-O-bridge, and their pharmacologically acceptable salts.
Protože mejí sloučeniny vzorce I asymetrické atomy uhlíku, jsou déle předmětem vynélezu opticky aktivní formy a racemické směsi těchto sloučenin.Since the compounds of formula I have asymmetric carbon atoms, they have long been subject to an optically active form and racemic mixtures of these compounds.
Sloučeniny vzorce I a jejich farmakologicky vhodné soli mají při nepatrné toxicitě výrazná vasodilatsční vlastnosti, které se projevují v podstatě při snižování krevního tlaku, kromě toho brzdí adrenergické beta-receptory. Sloučeniny podle vynélezu jsou proto vhodné obzvláště k léčení a profylaxi srdečních a oběhových onemocnění.In addition, the compounds of formula I and their pharmacologically acceptable salts exhibit, at low toxicity, marked vasodilatory properties which manifest themselves essentially in the lowering of blood pressure, and in addition inhibit the adrenergic beta-receptors. The compounds according to 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 a 27 00 193 jsou popsány a nárokovány sloučeniny podobné struktury a účinku. Změnou heterocyklické fenolové části a aminopropoxy-postranního řetězce bylo docíleno překvapujícího zlepšení účinku.German Offenlegungsschrift 19 48 507, 22 30 426, 26 19 164, 26 51 574 and 27 00 193 disclose and claim compounds of similar structure and activity. By altering the heterocyclic phenol moiety and the aminopropoxy side chain, a surprising improvement was achieved.
Pod alkylovou skupinou substituentů R,, 82» R3> R5> a6> R7> R9> R10> R11 8 R12 se rozumí přímé nebo rozvětvené skupiny s 1 až 6, s výhodou a 1 až 4 atomy uhlíku, jako například metyl, etyl, propyl, lsopropyl, butyl, isobutyl, terč. butyl nebo n-hexyl. Obzvláště věak přichází v úvahu metylová nebo etylová skupina. Alkylenový zbytek případně vytvořený společně substituenty Rg s R^ mé 3 až 4, s výhodou 3 atomy uhlíku.Under the alkyl substituents R ,, 82 »R 3> R 5> 6> R 7> R 9> R 10> R 11 R 12 8 means a straight or branched group having 1-6, and preferably 1-4 carbon carbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl or n-hexyl. Especially methyl or ethyl is particularly suitable. An alkylene radical optionally formed together with the substituents R 8 with R 6 of from 3 to 4, preferably 3 carbon atoms.
Hydroxyalkylové skupiny substituentů Rg a R3 obsahují 1 až 4 atomy uhlíku, výhodné je 2-hydroxyetylové a hydroxymetylové skupina.Hydroxyalkyl groups of substituents R 8 and R 3 contain 1 to 4 carbon atoms, 2-hydroxyethyl and hydroxymethyl groups are preferred.
Alkoxyskuplny substituentů Rg, Rg a R,θ obsahují 1 až 6, s výhodou 1 až 4 atomy Uhlíku, jako například metoxy-, etoxy-, propoxy-, butoxy- nebo pentoxyskupina. Výhodné je metoxy-, etoxy- a propoxy-skuplna.The alkoxy groups of the substituents R 8, R 8 and R 10 contain from 1 to 6, preferably from 1 to 4, carbon atoms, such as, for example, methoxy, ethoxy, propoxy, butoxy or pentoxy. Preference is given to methoxy, ethoxy and propoxy groups.
Alkylthloakuplny substituentů Rg, Rg a Η,θ jsou skupiny s 1 až 6, s výhodou 1 až 4 atomy uhlíku. Výhodný je metylmerkepto zbytek.The alkylthioalkyl substituents R 8, R 8 and Η, θ are groups having 1 to 6, preferably 1 to 4, carbon atoms. Methylmerkepto is preferred.
Alkanoylové skupiny substituentů R,, R4, Rg, Rg a R,o a alkanoylové část alkanoyloxyalkyloVé skupiny v definici substituentů Rg e R^ a alkenoylaminoskupine substituentů Rg,Alkanoyl groups, the substituents R ,, R4, Rg, Rg and R, o and the alkanoyl part alkanoyloxyalkyl groups in the definition of substituents R g, and R e alkenoylamino Rg,
Rg a «10 obsahují 1 až 8,s výhodou 1 až 5 atomů uhlíku, přičemž jejich alkylové skupiny nohou hýt přímé, rozvětvené nebo cyklické. Výhodný je formylový, acetylový nebo piveloylový zbytek. Jako alkanoyloxyalkylové skupiny jsou obzvláště výhodné alkanoyloxymetylové skupiny.R 8 and C 10 contain 1 to 8, preferably 1 to 5 carbon atoms, wherein their alkyl groups can be straight, branched or cyclic. A formyl, acetyl or piveloyl residue is preferred. Particularly preferred alkanoyloxyalkyl groups are alkanoyloxymethyl groups.
Jako alkylsndloxyskupina společně vytvořená substituenty Rg a Rg přichází s výhodou v úvahu metylén- a etylendioxyskupina.Suitable alkyl-indoxy groups together formed by Rg and Rg are preferably methylene- and ethylenedioxy.
Označení A v obecném vzorci 1 má obzvláště význam, že jako heterocykly se rozumí benz imldazolinon-2, benzialdazolinthlon-2, benzimidazol, benztriazol, indol, indolin a indazolThe designation A in formula 1 is of particular importance that heterocycles are benzimidazolinone-2, benzialdazolinthlon-2, benzimidazole, benztriazole, indole, indoline and indazole
Pod halogene· ae rozumí podle vynálezu fluor, chlor, brom a jod, obzvláště fluor, chlor a hro·.Halogenates according to the invention are fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.
Příprava nových sloučenin obecného vzorce I se vyznačuje tlm, že. se nechá reagovat sloučenina obecného vzorce II or4 ,r8 The preparation of the novel compounds of the formula I is characterized in that:. reacting a compound of formula II or 4 , r 8
O-CH5-CH-CH7—N—CH—CH—Z - (Arj-Rq i IIIO-CH5-CH-CH7-N-CH-CH-Z- (Arj-Rq III)
R3-fVXH R5 R® R? R10 r2 r1.R 3 -fV XH R 5 R ® R? R 10 r 2 r 1 .
(II) kde Sp Sg· B3> 84» ®5> fi6> Βγ, ^g· H,o’ z * mají výše uvedený význam a X má význam uvedený výše pro X,, ae sloučeninou obecného vzorce III(II) wherein Sp Sg · B 3> 84 ®5 fi 5 fi 6 Βγ, g g · H , o ' z have the above meaning and X has the meaning given above for X 1 and e with a compound of formula III
kde If mé výše uvedený význam, Lj znamená atom vodíku, hydroxylovou skupinu nebo reaktivní zbytek jako chlor nebo brom, eminoskupinu, imidazolylovou skupinu, alkoxyskupinu s 1 až 6 atomy uhlíku, fenoxyskupinu, merkaptoskupinu a alkoxythiokarbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku a L2 znamená atom vodíku nebo reaktivní zbytek jako chlor nebo brom, aainoskupinu, imidazolylovou skupinu, alkoxyskupinu s 1 až 6 atomy uhlíku, fenoxyskupinu, merkaptoskupinu a alkoxythíokerbonylovou skupinu s 1 až 2 atomy uhlíku v alkylovém zbytku, a vzniklý produkt se cyklizuje, případné se dodatečně v získané sloučenině obecného vzorce I převede jeden ze zbytků R,, S2, Hj, 84, 85, Bg, Sg, R10 nebo Bf2 obvyklým způsobem ne jiný definicí definovaný zbytek fif, R2, B-j, B^, Rg, Sg, Rg, fl1Q nebo Rf2 a získané sloučeniny-se případně přeašní na farmakologický vhodné soli,wherein If I is as defined above, L 1 is a hydrogen atom, a hydroxyl group, or a reactive radical such as chlorine or bromine, an amino group, an imidazolyl group, an alkoxy group having 1 to 6 carbon atoms, a phenoxy group, a mercapto group and an alkoxythiocarbonyl group having 1 to 2 carbon atoms. and L 2 represents a hydrogen atom or a reactive radical such as chlorine or bromine, an amino group, an imidazolyl group, an alkoxy group having 1 to 6 carbon atoms, a phenoxy group, a mercapto group and an alkoxythiocarbonyl group having 1 to 2 carbon atoms in the alkyl radical; additionally in the resulting compound of formula I into one of the radicals R ,, S 2, Hj, 84, 85, Bg, Sg, R10 or BF 2 in the usual manner no different definitions defined FIF radical, R 2, Bj, B ' Rg Sg Rg fl 1Q or R 2 and the obtained compound is optionally-přeašní to pharmacologically acceptable salts,
Reaktivní zbytky T ve sloučeninách vzorce III značí věechny zbytky, které se mohou nukleofllně substituovat. Takovými zbytky jsou s výhodou atomy halogenu, jako chlor, nebo brom, amino-, imidažolylové, nízké alkoxy-, nízké ecyloxy-, fenoxy-, merkaptoakupina a nízké alkoxy thiokerbony1ové skupiny; například se mohou jako sloučeniny obecného vzorce III použít karbonylhalogenidy, močovina, Ν,Ν'-karbonyldiimldezol, a pro případ, že Q znamená síru, thlokarbonylhalogenldy, thiomočovina nebo také xantogenéty. Sloučeniny obecného vzorce III ae mohou také připravit ln šitu z jiných sloučenin, například sirouhlíku v alkalickém roztoku, v reakčním roztoku.The reactive T moieties in the compounds of formula III denote any moieties which can be nucleophilically substituted. Such radicals are preferably halogen atoms such as chlorine or bromine, amino, imidazolyl, low alkoxy, low ecyloxy, phenoxy, mercaptoacid and low alkoxy thiocarbonyl groups; for example, carbonyl halides, urea, Ν, Ν'-carbonyldiimldezole and, in the case where Q is sulfur, thlokarbonyl halides, thiourea or xanthenes, can be used as compounds of the formula III. Compounds of formula (III) and (e) may also prepare 1n sieve from other compounds, such as carbon disulfide in an alkaline solution, in the reaction solution.
Způsob podle vynálezu se účelně provádí v rozpouštědle inertním ze reakčních podmínek, například ve vodš, metanolu, etanolu. n-butanolu, dioxanu, dimetylformamidu nebo hexametyl. triamidu kyseliny fosforečné, případně za přítomnosti činidla vázajícího kyselinu. Beakce se může také provádět smícháním reakčních složek bez rozpouštědle. Reakce probíhá při teplotě místnosti nebo při zahřívání, případně v atmosféře ochranného plynu.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 hexamethyl. of a phosphoric acid triamide, 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 under a protective gas atmosphere.
Výchozí sloučeniny použité ve způsobech podle vynálezu jsou zpravidla sloučeniny znémé 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 in the literature. The novel compounds are generally obtained analogously to the methods described for the preparation of these known compounds.
Jako případně dodatečně prováděné přeměna jednoho ze substituentů Ε,, R2, R^, R^, Rg, Rg, Rg, RfQ nebo Rf2 ve sloučeninách obecného vzorce I ne jiný, definicí definovaný zbytek Rf , R2, B^, R^, Rg, Rg, Rg, RfQ nebo R,2 přichází například v úvahu dodatečné acylece CH-skupiny na alkanoyloxy- nebo aroyloxyskupinu, redukce alkoxykerbonylové skupiny na hydro xymetylový zbytek, hydrolýze alkanoyloxymetylové skupiny na hydroxymetylový zbytel^ redukce alkanoyloxymetylové skupiny na metylové substituenty nebo odštěpení benzylové skupiny.As the optionally additionally carried out by conversion of one substituent Ε ,, R 2, R, R, Rg, Rg, Rg, Rf Q or R 2 in compounds of formula I, not the other, the definition defined by the radical R f, R 2, B ^ R R 2, R 8, R 8, R 8, R 8, R 8, R 8 or R 12 are, for example, additional acylation of the CH group to alkanoyloxy or aroyloxy, reduction of alkoxycarbonyl to hydroxymethyl, hydrolysis of alkanoyloxymethyl to hydroxymethyl cleavage of the benzyl group.
Esterifikace hydroxylové skupiny pro -OR^ se může provádět obvyklým způsobem reekcí s helogenidem nebo anhydridem kyseliny, případně za přítomnosti činidla vázajícího kyselinu, jako například pyridinu nebo trietylaminu.The esterification of the hydroxyl group for -OR 4 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 1, ve kterém Rg a/nebo R^ představuje alkoxykerbonylovou nebo elkanoyloxymetylovou skupinu, na sloučeniny vzorce I, ve kterém Rg e/nebo R-j představuje hydroxymetylový nebo metylový substituent, se provádí účelně pomocí komplexních hydridů kovu, jako například hydridu lithno-hlinitého, nebo katalytickou hydrogenaci za přítomnosti vzácného kovu nebo Raneyova niklu Jako katalyzátoru.Optionally, the reduction of compounds of formula I in which R8 and / or R1 represents an alkoxycarbonyl or elkanoyloxymethyl group to compounds of formula I in which R8 and / or R1 represents a hydroxymethyl or methyl substituent is conveniently carried out by complex metal hydrides such as lithium aluminum hydride, or catalytic hydrogenation in the presence of a noble metal or Raney nickel catalyst.
Hydrolýza alkanoyloxymetylových skupin Rg a/nebo R^ ve sloučeninách obecného vzorce I na hydroxymatylové zbytky Rg a/nebo R^, se může provádět známým způsobem v kyselám nebo alkalickém prostředí.The hydrolysis of the alkanoyloxymethyl groups R 8 and / or R 8 in the compounds of the formula I into the hydroxymatyl radicals R 8 and / or R 8 can be carried out in known manner in an acidic or alkaline medium.
Odštěpení benzylové skupiny pro R, e nebo obsažené v Rg, Rg, H,q, se provádí na? příklad hydrogenaci za přítomnosti vzácného kovu jako katalyzátoru.The cleavage of the benzyl group for R, e or contained in Rg, Rg, H, q, is carried out at? hydrogenation in the presence of a noble metal catalyst.
Pro převedení sloučenin vzorce I na fermakologicky vhodná soli se nechají tyto reagovat s výhodou v organickém rozpouětědle s anorganickou nebo organickou kyselinou, například kyselinou chlorovodíkovou, bromovodíkovou, fosforečnou, sírovou, octovou, citrónovou, aaleinovou nebo benzoovou.In order to convert the compounds of formula I into phermacologically acceptable salts, they are preferably reacted in an organic solvent with an inorganic or organic acid, for example hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, citric, aaleinic or benzoic acids.
Sloučeniny obecného vzorce I podle vynélezu se mohou získat ve formě racemické směsi. Dělení racemátu má opticky aktivní formy se provádí známými způsoby přes doastereomerní soli. Jako aktivní kyseliny se mohou použít kyselina vinná, jablečné, kafrová a kafrsulfonová.The compounds of the formula I according to the invention can be obtained in the form of a racemic mixture. Separation of the racemate has optically active forms by known methods via doastereomeric salts. 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 příslušných pomocných látek ve vodě nebo v oleji, jako například 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 shaped, for example, as tablets or dragees or suspended or dissolved in water or in oil, such as olive oil .
Nové sloučeniny podle vynélezu vzorce I a jejich soli se mohou aplikovat v kapalná nebo pevné formě enterálně nebo perenterálně. Jeko injekční prostředí ee s výhodou použije voda, která obsahuje přísady obvyklá v injekčních roztocích jako stabilizační prostředek, látku usnadňující rozpouštění nebo pufr. Takovou přísadou je například vinanový nebo cltřenový pufr, etanol, komplexotvorná látka (jako etyléndiamintetreoctová kyselina a její netoxické soli), vysokomolekulární polymery (jako kapalný polyetylénoxid) k regulaci viskosity. Jako pevné nosiče přicházejí v úvahu škroby, laktoza, mannit, metylcelulóza, talek, vysoce dispersnl kyselina křemičitá, vysokomolekulární mastná kyseliny (jako kyselina stearová), želetlne, agar-agar, fosforečnan vápenatý, etearen hořečnatý, živočlSné tuky a pevné vysokomolekulární polymery (jeko polyetylénglykoly). Přípravky vhodné pro orální aplikaci mohou případně obsahovat chulové látky a sladidla.The novel compounds of the invention and their salts can be administered in liquid or solid form enterally or perenterally. Preferably, the injectable medium will use water which contains additives customary in injectable solutions as a stabilizing agent, solubilizer or buffer. Such an additive is, for example, tartrate or nitrate 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 starches, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium etearene, animal fats and solid high molecular polymers (e.g. 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 dalěích 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 účinná 0,5 ež 40 e a výhodou 1,0 až 20 mg/kg/den v jedné nebo více dávkách ze den, aby ae dosáhlo žádaných výsledků.The dose to be administered depends on the age, health and weight of the recipient, the severity of the disease, the type of concomitant concurrent treatment, 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 e, and preferably 1.0 to 20 mg / kg / day, is effective in one or more doses per day to achieve the desired results.
Kromě sloučenin uvedených v následujících příkladech jsou v rámci vynálezu dále výhodné následující sloučeniny:In addition to the compounds exemplified in the following examples, the following compounds are also preferred within the scope of the invention:
4-(2-hydroxy-3-(2-/2,6-dimetoxyřenoxy/etylemino]propoxy)-7-metyl-3-propyl-2-benzimid azollnon4- (2-hydroxy-3- (2- (2,6-dimethoxyphenoxy) ethylemino] propoxy) -7-methyl-3-propyl-2-benzimidazole
4-f2-hydroxy-3-[2-/2-allyloxyfanoxy/etylaminc]propoxy)-6-metylindol 4-(2-hydroxy-3-[2-/2-metylmerkaptofenoxy/e ty lamino]propoxy)-1-formylindolin 4-f2-hydroxy-3- [2-/2-sulfmmoylfenoxy/ety lamino] propoxy)-lndazol4- (2-hydroxy-3- [2- (2-allyloxyphanoxy / ethylamino) propoxy) -6-methylindole 4- (2-hydroxy-3- [2- (2-methylmercaptophenoxy) ethylamino] propoxy) -1- Formylindoline 4- (2-hydroxy-3- [2- (2-sulfmmoylphenoxy) ethylamino] propoxy) indazole
4-(2-hydroxy-3-[2-/3,4-etyléndioxyfenyl/etylamino] propoxy)indezol 4-(2-hydroxy-3- [2-/3,4,5-trlmetoxyfenyl/etylamino] propoxy)lndezol 4-f 2-hydroxy -3- [2-/3-metoxy-4-hydroxyf enyl/etylamino] propoxy) lndazol 4-f2-hydroxy-3-[2-/3-hydroxy-4-n-butoxyfenyl/etylamino] propoxy)indezol 4-f2-hydroxy-3- [2-/3,4-dlhydroxyf enyl/etylamino]propoxy)lndazol 4-f2-hydroxy-3- [3-/3,4-dimetoxyfenyl/propylamino] propoxy) lndazol 4-f 2-hydroxy-3-[2-/3-etoxy-4-metoxyf eny l/etylamino]propoxy)indazol 4-(2-hydroxy-3-[1-/3,4-dlmetoxyfenyl/propyl-2-amino] propoxy)indezol 1 -metyl-4-f 2-hydroxy- 3- [2-/3,4-dime toxyfenyl/etylamino] propoxy)lndazol 1-metyl-4-f2-hydroxy-3-[2- 2-/3,4-dimetoxyfenyl/etylamino]propoxy)indolin 4-f2-hydroxy-3-[2-/2-/2-metoxyfenylmerkapto/etylamino] propoxy)-)-formylindolin 4-f2-benzoyloxy-3-[2-/3,4-dime toxyfenyl/etylamino] propoxy)lndazol 4-f2-hydroxy-3-[,-/3,4-dihydroxyfenyl/-2-amino-1-propanol] propoxy)-6-metylindol4- (2-hydroxy-3- [2- / 3,4-ethylenedioxyphenyl / ethylamino] propoxy) indezole 4- (2-hydroxy-3- [2- / 3,4,5-trimethoxyphenyl / ethylamino] propoxy) indezole 4- (2-hydroxy-3- [2- / 3-methoxy-4-hydroxyphenyl / ethylamino] propoxy) indazole 4- [2-hydroxy-3- [2- / 3-hydroxy-4-n-butoxyphenyl] ethylamino [propoxy] indezole 4- (2-hydroxy-3- [2- / 3,4-dihydroxyphenyl / ethylamino] propoxy) indazole 4-f-hydroxy-3- [3- / 3,4-dimethoxyphenyl / propylamino] propoxy) Indazole 4- [2-hydroxy-3- [2- / 3-ethoxy-4-methoxyphenyl / ethylamino] propoxy] indazole 4- (2-hydroxy-3- [1- / 3,4-dimethoxyphenyl] propyl- 2-amino] propoxy) indezole 1-methyl-4- [2-hydroxy-3- [2- / 3,4-dimethoxyphenyl / ethylamino] propoxy] indazole 1-methyl-4- [2-hydroxy-3- [2] 2- (3,4-dimethoxyphenyl / ethylamino] propoxy) indoline 4- (2-hydroxy-3- [2- / 2- / 2-methoxyphenylmercapto / ethylamino] propoxy) -1-formylindoline 4- (2-benzoyloxy-3-) [2- (3,4-Dimethoxyphenyl / ethylamino] propoxy) indazole 4- [2-hydroxy-3 - [[1- (3,4-dihydroxyphenyl) -2-amino-1-propanol] propoxy] -6-methylindole
Následující příklady ukazují některá z četných variant přípravy, která se nohou použít k syntéze sloučenin podle vynálezu, aniž by omezovaly rozsah vynálezu.The following examples illustrate some of the numerous preparation variants that can be used to synthesize the compounds of the invention without limiting the scope of the invention.
Příklad 1Example 1
4-f2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino] propoxy)-7-metyl-2-benzimidazolinon-hydrochlorid4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) -7-methyl-2-benzimidazolinone hydrochloride
12,3 g 2,3-diamlno-l -(2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino]propoxy)-4-metylben zen-trlhydrochloridu se rozpustí v 500 ml vody. So tohoto roztoku se uvádí 45 minut při teplotě místnosti fosgen, propláchne se dusíkem a odsaje se. Krystalizát se překrystaluje ze 300 ml etanolu a 200 ml metanolu za přídavku aktivního uhlí. Získá se 5,0 g (46 * teorie) sloučeniny o teplotě tání 228 až 230 °C.12.3 g of 2,3-diamino-1- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy) -4-methylbenzenil hydrochloride are dissolved in 500 ml of water. Phosgene was added to this solution at room temperature for 45 minutes, purged with nitrogen and aspirated. The crystallizate was recrystallized from 300 ml of ethanol and 200 ml of methanol with the addition of activated carbon. 5.0 g (46% of theory) of the compound with a melting point of 228 DEG-230 DEG C. are obtained.
Potřebná výchozí sloučenina se získá následujícím způsobem: 30,5 g 2,3-dlnitro-1-/2, 3-epoxypropoxy/-4-metylbenzenu β 32,6 g N-benzyl-2-/2-metoxyfenoxy/propylaminu se vaří 3 hodiny pod zpětným chladičem v 500 ml etanolu. Reakční směs se hydrogenuje za použití 10 g 10% paládia ne uhlí v 1 litru etanolu při 50 °C a 4 KPa. Katalyzátor se odstraní, okyselí se 2N kyselinou chlorovodíkovou, zjasní se aktivním uhlím a zahustí se do suché. Získá se 59 g 2,3-diamino-1*f2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino propoxy)-4-metylbenzen—trihydrochloridu.The desired starting compound is obtained as follows: 30.5 g of 2,3-dlnitro-1- (2,3-epoxypropoxy) -4-methylbenzene β 32.6 g of N-benzyl-2- (2-methoxyphenoxy) propylamine is boiled 3 hours under reflux in 500 ml of ethanol. The reaction mixture is hydrogenated using 10 g of 10% palladium on carbon in 1 liter of ethanol at 50 ° C and 4 KPa. The catalyst was removed, acidified with 2N hydrochloric acid, brightened with charcoal and concentrated to dryness. 59 g of 2,3-diamino-1 * (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino propoxy) -4-methylbenzene trihydrochloride are obtained.
Příklad 2Example 2
Analogicky podle příkladu 1 se získá z fosgenu a přísluěně substituovaného 1-propóxy -2,3-dieminobenzenového derivátu:Analogously to Example 1, the following is obtained from phosgene and the correspondingly substituted 1-propoxy -2,3-dieminobenzene derivative:
Výtěžek Teplote ténl °C % teorie (rozpouštědlo)Yield Temp. ° C% of theory (solvent)
OznačeniDesignation
e)E)
b)(b)
4-[2-hydroxy-3-/3,4-dimetoxyfenetylemino/propoxy1-7-metyl-2-benzimidazolinon-hydroehiorld4- [2-hydroxy-3- (3,4-dimethoxyphenethylemino) propoxy-7-methyl-2-benzimidazolinone-hydroehiorld
ZOF
2,3-diamino-1-[2-hydroxy-3-/3,4-dimetoxyfenetylamino/propoxy]-4-metylbenzen-trihydrochiorldu2,3-diamino-1- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -4-methylbenzene trihydrochiorld
4-C2-hydroxy-3-[2-/2-hydroxyf enoxy/etylamino] propoxy)-7-aetyí-2-benzlmidazolinon-hydrochlorid4-C2-hydroxy-3- [2- (2-hydroxyphenoxy / ethylamino) propoxy) -7-ethyl-2-benzimidazolinone hydrochloride
204 až 206 (isopropenol/metanol)204 to 206 (isopropenol / methanol)
e)E)
d)(d)
e)E)
f)F)
g)G)
h)(h)
i)and)
2,3-diamino-1-(2-hydroxy-3-[2-/2-hydroxyfenoxy/atylamino] propoxý)-4-metylbenzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- (2-hydroxyphenoxy) atylamino] propoxy) -4-methylbenzene trihydrochloride
6,7-dimetyl-4-(2-hydroxy-3-C2-/2-metylfenoxy/etylaaino]propoxy)2-benzimlaazollnon-hydrc chlorid J z6,7-dimethyl-4- (2-hydroxy-3-C2- / 2-methylphenoxy / etylaaino] propoxy) 2-hydrc benzimlaazollnon chloride of J
2,3-diamino-4,5-dimetyl-1-(2-hydroxy-3-[2-/2aetylfenoxy/etylamino]propoxy)benzen-trlhydroehloridu2,3-Diamino-4,5-dimethyl-1- (2-hydroxy-3- [2- (2-ethylphenoxy / ethylamino) propoxy) benzenetrichloride
4-( 2-hydr oxy-3- [2-/2-metoxyfenoxy/ety lamino] propoxy)-7-aetyl-2-benziaidezolinon-hydroehlorid4- (2-Hydroxy-3- [2- (2-methoxyphenoxy / ethylamino) propoxy) -7-ethyl-2-benziaidezolinone hydrochloride
2,3-diamino-1-(2-hydroxy-3-[2-/2-metoxyfenoxy/etylamino] propoxy) -4-matylbanzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- / 2-methoxyphenoxy / ethylamino] propoxy) -4-methylbenzene trihydrochloride
4-[2-hydroxy-3-/benze [bl -1,4-dioxan-2-yl-metylamíno/pr opoxy] -2-benzimidezolinon-hydrochlorid4- [2-hydroxy-3- / benzo [b1,4-dioxan-2-ylmethylamino / propoxy] -2-benzimidezolinone hydrochloride
2.3- diamino-1-[2-tíydroxy-3-/benzo[b] -1,4-dioxan-2-yl-metylamino/propoxy]benzen-trihydrochloridu2,3-diamino-1- [2-thiydroxy-3- / benzo [b] -1,4-dioxan-2-ylmethylamino / propoxy] benzene trihydrochloride
4- [2-hydroxy-3-/2-fenoxyetylemino/propoxy]-7-metyl-2-benziaidezolinon-hydrochlorid z .4- [2-hydroxy-3- (2-phenoxyethylemino) propoxy] -7-methyl-2-benziaidezolinone hydrochloride z.
2.3- diemino-1-[2-hydroxy-3-/2-fenoxyetylamino/propoxy]-4-aetylbenzen-trihydrochloridu2,3-diemino-1- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] -4-ethylbenzene trihydrochloride
4-[2-hydroxy-3-/2-fenoxyetylaaino/propoxy]-6-metyl-2-benzimidazolinon hydrochlorid z .4- [2-hydroxy-3- (2-phenoxyethylaaino) propoxy] -6-methyl-2-benzimidazolinone hydrochloride z.
2.3- diamino-1-[2-hydroxy-3-/2-fenoxyetylamino/propoxy]-5-aetylbenzen-trihydroehloridu2,3-diamino-1- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] -5-ethylbenzene trihydro chloride
4-(2-hydroxy-3-[2-/2-aetoxyfenoxy/etylemino}propoxy)-6-metyI-2-benzimÍdazolinon-hydrochlorid z4- (2-hydroxy-3- [2- (2-aetoxyphenoxy) ethylemino} propoxy) -6-methyl-2-benzimidazolinone hydrochloride from
2.3- diamino-1-(2-hydroxy-3-[2-/2-metoxyfenoxy/etylamino]propoxy)-5-metylbenzen-trihydroehloridu2,3-diamino-1- (2-hydroxy-3- [2- (2-methoxyphenoxy / ethylamino) propoxy) -5-methylbenzene trihydro chloride
4- [2-hydroxy-3-/3.4-dimetoxyfenety lamino/propoxy] -6-metyl-2-benzimidazolinon-hydrochlorid z . /4- [2-hydroxy-3- (3,4-dimethoxyphenethylamino / propoxy) -6-methyl-2-benzimidazolinone hydrochloride z. /
2,3-diamino-1 - [2-hydroxy-3-/3,4-dimetoxyfene tylaaino/propoxy]-5-metyl-benzentrihydroehlorldu2,3-diamino-1- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -5-methyl-benzentrihydro-chloride
4-( 2-hydr oxy-3- [2-/2-allyloxyf enoxy /etylamino] propoxy)-7-metyl-2-benzimidazolinon-hydrochlorid z .4- (2-hydroxy-3- [2- / 2-allyloxyphenoxy / ethylamino] propoxy) -7-methyl-2-benzimidazolinone hydrochloride z.
2,3-diamino-1-(2-hydroxy-3- [2-/2-allyloxyfenoxy/etylamino]pr opoxy)-4-aetylbenzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- / 2-allyloxyphenoxy / ethylamino] propoxy) -4-ethylbenzene trihydrochloride
262 až 263 (me tenol/vode)262 to 263 (meol / water)
273 ež 274 (metenol/vode)273 to 274 (methenol / water)
202 až 203 (etenol/metenol)202 to 203 (ethenol / methenol)
231 až 233 (e tenol/ae tanol)231 to 233 (tenol / ae tanol)
250 ež 252 (etenol/metenol)250 to 252 (ethenol / methenol)
213 ež 215 (etenol)213 to 215 (ethenol)
260 ež 262 (etenol)260 to 262 (ethenol)
3)3)
Příklad 3Example 3
4-[2-hydr oxy-3-/3,4-dimetoxyfenety lamino/propoxy] -2-benzimidazolinthi on-hydrochlorid4- [2-Hydroxy-3- (3,4-dimethoxyphenethylamino / propoxy) -2-benzimidazolinedione hydrochloride
17,4 g 2,3-diamino-1 - [2-hydroxy-3-/3,4-dlmetoxyfenetylamino/propoxy] benzen-tri hydrochloridu se rozpustí v 450 ml chloroformu e 50 ml etanolu e při teplotě místnosti se přidá po kapkách 3,2 ml thiofoegenu ve 30 ml chloroformu. Po dvou hodinách se přidá aktivní uhlí a zahustí se do sucha, čistí se na silikagelovám sloupci (chloroform-metanol 8:2) a získá se 10 g (62 % teorie) jednotného produktu. Po rozpuštění v isopropanolu a přidání áterickáho roztoku kyseliny chlorovodíková se vyloučí octonem žádané sloučenina o teplotě tání 108 až 110 °C.17.4 g of 2,3-diamino-1- [2-hydroxy-3- (3,4-dimethoxyphenethylamino / propoxy) benzene trihydrochloride are dissolved in 450 ml of chloroform and 50 ml of ethanol are added dropwise at room temperature. 3.2 ml thiofoegen in 30 ml chloroform. After two hours, charcoal is added and concentrated to dryness, purified on a silica gel column (chloroform-methanol 8: 2) to give 10 g (62% of theory) of a uniform product. After dissolution in isopropanol and addition of an ethereal solution of hydrochloric acid, the desired compound, m.p.
PřikládáHe attaches
Analogiéky podle příkladu 3 se získá z thiofoegenu a přísluěně substituovaného 1-propoxy-2,3-diaminobenzoováho derivátu:The analogs of Example 3 are obtained from thiophoegene and the appropriately substituted 1-propoxy-2,3-diaminobenzoate derivative:
OznačeníDesignation
Výtěžek Teplote tání °C % teorie (rozpouštědlo)Yield Melting point ° C% of theory (solvent)
a) 4-[2-hydroxy-3-/3,4-dlmetoxyfenetylamino/propoxyj-7-metyl-2-benzJAldazolinthionhydrochlorid z r (a) 4- [2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -7-methyl-2-benzyl-aldazolethione hydrochloride from r
2.3- di amino-1-L2-hydr oxy-3-/3,4-dimetoxyfenetylamino/propoxy]-4-metylbenzentrihydrochloridu2,3-di amino-1-L2-hydroxy-3- (3,4-dimethoxyphenethylamino) propoxy] -4-methylbenzene trihydrochloride
b) 4-(2-hydroxy-3-[2-/metoxyfenoxy/propylamino] propoxy)-7-metyl-2-benzimidazolinthionbenzoét z 14b) 4- (2-Hydroxy-3- [2- (methoxyphenoxy / propylamino) propoxy) -7-methyl-2-benzimidazolin thionobenzoate of 14
2.3- diamino-1-(2-hydroxy-3- [2-/2-metoxyfenoxy/propylamino] propoxy)-4-metylbenzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) -4-methylbenzene trihydrochloride
c) 4-(2-hydroxy-3-[2-/2-metylfenoxy/etylamino]propoxy)-2-benzimidazolinthionhydrochlorid zc) 4- (2-hydroxy-3- [2- (2-methylphenoxy / ethylamino) propoxy) -2-benzimidazolinethione hydrochloride
2.3- diamino-1 -(2-hydroxy- 3- [2-/2-metylf enoxyA etylamino] propoxy) benzen-trihydrochloridu2,3-diamino-1- (2-hydroxy-3- [2- / 2-methylphenoxyA ethylamino] propoxy) benzene trihydrochloride
169 až 170 (etanoléter)169 to 170 (ethanol ether)
Příklad 5Example 5
4-(2-hydroxy-3-[2-/2-hydroxyfenoxy/etylamino] propoxy)-6,7-cyklopento-2-benzimidazolinÉ)n-hydrochlorid4- (2-hydroxy-3- [2- (2-hydroxyphenoxy / ethylamino) propoxy) -6,7-cyclopento-2-benzimidazoline) n-hydrochloride
Do roztoku 6,5 g (0,017 5 mol) 4,5-diemino-6-(2-hydroxy-3-[2-/2-hydroxyfenoxy/etylemino]propoxy)indan-hydrochloridu ve 250'ml vody a 100 ml tetrahydrofurenu se uvádí 1 hodinu fosgen, důkladně se propláchne dusíkem, filtruje se, sraženina se rozpustí vs zředěném hydroxidu sodném, promyje se metylénchloridem, vodné fáze se upraví na pH 7, extrahuje se metylénchloridem, zahustí se, rozpustí se v acetonu a éterickým roztokem kyseliny chlorovodíková se vysráží hydrochlorid. Získá se 2,8 g žédané sloučeniny (36 % teorie) jako amorfní soli o teplotě tání 145 ež 155 °C.To a solution of 6.5 g (0.017 5 mol) of 4,5-diemino-6- (2-hydroxy-3- [2- (2-hydroxyphenoxy) ethylemino] propoxy) indane hydrochloride in 250 ml of water and 100 ml of tetrahydrofuran after 1 hour of phosgene, flush thoroughly with nitrogen, filter, dissolve the precipitate in dilute sodium hydroxide, wash with methylene chloride, adjust the aqueous phases to pH 7, extract with methylene chloride, concentrate, dissolve in acetone and ethereal hydrochloric acid hydrochloride precipitated. 2.8 g of the desired compound (36% of theory) are obtained as an amorphous salt, m.p. 145-155 ° C.
Diaminosloučenine použité jako výchozí produkt se může připravit následujícím způsobem:The diamino compound used as the starting product can be prepared as follows:
Kondenzací 5-amino-6/2,3-epoxypropoxy/-4-nitroindenu a N-benzyl-2-/2-benzyloxyfenoxy/~ etylaminu se získá 5-amino-6-(3-[N-benzyl-2-/2-benzyloxyfenoxy/etyleminoJ-2-hydroxypropoxy)-4-nitroinden jeko olej;Condensation of 5-amino-6 (2,3-epoxypropoxy) -4-nitroindene and N-benzyl-2- (2-benzyloxyphenoxy) ethylamine gives 5-amino-6- (3- [N-benzyl-2-] 2-benzyloxyphenoxy / ethylemino-2-hydroxypropoxy) -4-nitroindene as an oil;
227 312227 312
Hydrogenaci a hydrogenolytickou debenzylací předchozí sloučeniny jeko hydrochloridu v me tanolickém roztoku ne 1096 palédiu na uhlí se získá 4,5-diamino-6-(2-hydroxy-3-[2-/2-hydroxy fenoxy/etylaminojpropoxy)indanhydrochlorid o teplotě tání 193 až 195 °C.Hydrogenation and hydrogenolytic debenzylation of the preceding compound as the hydrochloride in methanolic solution over 1096 palladium on carbon gave 4,5-diamino-6- (2-hydroxy-3- [2- / 2-hydroxyphenoxy / ethylamino] propoxy) indane hydrochloride, m.p. 193 to 195 ° C.
Příklad 6Example 6
4- ( 3- [2-/3,4-dimetoxyfenyl/etylemino] -2-hydroxypropoxy)-6,7-cyklopento-2-benzimidezolinon-hydroehlorid4- (3- [2- / 3,4-dimethoxyphenyl / ethylemino] -2-hydroxypropoxy) -6,7-cyclopento-2-benzimidezolinone hydrochloride
Analogicky podle způsobu popsaného v příkladu 1 se získá z fosgenu a 4,5-diamino-6-(3[2-/3,4-dimetoxyfenyl/-etylaminoJ-2-hydroxypropoxý)indan-hydrochloridu žádaná sloučenina jako hydrochlorid o teplotě tání 193 až 195 °C.Analogously to the method described in Example 1, the title compound as the hydrochloride of melting point 193 is obtained from phosgene and 4,5-diamino-6- (3- [2- (3,4-dimethoxyphenyl) -ethylamino] -2-hydroxypropoxy) indane hydrochloride. to 195 ° C.
Diaminosloučenina použitá jako výchozí produkt se může připravit následujícím způsobem:The diamino compound used as the starting product can be prepared as follows:
Reakcí 5-amino-6-/2,3-epoxypropoxy/-4-nitroindanu a 3,4-dlmetoxyfenetyleminu se získáReaction of 5-amino-6- (2,3-epoxypropoxy) -4-nitroindane and 3,4-dimethoxyphenethylemine gives
5- amino-6-(3-[2-/3,4-dimetoxyfenyl/etylamino]-2-hydroxypřopoxy)-4-nltroinden o teplotě tání 230 až 236 °C (jako hydrochlorid).5-amino-6- (3- [2- (3,4-dimethoxyphenyl) ethylamino] -2-hydroxypropoxy) -4-nitroindene, m.p. 230-236 ° C (as hydrochloride).
Hydrogenaci předchozí sloučeniny v metenollckém roztoku za použití kysličníku platlčitého se získá 4,5-diamino-6-(3-[2-/3,4-dimetoxyfenyl/etylamino]-2-hydroxypropoxy)lndan, který se izoluje jako amorfní hydrochlorid.Hydrogenation of the preceding compound in a methanol solution using platinum oxide gives 4,5-diamino-6- (3- [2- / 3,4-dimethoxyphenyl / ethylamino] -2-hydroxypropoxy) indane which is isolated as amorphous hydrochloride.
Příklad 7Example 7
4-[2-hydroxy-3-/2-fenoxypropylamino/propoxy]-6,7-cyklopenteno-2-benzimldazolinon-hydrochlorid4- [2-hydroxy-3- (2-phenoxypropylamino) propoxy] -6,7-cyclopenteno-2-benzimldazolinone hydrochloride
Analogicky podle způsobu popsaného v příkladu 1 se získá z fosgenu e 4,5-diamtno-6-[2-hydroxy-3-/2-fenoxypropylemino/propoxyJ indan-hydrochloridu žádaná sloučenina jako hydrochlorid o teplotě tání 261 ež 263 °C.Analogously to the method described in Example 1, the title compound as the hydrochloride is obtained from phosgene e 4,5-diamino-6- [2-hydroxy-3- (2-phenoxypropylemino) propoxy] indane hydrochloride, m.p. 261-263 ° C.
Diaminosloučenina použité jako výchozí produkt se připraví následujícím způsobem:The diamino compound used as the starting product is prepared as follows:
Kondenzaci 5-amino-6-/2,3-epoxypropoxy/-4-nltroindanu a N-benzyl-2-fenoxypropylaminu se získá 5-amino-6-[3-/N-benzyl-2-fenoxypropylemlno/-2-hydroxypropoxy]-4-nitroindan o teplo tě tání 70 až 80 °C (jako amorfní hydrochlorid).Condensation of 5-amino-6- (2,3-epoxypropoxy) -4-nitroindane and N-benzyl-2-phenoxypropylamine gives 5-amino-6- [3- (N-benzyl-2-phenoxypropylemino) -2-hydroxypropoxy] 4-nitroindane, m.p. 70-80 ° C (as amorphous hydrochloride).
Hydrogenaci a hydrogenolytickou debenzylecí předchozí sloučeniny v. metanolickém roztoku za použití 1096 paládia na uhlí se získá 4,5-diamino-6-[2-hydroxy-3-/2-fenoxypropylamino/pr opoxy] indan-hydrochlorid o teplotě tání 153 až 155 °C.Hydrogenation and hydrogenolytic debenzylation of the preceding compound in methanolic solution using 1096 palladium on carbon gave 4,5-diamino-6- [2-hydroxy-3- (2-phenoxypropylamino) propoxy] indane hydrochloride, m.p. 153-155 Deň: 32 ° C.
Příklad 8Example 8
4-[2-hydroxy-3-/2-fenoxypropylamino/propoxy]-6-metylindol-p-chlorbenzoét 8 g 4-[2-hydroxy-3-/2-fenoxy-N-benzylpropylamino/propoxy]-6-metyllndolu ee hydrogenuje ve 200 ml metanolu a 5 ml trietylaminu při teplotě místností a 0,1 MPa tlaku vodíku za použití 2 g 10% pelédie na uhlí, filtruje se, zahustí se, zbytek se rozpustí v 50 ml octanu etylnatého a přidá se vypočítané množství kyseliny p-chlorbenzoové. Po odsátí a překryetalovéní se získá 4,3 g 4-[2-hydroxy-3-/2-fenoxypropylamino/propoxy]-6-metyllndol-p-ehlorbenzoátu a o teplotě tání 134 až 136 °C (42 % teorie).4- [2-hydroxy-3- (2-phenoxypropylamino) propoxy] -6-methylindole-p-chlorobenzoate 8 g of 4- [2-hydroxy-3- (2-phenoxy-N-benzylpropylamino) propoxy] -6-methylindole ee is hydrogenated in 200 ml of methanol and 5 ml of triethylamine at room temperature and 0.1 MPa of hydrogen pressure using 2 g of 10% palladium on carbon, filtered, concentrated, dissolved in 50 ml of ethyl acetate and the calculated amount of acid is added p-chlorobenzoic acid. After aspiration and recrystallization, 4.3 g of 4- [2-hydroxy-3- (2-phenoxypropylamino) propoxy] -6-methylindole-p-chlorobenzoate is obtained, m.p. 134-136 ° C (42% of theory).
Výtěžek Teplote tání °C % teorie (rozpouštědlo)Yield Melting point ° C% of theory (solvent)
OznačeníDesignation
Příklad SExample S
Analogickým Způsobem, jak je popsáno v přikladu 8, se získá:In an analogous manner to that described in Example 8, one obtains:
é) 4-(2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino] propoxy)-6-metylindol z ‘ 58é) 4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) -6-methylindole of ‘58
4-f2-hydroxy-3-Γ2-/2-πβΐoxyfenoxy/-N-benzylpr opylamino)propoxy)-6-me tylindolu4- (2-hydroxy-3- [2- (2-p-oxyphenoxy) -N-benzylpropylamino) propoxy) -6-methylindole
b) 4-f2-hydroxy-3- [2-/5-karbamido-2-pyridoxy/~ atylamino]propoxy)-6-metylindol-di-p-chlorbenzoét z 11b) 4- (2-hydroxy-3- [2- (5-carbamido-2-pyridoxy) -tylamino] propoxy) -6-methylindole-di-p-chlorobenzoate of 11
4-f2-hydr oxy-3-L2-/5-kar bamld o-2pyri doxy/-N-benzyletylami no]pr opoxy)-6-me tylindolu4- (2-Hydroxy-3-L2- (5-carbamido-2-pyridoxy) -N-benzylethylamino) propoxy) -6-methylindole
c) 4-f2-hydroxy-3-[2-/2-hydr oxyfenoxy/ety lamino] propoxy)-6-metylindolbenzoét z 72c) 4- (2-hydroxy-3- [2- (2-hydroxyphenoxy) ethylamino] propoxy) -6-methylindolbenzoate of 72
4-(2-hydroxy-3-[2-/2-benzyloxyfenoxy/etylamino] propoxy)-6-metylindolu4- (2-hydroxy-3- [2- (2-benzyloxyphenoxy / ethylamino) propoxy) -6-methylindole
104 až 106 (octan)104 to 106 (acetate)
141 až 143 (isopropanol) až 90 (metanol)141 to 143 (isopropanol) to 90 (methanol)
Příklad 10Example 10
4-(2-hydroxy-3-[2-/3,4~dimetoxyfenyl/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 přikepe roztok 5,0 g 4-f 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 10 N hydroxidem sodným, filtruje se, promyje se tetrahydrofuranem a zahustí se.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 / ethylamino) propoxy) -6-methoxycarbonylindole (5.0 g) in 150 ml of absolute tetrahydrofuran, stirred at room temperature for 12 hours, quenched with cooling with sodium chloride solution and 10 N sodium hydroxide solution, filtered, washed with tetrahydrofuran and concentrated.
Zbytek se čistí ne silikagelovém sloupci směsí metyle'nchlorid/metanol 9:1. Báze se vysréží éterem a odsaje se. Získá se 2,4 g 4-(2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etyleminoJpropoxy)-6-hydroxymetylindolu o teplotě slinutí 60 °C (51 % teorie).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) ethylemino] propoxy) -6-hydroxymethylindole of sintering temperature of 60 DEG C. (51% of theory) are obtained.
Příklad 11Example 11
4-f2-hydroxy-3-[2-/3,4-dimetoxyfeny1/etylamino]propoxy) indazol4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylamino] propoxy) indazole
19,1 g 2-benzyl-4-f2-hydroxy-3-(2-/3,4-dimetoxyfenyl/etylamino]propoxy)indazolu se hyúro genuje v 700 ml metanolu a 22,4 ml koncentrované kyseliny chlorovodíkové ze přítomnosti 2 g 10% palédia na uhlí. Po odsátí se zahustí, rozpustí ve vodě, zalaklizuje se hydroxidem sodným a extrahuje se metylénchloridem. Organické fáze se zahustí, rozetře se s éterem a od· saje se. Získé se 9,1 g žádané sloučeniny o teplotě tání ,18 až 119 °C (59 % teorie).19.1 g of 2-benzyl-4- (2-hydroxy-3- (2- (3,4-dimethoxyphenyl / ethylamino) propoxy) indazole are hydrogenated in 700 ml of methanol and 22.4 ml of concentrated hydrochloric acid from the presence of 2 g. 10% palladium on coal. After aspiration, it is concentrated, dissolved in water, basified with sodium hydroxide and extracted with methylene chloride. The organic phases are concentrated, triturated with ether and suction filtered. 9.1 g of the title compound of melting point 18 DEG-119 DEG C. (59% of theory) are obtained.
Rozpuětěním v etanolu a přídavkem éterického roztoku kyseliny chlorovodíkové se získá hydrochlorid o teplotě táni 157 až 159 °C.Dissolution in ethanol and addition of ethereal hydrochloric acid gave the hydrochloride, m.p. 157-159 ° C.
Výtěžek Teplote tání °C % (rozpouštědlo)Yield Melting point ° C% (solvent)
OznačeníDesignation
Analogickým způsobem, jek popsáno výše, se získá:In an analogous manner to that described above:
a) 4-C2-hydroxy-3-[2-/2-hydroxyfenoxy/etylamino]propoxý) Indazola) 4-C2-hydroxy-3- [2- (2-hydroxyphenoxy / ethylamino) propoxy] indazole
2-benzyl-4-(2-hydroxy-3-[2-/2-benzyloxyfenoxy/etylamino] propoxy)indezolu2-Benzyl-4- (2-hydroxy-3- [2- (2-benzyloxyphenoxy / ethylamino) propoxy) indezole
b) 4-[2-hydr oxy-3-/2-fenoxye tylamino/pr opoxy]indazol zb) 4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] indazole z
2-benzyl-4-[2-hydroxy-3-/2-fenoxyetylamino/pr opoxy] indazolu2-Benzyl-4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] indazole
c) 4-(2-hydroxy-3-[2-/2-metoxyfenoxy/etylamlno] propoxy)indazolc) 4- (2-hydroxy-3- [2- (2-methoxyphenoxy / ethylamino) propoxy) indazole
ZOF
2-benzyl-4-f 2-hydroxy-3-[2-/2-metoxyfenoxy/etylamino] propoxy)indezolu2-Benzyl-4- (2-hydroxy-3- [2- (2-methoxyphenoxy / ethylamino) propoxy) indezole
d) 4-(2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino]propoxý) indazold) 4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) indazole
2-benzyl-4-(2-hydr oxy-3- [2-/2-metoxyfenoxy/propy lamino] propoxy)indazolu2-Benzyl-4- (2-hydroxy-3- [2- (2-methoxyphenoxy) propylamino] propoxy) indazole
e) 4-(2-hydroxy- 3- [2-/4-pyridyl/ety lamino] propoxy)indazol ze) 4- (2-hydroxy-3- [2- (4-pyridyl) ethylamino] propoxy) indazole;
2-benzyl-4-(2-hydroxy-3-[2-/4-pyridyl/eťylamino] propoxy) indezolu2-Benzyl-4- (2-hydroxy-3- [2- (4-pyridyl) ethylamino] propoxy) indazole
f) 4-[2-hydroxy-3-/benzo [b]-1 ,4-dioxan-2-yl-metylamino/propoxy] Indazol zf) 4- [2-hydroxy-3- / benzo [b] -1,4-dioxan-2-ylmethylamino / propoxy] indazole;
2-benzyl-4-[2-hydr oxy-3-/benzo [b] -1,4— -dioxan-2-yl-metylemino/propoxy]indazolu2-Benzyl-4- [2-hydroxy-3- / benzo [b] -1,4-dioxan-2-ylmethylemino / propoxy] indazole
g) 4-(2-hydroxy-3- [2-/2-hydroxyfenoxy/propylamino]propoxy) indazol z(g) 4- (2-hydroxy-3- [2- (2-hydroxyphenoxy / propylamino) propoxy) indazole;
2-benzyl-4-(2-hydroxy-3-[2-/2-hydroxyfenoxy/-N-benzylpropylamino] propoxy)indazolu2-Benzyl-4- (2-hydroxy-3- [2- (2-hydroxyphenoxy) -N-benzylpropylamino] propoxy) indazole
h) 4-(2-hydroxy-3-[2-/4-acetamidofenoxy/etylaminoj propoxy) indazol z(h) 4- (2-hydroxy-3- [2- (4-acetamidophenoxy / ethylamino) propoxy) indazole;
2-benzyl-4-(2-hydroxy-3- [2-/4-acetemidofenoxy/-N-benzyletylamino]propoxy) indezolu2-Benzyl-4- (2-hydroxy-3- [2- (4-acetemidophenoxy) -N-benzylethylamino] propoxy) indezole
i) 4-(2-hydroxy-3-[2-/4-acetamidofenoxy/-N-benzylety lamino] propoxy) indazoli) 4- (2-hydroxy-3- [2- (4-acetamidophenoxy) -N-benzylethylamino] propoxy) indazole
2-benzyl-4-f2-hydr oxy-3-[2—/3,4-etyléndi oxyf enyl/etylamino] propoxy)indezolu2-Benzyl-4- (2-hydroxy-3- [2- (3,4-ethylenedioxyphenyl) ethylamino] propoxy) indezole
j) 4-(2-hydroxy-3-[2-/3-etoxy-4-metoxyfenyl/etylamino] propoxy) indazolj) 4- (2-hydroxy-3- [2- (3-ethoxy-4-methoxyphenyl / ethylamino) propoxy) indazole
ZOF
2-benzyl-4-(2-hydroxy-3-[2-/3-etoxy-4-metoxyfenyl/etylemino] propoxy) indezolu2-Benzyl-4- (2-hydroxy-3- [2- (3-ethoxy-4-methoxyphenyl) ethylemino] propoxy) indezole
k) 4-(2-hydroxy-3-[2-/3,4,5-trimetoxyfenyl/etylamino] propoxy) indazol z(k) 4- (2-hydroxy-3- [2- / 3,4,5-trimethoxyphenyl / ethylamino] propoxy) indazole;
2-tienzyl-4-(2-hydroxy-3-[2-/3,4,5-trimetoxyf enyl/etylemino] propoxy)indezolu2-Thienzyl-4- (2-hydroxy-3- [2- / 3,4,5-trimethoxyphenyl / ethylemino] propoxy) indezole
l) 4-(2-hydroxy-3- [2-/4-hydroxy-3-metoxyfenyl/etylemi.no] propoxy) Indazol β(l) 4- (2-hydroxy-3- [2- (4-hydroxy-3-methoxyphenyl / ethylthio) propoxy) indazole β
2-benzyl-4-(2-hydroxy-3-[2-/4-benzyloxy-3-metoxyfenyl/etylamino]propoxy)lndezolu ) 4-(2-hydroxy-3-[2-/4-butoxy-3-hydroxyfenyle ty lami no] pr opoxy) i nda z ol z2-Benzyl-4- (2-hydroxy-3- [2- / 4-benzyloxy-3-methoxyphenyl / ethylamino] propoxy) indole) 4- (2-hydroxy-3- [2- / 4-butoxy-3- hydroxyphenylthiamino] propoxy] nda z ol z
2-benzyl-4-( 2-hydroxy-3-[2-/3-benzyloxy-4-but oxyfenyl/etylamino]propoxy)inda z olu2-Benzyl-4- (2-hydroxy-3- [2- / 3-benzyloxy-4-butoxyphenyl / ethylamino] propoxy) indole
37 až 139 (isopropanol)37 to 139 (isopropanol)
134 až 135 (octan)134-135 (acetate)
106 až 107 (octan)106 to 107 (acetate)
127 až 128 (octan)127 to 128 (acetate)
123 až 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 až 119 (octan)118 to 119 (acetate)
171 až 172 (octan)171-172 (acetate)
139 až 141 (isopropanol) až 97 (octan) pokračování139-141 (isopropanol) to 97 (acetate) continued
Příklad,2 ,-pivaloyl-4-(2-pivaloyloxy-3-[2-/3,4-dimetoxyfenyl/etylamino] propoxy)indazol-hydrochloridExample, 2'-Pivaloyl-4- (2-pivaloyloxy-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 př. 11), ;4»2 ml anhydridu kyseliny pivalové a 35 ml kyseliny pivalové se míchá 50 až 60 hodin při 75 °C. Získaná pevné hmota se míchá s ligroinem, odsaje se a promyje ligroinem. Získá se 4,1 g žádané sloučeniny o teplotě tání 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 (for preparation see Example 11); 4.2 ml of pivalic anhydride and 35 ml The pivalic acid was stirred at 75 ° C for 50-60 hours. The solid obtained is stirred with ligroin, filtered off with suction and washed with ligroin. 4.1 g of the desired compound of melting point 155 DEG-158 DEG C. is obtained. (69% of theory)
Příklad 13Example 13
4-(2-plvaloyloxy-3-[2-/3,4-dimetoxyfenyl/etylamino]propoxy) indazol4- (2-plvaloyloxy-3- [2- / 3,4-dimethoxyphenyl / ethylamino] propoxy) indazole
4,0 g pi valoyl-4-(2-pivaloyloxy-3- [2-/3-dimetoxyfenyl/ety lamino]propoxy)indazol-hydroehloridu (příprava viz př. 12) se zahřívá 2,5 hodiny pod zpětným chladičem se ,50 ml isopropylaminu. Zahustí se, rozpustí se v éteru, třepe se s ,N hydroxidem sodným, a organické fáze se čistí chromatograficky na sllikegelovém sloupci Xeluensj metylanehlorld:octan etylnatý 1:1).4.0 g of pi-valoyl-4- (2-pivaloyloxy-3- [2- (3-dimethoxyphenyl / ethylamino) propoxy) indazole hydrochloride (preparation see Example 12) was heated at reflux for 2.5 hours, 50 ml of isopropylamine. Concentrate, dissolve in ether, shake with N sodium hydroxide, and purify the organic phases by column chromatography (1: 1 methylene chloride: ethyl acetate).
Získá se 2,7 g žádaná sloučeniny jako olej (85 % teorie).2.7 g of the desired compound are obtained as an oil (85% of theory).
Přiklad 14Example 14
4-(2-hydroxy-3-[2-/2-metoxyfenoxy/propylamino] propoxy)-,-formylindolin-benzoét4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylamino) propoxy) -, - formylindoline benzoeth
6,7 g 4-(2-hydroxy-3-[2-/2-metoxyfenoxy/-N-benzylpropylamino] propoxy)-1-formylindolinu se hydrogenuje ve 250 ml metanolu a 20 ml trietyleminu při teplotě místnosti a 0,1 MPa tlaku vodíku za použiti 2 g 1036 paládia na uhlí, filtruje se, zahustí se a zbytek se roz* pustí v 50 ml octanu a přidá se ekvivalentní množství kyseliny benzoové. Po odsátí se získá 2,' 8 4-(2-hydroxy-3-[2-/2-metoxyfenoxy/propylemino]propoxy)-1-formylindolin-benzoétu o teplotě tání 131 až 133 °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 triethylemine at room temperature and 1 bar. hydrogen pressure using 2 g of 1036 palladium on carbon, filtered, concentrated, and the residue was dissolved in 50 ml of acetate and an equivalent amount of benzoic acid was added. After aspiration 2, 8 4- (2-hydroxy-3- [2- (2-methoxyphenoxy / propylemino) propoxy) -1-formylindoline benzoate is obtained, m.p. 131-133 ° C (31% of theory).
Příklad ,5Example, 5
Výchozí létky potřebné pro přípravu předchozích sloučenin se připraví následujícím způsobem:The starting flights required to prepare the foregoing compounds are prepared as follows:
4- /2,3-epoxypropoxy/-1-formylindolin4- (2,3-epoxypropoxy) -1-formylindoline
48,6 g 2-benzyloxy-6-nitrotoluenu se rozpustí v 670 ml dimetylformamidu a přidá se 29,9 g pareformeldehydu a potom se přikape 200 ml 1 N roztoku terč. butylétu draselného.48.6 g of 2-benzyloxy-6-nitrotoluene are dissolved in 670 ml of dimethylformamide and 29.9 g of pareformeldehyde are added, followed by dropwise addition of 200 ml of a 1 N solution of tert. potassium butylate.
Po hodinovém míchání při teplotě místnosti se rozmíché ve 3 1 ledové vody a extrahuje se éterem. Éterové fáze se suěí síranem sodným a zahustí se ve vakuu. Získé se 62 g 2-benzyloxy-6-nitrofenyletanolu, který se použije jako surový produkt v následujícím stupni.After stirring at room temperature for 1 hour, it is stirred in 3 l of ice-water and extracted with ether. The ether phases were 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 next step.
g 2-benzyloxy-6-nitrofenyletanolu se rozpustí v 500 ml bezvodého pyridinu a za chlazení se přidé cca 10 °C 47,7 g p-toluensulfonylchloridu. Teplota se nechá zvýSit 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 suěenl se získají 74 g 2-/2-benzyloxy-6-nitrofenyl/etylesteru kyseliny p-toluensulfonové o teplotě tání 96 ež 98 °C (86 já teorie, vztaženo ne 2-benzyloxy-6-nitrotoluen).g of 2-benzyloxy-6-nitrophenylethanol is dissolved in 500 ml of anhydrous pyridine and 47.7 g of p-toluenesulfonyl chloride are added under cooling at about 10 ° C. 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 etylénglykolmonometylesteru, přidá se 5 g 10% pelédla na aktivním uhlí a hydrogenuje se pří teplotě místnosti a 0,1 MPa tlaku vodíku. Fo odstranění katalyzátoru se zahusti a zbytek se formyluje směsí 227 ml anhydridu kyseliny octevé a 91 ml kyseliny mravenčí (podle C. W. Huffmenna, J. org. Chem. 23, 727 /1958/). Po reakci se rozloží ledovou vodou e extrahuje se octenem.g of 2- (2-benzyloxy-6-nitrophenyl) ethyl p-toluenesulfonic acid ester is dissolved in 2 l of ethylene glycol monomethyl ester, 5 g of 10% charcoal is 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. W. Huffmenn, J. org. Chem. 23, 727 (1958)). After the reaction, it is decomposed with ice-water and extracted with acetic acid.
Organické fáze se neutralizuje, suží síranem sodným a odpaří se ve vakuu. Zbytek se smíchá s 320 ml epichlorhydřinu a přidá se 173 ml 2N roztoku metylátu sodného. Po míchání přes noc se zahustí a zbytek se rozpustí ve vodě a octanu. Z octanového zbytku se získá po rozetření s lsopropylalkobolem a odsátím 15,8 g 4-/2,3-epoxypropoxy/-1-formyllndolinu o teplotě tání 88 až 89 °C (42 % teorie).The organic phases are neutralized, dried with 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. From the acetate residue, after trituration with isopropylalcobol and suction filtration, 15.8 g of 4- (2,3-epoxypropoxy) -1-formylindoline are obtained, m.p. 88 DEG-89 DEG C. (42% of theory).
Příklad. 16Example. 16
Byly připraveny teblety:Teblets were prepared:
Každá tableta obsahuje ,0 mg 4-(2-hydroxy-3-L2-metoxyfenoxy/etylemino]propoxy)-7-metyl-2-benzimidazolinonhydrochloridu. Připravené teblety mají následující složení:Each tablet contains 0 mg of 4- (2-hydroxy-3-L2-methoxyphenoxy / ethylemino] propoxy) -7-methyl-2-benzimidazolinone hydrochloride. Prepared teblets have the following composition:
4-(2-hydroxy-3-[2-/2-metoxyfenoxy/etylamino]propoxy)-7-metyl-2-benzimidazolinon-hydrochlorld 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 laktózou a škrobem. Směs se obvyklým způsobem granuluje. Ke granulátu se přidá steeran hořečnatý a směs se lisuje naThe preceding compound is finely divided and mixed with lactose and starch. The mixture is granulated in the usual manner. Magnesium steerate is added to the granulate and the mixture is compressed to
000 tablet o hmotnosti 0,12 g.000 tablets weighing 0.12 g.
Způsobem podle vynálezu se déle získá:The process according to the invention yields:
4-( 2-hydr oxy-3-[/1-metyl-3-f enyl/propylamino] propoxy )-6-mety lindol-benzoát, t. t. 119 až 122 °C,4- (2-hydroxy-3- [(1-methyl-3-phenyl) propylamino] propoxy) -6-methylindole benzoate, m.p. 119-122 ° C,
4-(2-hydroxy-3- 2-/3,4-diaetoxyfenyl/etylamino propoxy)-6-metylindol-benzoát, t. t. 147 až 148 °C,4- (2-hydroxy-3- 2- (3,4-diaethoxyphenyl) ethylamino propoxy) -6-methylindole benzoate, m.p. 147-148 ° C,
4-(2-hydroxy-3-[2-/2-pyridinyl/etylamino] propoxy)-6-metylindol-di-p-nitrobenzoét, t. t. 146 °C,4- (2-hydroxy-3- [2- (2-pyridinyl) ethylamino] propoxy) -6-methylindole-di-p-nitrobenzoate, mp 146 ° C,
4-[2-hydroxy-3-/2-fenoxyetylamino/propoxy]-6-metylindobenzoát, t. t. 123 až 125 °C,4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] -6-methylindobenzoate, mp 123-125 ° C,
4-(2-hydroxy-3-[/1-metyl-2-fenyl/etylamino]propoxy)-6-metylindol-benzoét, t. t. 125 až 128 °C,4- (2-hydroxy-3 - [(1-methyl-2-phenyl) ethylamino] propoxy) -6-methylindole benzoetide, m.p. 125-128 ° C,
4-(2-hydroxy-3-[2-/2-metoxyfenoxy/etylemino]propoxy)-6-metylindol, t. t. 123 až 125 °C,4- (2-hydroxy-3- [2- (2-methoxyphenoxy) ethylemino] propoxy) -6-methylindole, mp 123-125 ° C,
4-( 2-hydr oxy-3-[2-/4-karbamidofenoxy/etylemino]propoxy)-6-metylindol, t. t. 128 až 130 °C,4- (2-hydroxy-3- [2- (4-carbamidophenoxy) ethylemino] propoxy) -6-methylindole, m.p. 128-130 ° C,
4-[2-hydroxy-3-/benzo [b] -1,4-dioxan-2-yl-metylamino/propoxy]-6-metylindol-p-chlorbenzoét, t. t. ,68 až 170 °C,4- [2-hydroxy-3- / benzo [b] -1,4-dioxan-2-ylmethylamino / propoxy] -6-methylindole-p-chlorobenzoate, m.p. 68-170 ° C,
4-(2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etylemino]propoxy -6-metoxykarbonylindol, t. t. 145 až ,47 °C,4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylemino] propoxy-6-methoxycarbonylindole, m.p. 145 DEG-47 DEG C.,
4-(2-hydroxy-3-[2-/2-allyloxyfenoxy/etylamino]peopoxy)-6-metylindol, t. t. ,25 °C,4- (2-hydroxy-3- [2- (2-allyloxyphenoxy / ethylamino) peopoxy) -6-methylindole, m.p. 25 ° C,
2-etoxykarbonyl-4-[2-hydr oxy-3-/2-fenylpropylamino/propoxy] -6-metjiJindol, t. t. 127 °C,2-ethoxycarbonyl-4- [2-hydroxy-3- (2-phenylpropylamino) propoxy] -6-methylindole, mp 127 ° C,
2-etoxykarbonyl-4-(2-hydroxy-3-[/1 -ijietyl-3-fenyl/propylamino] propoxy) -6-aetylindol, t. t. ,33 až ,34 °C,2-ethoxycarbonyl-4- (2-hydroxy-3 - [(1-diethyl-3-phenyl) propylamino] propoxy) -6-ethylindole, m.p. 33-34 ° 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 [deg.] C,
2-etoxykarbonyl-4-(2-hydroxy-3-[2-/4-pyridlnyl/etyleminoJ propoxy)-6-metylindol , t. t. 133 až 134 °C,2-ethoxycarbonyl-4- (2-hydroxy-3- [2- (4-pyridinyl) ethylemino] propoxy) -6-methylindole, m.p. 133-134 ° C,
2-etoxykarbonyl-4-[2-hydr oxy-3-/2-fenoxyetylamino/propoxy]-6-iaetyllndol-benzoét, t. t. 147 °C2-ethoxycarbonyl-4- [2-hydroxy-3- (2-phenoxyethylamino) propoxy] -6-diethylindole-benzoate, m.p. 147 ° C
2-etoxykarbonyl-4-(2-hydroxy-3-[/l-metyl-2-fenoxy/etylaaino] propoxy)-6-metylindol-ben- . zoét, t. t. 135 až 137 °C,2-ethoxycarbonyl-4- (2-hydroxy-3 - [(1-methyl-2-phenoxy) ethylamino] propoxy) -6-methylindole-benzene. zoet, mp 135-137 ° C,
2-etoxykarbonyl-4-C2-hydroxy-3-[2-/2-metoxyfenoxy/etylamino]propoxy)-6-metylindol, t. t. 145 až ,47 °C,2-ethoxycarbonyl-4-C2-hydroxy-3- [2- (2-methoxyphenoxy / ethylamino) propoxy) -6-methylindole, m.p. 145 DEG-47 DEG C.,
2-etoxykerbonyl-4-(2-hydroxy-3- [2-/4-karbamidofenoxy/etylamino]propoxy)-6-metylindol-acetét, t. t. 160 až 165 °C,2-ethoxycarbonyl-4- (2-hydroxy-3- [2- (4-carbamidophenoxy / ethylamino) propoxy) -6-methylindole acetate, mp 160-165 ° C,
2-etoxykarbonyl-4-[2-hydroxy-3-/benzo [b] -1,4-dioxan-2-yl-metylamino/propoxy]-6-metylindol, t. t. ,35 až 137 °C,2-ethoxycarbonyl-4- [2-hydroxy-3- / benzo [b] -1,4-dioxan-2-ylmethylamino / propoxy] -6-methylindole, m.p. 35-137 ° C,
4-[2-hydroxy-3-/3-fenylpropylamino/propoxy]indazol, t. t. ,22 až ,24 °C,4- [2-hydroxy-3- (3-phenylpropylamino) propoxy] indazole, m.p. 22-22 ° C,
4-(2-hydroxy-3-[/1-metyl-2-fenoxy/etylamlno]propoxy)indazol, t. t. 175 až 177 °C,4- (2-hydroxy-3- [(1-methyl-2-phenoxy) ethylamino] propoxy) indazole, m.p. 175-177 ° C,
2-benzyl-4-(2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etylemino] propoxy)indazol, t. t. 10, až ,02 °C,2-Benzyl-4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylemino] propoxy) indazole, m.p. 10-10 ° C,
2-benzyl-4-(2-hydroxy-3-[2-/2-benzyloxyfenoxy/etylemino]propoxy)indazol, t. t. 81 až 83 °C,2-Benzyl-4- (2-hydroxy-3- [2- (2-benzyloxyphenoxy) ethylemino] propoxy) indazole, m.p. 81-83 ° C,
2-benzyl-4-(2-hydroxy-3-[2-/3,4-etylěndioxyfenyl/etylamino]propoxy)indazol, t. t. ,65 až ,68 °C,2-Benzyl-4- (2-hydroxy-3- [2- (3,4-ethylendioxyphenyl) ethylamino] propoxy) indazole, m.p. 65-68 ° C,
2-benzyl-4-( 2-hydroxy-3-[2-/4-benzyloxy- 3-metoxyfenyl/etylamino] propoxy)indazol, t. t. 96 až 98 °C,2-Benzyl-4- (2-hydroxy-3- [2- (4-benzyloxy-3-methoxyphenyl / ethylamino) propoxy) indazole, m.p. 96-98 ° C;
4-( 2-hydroxy-3-[l-/3,4-dimetoxyfenyl/propyl-2-amino]propoxy)indazol, t. t. ,13 až ,15 °C4- (2-hydroxy-3- [1- (3,4-dimethoxyphenyl) propyl-2-amino] propoxy) indazole, m.p. 13-13 ° C
4-(2-hydroxy-3-[3-/3,4-dimetoxyfenyl/propylamino]propoxy)indazol-benzoét, t. t. ,3, až 134 °C,4- (2-hydroxy-3- [3- (3,4-dimethoxyphenyl) propylamino] propoxy) indazole benzoate, m.p., 3-134 ° C,
4-(2-hydroxy-3-[2-/3,4-dimetoxyfenyl/etylemino]propoxy)-1-formyllndolih-benzoét, t. t. 136 až 138 °C,4- (2-hydroxy-3- [2- (3,4-dimethoxyphenyl) ethylemino] propoxy) -1-formylindole di-benzoetide, m.p. 136-138 ° C,
4-(2-hydroxy-3-L2-/4-fluorfenoxy/etylamino]propoxy)-,-formylindolin-benzoát, t. t. ,21 až ,23 °C,4- (2-hydroxy-3-L2- (4-fluorophenoxy) ethylamino] propoxy) -1-formylindoline benzoate, m.p. 21 DEG-23 DEG C.,
4-(2-hydroxy-3-[2-/2-iaetoxyfenoxy/etylaminoJpropoxy)-,-formylindolinbenzoét, t. t. 78 až 79 °C,4- (2-hydroxy-3- [2- (2-ethoxyphenoxy / ethylamino) propoxy) -, - formylindoline benzoate, m.p. 78-79 ° C,
4-[2-hydroxy-3-/2-fenyletylemino/propoxy]-1-formylindolin, t. t. ,21 až ,23 °C, 4-(2-hydroxy-3-C2-/2-chlorfenoxy/etylamÍnoJpropoxy)-1-formylindolin, t. t. 104 až ,07 °C,4- [2-hydroxy-3- (2-phenylethylemino) propoxy] -1-formylindoline, mp 21-21.2 ° C, 4- (2-hydroxy-3-C2- / 2-chlorophenoxy / ethylamino) propoxy) -1 -formylindoline, mp 104-107 ° C,
4-(2-hydroxy-3-[2-/2-metylmerkaptofenoxy/etyleinÍnoJ propoxy)-,-formylindolin, t. t. ,29 až 130 °C,4- (2-hydroxy-3- [2- (2-methylmercaptophenoxy / ethyleinino) propoxy) -1-formylindoline, m.p. 29-130 ° C,
4-(2-hydroxy-3-[2-/2-allylfenoxy/etylaminoJpropoxy)lndazol, t. t. ,25 až ,26 °C, 4-*(2-hydroxy-3-[.2-/2-allyloxyfenoxy/etylamino]propoxy)inůazol, t. t. 137 až ,39 °C.4- (2-hydroxy-3- [2- (2-allylphenoxy / ethylamino) propoxy) indazole, mp 25-25 ° C, 4 - * (2-hydroxy-3- [2- (2-allyloxyphenoxy) ethylamino) m.p. 137 DEG-39 DEG.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS806604A CS227312B2 (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 |
| CS806604A CS227312B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS227312B2 true CS227312B2 (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 (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS806605A CS227313B2 (en) | 1979-02-16 | 1980-09-30 | Method of preparing heterocyclic oxypropanolamine derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
| CS227313B2 (en) | 1984-04-16 |
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