CS228109B2 - Production of novel derivatives of 3-/4-phenoxymethylpi - Google Patents
Production of novel derivatives of 3-/4-phenoxymethylpi Download PDFInfo
- Publication number
- CS228109B2 CS228109B2 CS785460A CS546078A CS228109B2 CS 228109 B2 CS228109 B2 CS 228109B2 CS 785460 A CS785460 A CS 785460A CS 546078 A CS546078 A CS 546078A CS 228109 B2 CS228109 B2 CS 228109B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- propoxy
- hydroxy
- phenoxymethylpiperidino
- hydrogen
- group
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- BNIFVTPIXGUZCU-UHFFFAOYSA-N 1h-indazole Chemical class C1=CC=C2C=NNC2=C1.C1=CC=C2C=NNC2=C1 BNIFVTPIXGUZCU-UHFFFAOYSA-N 0.000 claims description 2
- ZRZLIXKKYZCXKZ-UHFFFAOYSA-N 3-[4-(phenoxymethyl)piperidin-1-yl]propan-1-ol Chemical compound O(C1=CC=CC=C1)CC1CCN(CC1)CCCO ZRZLIXKKYZCXKZ-UHFFFAOYSA-N 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- -1 alkoxy radicals Chemical class 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 30
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 15
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 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 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 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 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 5
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 5
- FUWVFGJQAVUIFN-UHFFFAOYSA-N 3-[3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]benzene-1,2-diamine;trihydrochloride Chemical compound Cl.Cl.Cl.NC1=CC=CC(OCCCN2CCC(COC=3C=CC=CC=3)CC2)=C1N FUWVFGJQAVUIFN-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 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
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- MOYSKNAMCCSLAO-UHFFFAOYSA-N 1-(1h-indazol-4-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C=1C=CC=2NN=CC=2C=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 MOYSKNAMCCSLAO-UHFFFAOYSA-N 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- NMGLVHXJOMBIJW-UHFFFAOYSA-N 1h-benzimidazole;dihydrochloride Chemical compound Cl.Cl.C1=CC=C2NC=NC2=C1 NMGLVHXJOMBIJW-UHFFFAOYSA-N 0.000 description 3
- KMRIUKNMUKDUCJ-UHFFFAOYSA-N 2-nitro-6-[3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]aniline;hydrochloride Chemical compound Cl.C1=CC=C([N+]([O-])=O)C(N)=C1OCCCN1CCC(COC=2C=CC=CC=2)CC1 KMRIUKNMUKDUCJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- YPYSERZXQBYPNJ-UHFFFAOYSA-N ethyl 4-[2-hydroxy-3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]-1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=CC2=C1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 YPYSERZXQBYPNJ-UHFFFAOYSA-N 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- BEPZGBDTTOZVTR-UHFFFAOYSA-N 1-(2,3-diaminophenoxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol;trihydrochloride Chemical compound Cl.Cl.Cl.NC1=CC=CC(OCC(O)CN2CCC(COC=3C=CC=CC=3)CC2)=C1N BEPZGBDTTOZVTR-UHFFFAOYSA-N 0.000 description 2
- OHIFCYWGLKGPNX-UHFFFAOYSA-N 1-[[2-(hydroxymethyl)-1h-indol-4-yl]oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C1=CC=C2NC(CO)=CC2=C1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 OHIFCYWGLKGPNX-UHFFFAOYSA-N 0.000 description 2
- COOZHSHTBOSLGZ-UHFFFAOYSA-N 1-[[3-(hydroxymethyl)-2h-indazol-4-yl]oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol;dihydrochloride Chemical compound Cl.Cl.C=12C(CO)=NNC2=CC=CC=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 COOZHSHTBOSLGZ-UHFFFAOYSA-N 0.000 description 2
- VPLIYRLGJUFEJR-UHFFFAOYSA-N 1-[[6-(hydroxymethyl)-1h-indol-4-yl]oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C=12C=CNC2=CC(CO)=CC=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 VPLIYRLGJUFEJR-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- JNQPINGKMBCWMD-UHFFFAOYSA-N 2-(3-chloropropoxy)-6-nitroaniline Chemical compound NC1=C(OCCCCl)C=CC=C1[N+]([O-])=O JNQPINGKMBCWMD-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- BFMMAUDEALXUMD-UHFFFAOYSA-N 2-nitro-6-(oxiran-2-ylmethoxy)aniline Chemical compound C1=CC=C([N+]([O-])=O)C(N)=C1OCC1OC1 BFMMAUDEALXUMD-UHFFFAOYSA-N 0.000 description 2
- LSONXNMNZYBRDE-UHFFFAOYSA-N 2h-benzotriazole;hydrochloride Chemical compound Cl.C1=CC=C2NN=NC2=C1 LSONXNMNZYBRDE-UHFFFAOYSA-N 0.000 description 2
- BREBKAKBNYXIOP-UHFFFAOYSA-N 4-(phenoxymethyl)piperidine Chemical compound C1CNCCC1COC1=CC=CC=C1 BREBKAKBNYXIOP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- SQAKCHLNRCFMOM-UHFFFAOYSA-N [4-[2-hydroxy-3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]-1h-indol-2-yl]methyl 2,2-dimethylpropanoate Chemical compound C1=CC=C2NC(COC(=O)C(C)(C)C)=CC2=C1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 SQAKCHLNRCFMOM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 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
- YGIZRQIPDVYAQJ-UHFFFAOYSA-N methyl 4-[2-hydroxy-3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]-1H-indole-6-carboxylate Chemical compound OC(COC1=C2C=CNC2=CC(=C1)C(=O)OC)CN1CCC(CC1)COC1=CC=CC=C1 YGIZRQIPDVYAQJ-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OLENANGIJWDOPG-UHFFFAOYSA-N (2-chlorobenzoyl) 2-chlorobenzoate Chemical compound ClC1=CC=CC=C1C(=O)OC(=O)C1=CC=CC=C1Cl OLENANGIJWDOPG-UHFFFAOYSA-N 0.000 description 1
- 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
- BJMLLSSSTGHJJE-UHFFFAOYSA-N (4-methylbenzoyl) 4-methylbenzoate Chemical compound C1=CC(C)=CC=C1C(=O)OC(=O)C1=CC=C(C)C=C1 BJMLLSSSTGHJJE-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RKUKNWAWXPCTEO-UHFFFAOYSA-N 1-(1H-indol-4-yloxy)-3-[4-[(4-phenylmethoxyphenoxy)methyl]piperidin-1-yl]propan-2-ol Chemical compound C=1C=CC=2NC=CC=2C=1OCC(O)CN(CC1)CCC1COC(C=C1)=CC=C1OCC1=CC=CC=C1 RKUKNWAWXPCTEO-UHFFFAOYSA-N 0.000 description 1
- ZMYWQGNLHHILTC-UHFFFAOYSA-N 1-(1H-indol-5-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound OC(COC=1C=C2C=CNC2=CC=1)CN1CCC(CC1)COC1=CC=CC=C1 ZMYWQGNLHHILTC-UHFFFAOYSA-N 0.000 description 1
- RLEPYMXVKJWNIM-UHFFFAOYSA-N 1-(1H-indol-6-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound OC(COC1=CC=C2C=CNC2=C1)CN1CCC(CC1)COC1=CC=CC=C1 RLEPYMXVKJWNIM-UHFFFAOYSA-N 0.000 description 1
- RGQAACOCUCKZGG-UHFFFAOYSA-N 1-(1h-benzimidazol-4-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C=1C=CC=2N=CNC=2C=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 RGQAACOCUCKZGG-UHFFFAOYSA-N 0.000 description 1
- KKEDMLMUHDQOQU-UHFFFAOYSA-N 1-(2,3-diamino-5-methylphenoxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol;trihydrochloride Chemical compound Cl.Cl.Cl.CC1=CC(N)=C(N)C(OCC(O)CN2CCC(COC=3C=CC=CC=3)CC2)=C1 KKEDMLMUHDQOQU-UHFFFAOYSA-N 0.000 description 1
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- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Předložený vynález se týká způsobu výroby nových derivátů 3-(4-fenoxymethylpiperidino)propanolu obecného vzorce IThe present invention relates to a process for the preparation of novel 3- (4-phenoxymethylpiperidino) propanol derivatives of the general formula I
v němžin which
Ri a Rz jsou stejné nebo rozdílné a znamenají vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, hydroxyalkylovou skupinu s 1 až 4 atomy uhlíku, alkanoyloxyalkylovou skupinu s až 6 atomy uhlíku nebo skupinu -CO-Z, přičemžR 1 and R 2 are the same or different and are hydrogen, (C 1 -C 6) alkyl, (C 1 -C 4) hydroxyalkyl, (C 1 -C 6) alkanoyloxyalkyl or -CO-Z, wherein:
Z znamená hydroxyskupinu, alkaxyskupinu s 1 až 6 atomy uhlíku nebo skupinu vzorceZ is hydroxy, C1-C6alkoxy or Formula
Re /Re /
—N \—N \
R7 kdeR7 where
R6 a R? mohou být stejné nebo rozdílné a znamenají vodík, alkylovou skupinu s 1 až 6 atomy uhlíku nebo hydroxyalkylovou skupinu s 1 až 4 atomy uhlíku,R6 and R? may be the same or different and are hydrogen, (C 1 -C 6) alkyl or (C 1 -C 4) hydroxyalkyl,
R3 znamená vodík nebo skupinu —O—Re, přičemžR 3 is hydrogen or -O-R e, wherein
Re znamená vodík, alkanoylovou skupinu s 1 až 8 atomy uhlíku nebo benzoylovou či naftoylovou skupinu, která je popřípadě substituována halogenem, alkylem s 1 až 6 atomy uhlíku, alkyloxyskupinou s 1 až 6 atomy uhlíku, alkoxykarbonylovou skupinou s 1 až 2 atomy uhlíku v alko-xyskupině, hydroxyskupinou, alkylthioskupinou s 1 až atomy uhlíku, nltrilovou skupinou, nitroskupinou nebo trifluormethylovou skupinou,R 6 is hydrogen, C 1 -C 8 alkanoyl or benzoyl or naphthoyl optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 2 alkoxycarbonyl -xy, hydroxy, C 1 -C 4 alkylthio, nitrile, nitro or trifluoromethyl,
R.4 a Rs mohou být stejné nebo vzájemně rozdílné a znamenají vodík, halogen, hydroxylovou skupinu, benzyloxyskupinu, alkylovou skupinu s 1 až 6 atomy uhlíku, alkyloxyskupinu s 1 až 6 atomy uhlíku, alkylthioskupinu s 1 až 6 atomy uhlíku, karboxylovou skupinu, benzyloxykarbonylovou skupinu nebo alkoxykarbonytovou skupinu s 1 až 2 atomy uhlíku v alkoxyskupině,R 4 and R 5 may be the same or different from each other and are hydrogen, halogen, hydroxyl, benzyloxy, (C 1 -C 6) alkyl, (C 1 -C 6) alkyloxy, (C 1 -C 6) alkylthio, carboxyl, a benzyloxycarbonyl or C 1 -C 2 alkoxycarbonyl group,
X a Y jsou stejné nebo mohou být vzájemně rozdílné a znamenají atom dusíku nebo skupinu —0=X and Y are the same or can be different from each other and are nitrogen or -O =
IAND
R9 přičemžR9 where
Rg znamená vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, která je popřípadě substituována skupinou —O—Rs, přičemž Rs má shora uvedený význam, nebo znamená skupinu —CO—Z, kde Z má shora uvedený význam, jejich farmakologicky použitelných solí, způsobu jejich výroby, jakož i farmaceutických přípravků s obsahem sloučenin vzorce I.R 8 is hydrogen, C 1 -C 6 alkyl optionally substituted with -O-R 5, wherein R 5 is as defined above, or is -CO-Z, wherein Z is as defined above, their pharmacologically acceptable salts, processes for their preparation, as well as pharmaceutical preparations containing compounds of formula I.
Vzhledem k tomu, že sloučeniny vzorce I v případě, že R3 neznamenají vodík, obsahují asymetrický atom uhlíku, jsou dále předmětem vynálezu opticky aktivní formy a racemické směsi těchto sloučenin.Since the compounds of formula I, when R3 is not hydrogen, contain an asymmetric carbon atom, the invention further provides optically active forms and racemic mixtures of these compounds.
Sloučeniny vzorce I a jejich farmakologicky použitelné soli mají při nízké toxicitě výrazné vasodilatační vlastnosti, které se hlavně projevují v poklesu krevního tlaku. Kromě toho bylo pozorováno potlačování adrenergických (S-receptorů.The compounds of formula I and their pharmacologically useful salts have, at low toxicity, marked vasodilatory properties, which are mainly manifested in a decrease in blood pressure. In addition, suppression of adrenergic (S-receptors) has been observed.
Alkylovými skupinami ve významu substituentů Ri, R2, R4, Rs, Re, R7, Rs a R9 jsou přímé nebo rozvětvené skupiny s 1 až 6, výhodně s 1 až 4 atomy uhlíku, jako je například methyl, ethyl, isopropyl, propyl, butyl, isobutyl, terc.butyl nebo n-hexyl. V úvahu přichází zejména však methylová a ethylová skupina.Alkyl groups R 1, R 2, R 4, R 5, R 6, R 7, R 8 and R 9 are straight or branched groups having 1 to 6, preferably 1 to 4, carbon atoms such as methyl, ethyl, isopropyl, propyl, butyl , isobutyl, tert-butyl or n-hexyl. However, methyl and ethyl are particularly suitable.
Hydroxyalkylové skupiny ve významu substituentů Ri, Ř2, Re a R7 obsahují 1 až 4 atomy uhlíku, s výhodně jsou jimi 2-hydroxyethylová a hydroxymethylová skupina.Hydroxyalkyl groups R 1, R 2, R 6 and R 7 contain 1 to 4 carbon atoms, preferably 2-hydroxyethyl and hydroxymethyl.
Alkoxyskupiny ve významu substituentů Rd, Rs, Re a Z obsahují 1 až 6, výhodně 1 až 4 atomy uhlíku, jako je například methoxyskupina, ethoxyskupina, propoxyskupina, butoxyskupina nebo pentyloxyskupina. Výhodná je však methoxyskupina a ethoxyskupina.The alkoxy radicals R d, R s, R e and Z contain 1 to 6, preferably 1 to 4 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, butoxy or pentyloxy. However, methoxy and ethoxy are preferred.
Jako alkoxykarbonylová skupina ve významu symbolů R4, Rs a Rs přichází v úvahu zejména metboxy- a ethoxykarbonylová skupina.Suitable alkoxycarbonyl groups in the meaning of R4, R5 and R5 are, in particular, methoxy and ethoxycarbonyl.
Alkylthioskupinami ve významu substituentů Rd, Rs a Rs jsou skupiny s 1 až 6, výhodně s 1 až 4 atomy uhlíku. Výhodná je methylmerkaptoskupina.The alkylthio groups represented by Rd, R5 and R5 are those having 1 to 6, preferably 1 to 4, carbon atoms. Methyl mercapto is preferred.
Alkanoylové skupiny ve významu symbolu Rs obsahují 1 až 8, výhodně 1 až 6 atomů uhlíku, přičemž alkylové skupiny mají řetězec přímý, rozvětvený nebo cyklický. Výhodně přichází v úvahu zbytek acetylový a pivaloylový.The alkanoyl groups R @ 5 contain from 1 to 8, preferably from 1 to 6 carbon atoms, the alkyl groups having a straight, branched or cyclic chain. Preferably, the acetyl and pivaloyl radicals are suitable.
Alkanoyloxyalkylovou skupinou ve významu substituentů Ri a R2 jsou zbytky obsahující 1 až 6 atomů uhlíku, zejména acetoxymethylový zbytek.The alkanoyloxyalkyl radicals R @ 1 and R @ 2 are radicals having 1 to 6 carbon atoms, in particular an acetoxymethyl radical.
Aroylovými skupinami ve významu symbolu Rs jsou skupina benzylová a naftoylová, které mohou být výhodně substituovány methylem, halogenem a methoxyskupinami.Aroyl groups R @ 5 are benzyl and naphthoyl, which may preferably be substituted by methyl, halogen and methoxy.
Halogenem se ve smyslu vynálezu rozumí fluor, chlor, brom a jod, zejména fluor, chlor a brom.For the purposes of the invention, halogen is fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.
Nové sloučeniny obecného vzorce I se podle tohoto vynálezu vyrábějí tím, že se o sobě známým způsobem sloučenina obecného vzorce VIThe novel compounds of the formula (I) according to the invention are prepared by the preparation of a compound of the formula (VI) in a manner known per se
v němžin which
Ri až Rs a Y mají shora uvedený význam aR 1 to R 5 and Y are as defined above and a
R10 znamená vodík nebo zbytek acetylový, benzoylový, benzylový nebo tetrahydropyranylový, přičemž v případě indazolů schopných tautomerie může být zbytek acetylový, benzoylový, benzylový nebo tetrahydropyranylový také na druhém atomu dusíku X, uvádí v reakci se sloučeninou obecného vzorce VII nebo s jejím reaktivním derivátemR10 is hydrogen or an acetyl, benzoyl, benzyl or tetrahydropyranyl radical, and in the case of tautomerically indazole indazoles, the acetyl, benzoyl, benzyl or tetrahydropyranyl radical may also be on the second nitrogen atom X, reacted with a compound of formula VII or a reactive derivative thereof
OO
ZOF
X \X \
OH (VII) v němžOH (VII) where
X má shora uvedený význam, a provádí se cyklizace, načež se v případě, že Rs znamená aíkanoylovou skupinu s 1 až 8 atomy uhlíku nebo popřípadě substituovanou benzoylovou nebo naftoylovou skupinu, hydroxylová skupina, která je popřípadě přítomna ve významu symbolu Rs, esterifikuje, nebo v případě, že Re znamená vodík, pak se esterová skupina, která je popřípadě ve významu Rs, hydrolyzuje a případně přítomná acetylová, benzoylová, benzylová nebo tetrahydropyranylová skupina, jakožto krycí skupina se odštěpí, nebo v případě, že jedna nebo několik skupin Ri, Rz a Rg představují hydroxymethylovou skupinu, připraví se taková skupina z hydroxymethyiové, acyloxymethylové nebo alkoxykarbcnylové skupiny s 1 až 2 atomy uhlíku v alkoxylové části redukcí nebo z alkanoyloxymcthylové skupiny s až 6 atomy uhlíku hydrolýzou nebo se methylová skupina získá redukcí z alkoxykarbonylové skupiny s 1 až 2 atomy uhlíku v alkoxylové části, a získané sloučeniny se popřípadě převedou na své farmakologicky použitelné soli.X is as defined above and is cyclized, where, when R 5 is C 1 -C 8 alkanoyl or optionally substituted benzoyl or naphthoyl, the hydroxyl optionally present as R 5 is esterified, or in the case where R 6 is hydrogen, the ester group, optionally in the meaning of R 5, is hydrolyzed and the acetyl, benzoyl, benzyl or tetrahydropyranyl group optionally present as the capping group is cleaved, or when one or more R 1 groups are present, R 2 and R 8 are hydroxymethyl, prepared from hydroxymethyl, acyloxymethyl or alkoxycarbonyl of 1 to 2 carbon atoms in the alkoxy moiety by reduction or from alkanoyloxymethyl of up to 6 carbon atoms by hydrolysis, or methyl is obtained by reduction from alkoxycarbonyl of 1 to 2 carbon atoms 2 carbon atoms in alkoxy and the resulting compounds are optionally converted into their pharmacologically acceptable salts.
Jako reaktivní deriváty vzorce VII přicházejí v úvahu, jestliže X znamená skupinu —RgC=, zejména estery karboxylové kyseliny, dále orthoestery, halogenidy a amidy karboxylové kyseliny, jestliže X znamená atom dusíku, používá se kyseliny dusité získané účelně in sítu z anorganického dusitanu působením vodné minerální kyseliny, nebo při práci v bezvodém prostředí nižšího alkylesteru kyseliny dusité.Possible reactive derivatives of the formula VII are those, when X represents a group -RgC =, in particular carboxylic acid esters, furthermore orthoesters, halides and carboxylic acid amides, when X represents a nitrogen atom, nitrous acid obtained expediently in situ from inorganic nitrite by aqueous mineral acid, or when working in an anhydrous lower alkyl nitrous acid ester.
Případně prováděná redukce substituentů Ri, Rz a Rg ve sloučeninách vzorce I se provádí pomocí komplexních hydridů kovů, jako například lithiumaluminiumhydrldu nebo katalytickou hydrogenací pomocí katalyzátorů na bázi vzácných kovů nebo Raneyova niklu.Optionally, the reduction of R 1, R 2 and R 8 in the compounds of formula I is carried out by complex metal hydrides such as lithium aluminum hydride or by catalytic hydrogenation using noble metal catalysts or Raney nickel.
Hydrolýza skupin Ri, Rz a Rg sloučenin vzorce I se může provádět o sobě známým způsobem za kyselých nebo zásaditých podmínek.The hydrolysis of the groups R 1, R 2 and R 8 of the compounds of the formula I can be carried out in a manner known per se under acidic or basic conditions.
Esterifikace hydroxylové skupiny ve významu symbolu R3 se může provádět obvyklým způsobem reakcí s halogenidem nebo anhydridem kyseliny, popřípadě v přítomnosti činidla vázajícího kyselinu, jako například pyridinu.The esterification of the hydroxyl group R 3 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.
Jako krycí skupiny v substituentu R10 přicházejí v úvahu nižší alkanoylové skupiny, například acetylový zbytek, aroylové skupiny, například benzoylový zbytek, arylmethylové skupiny, například benzylový zbytek nebo cyklické ethery, například tetrahydropyranylový zbytek. Odštěpení krycích skupin v substituentu R10 se může provádět známým způsobem odpovídajícím jejich charakteru hydrolyticky nebo hydrogenolyticky.Suitable protecting groups in R 10 are lower alkanoyl groups, for example acetyl, aroyl groups, for example benzoyl, arylmethyl groups, for example benzyl or cyclic ethers, for example tetrahydropyranyl. The cleavage of the protecting groups in the R10 substituent can be carried out in a known manner corresponding to their nature hydrolytically or hydrogenolytically.
Za účelem převedení sloučenin vzorce I na jejich farmakologicky nezávadné soli se tyto sloučeniny uvádějí v reakci výhodně v organickém rozpouštědle s anorganickou nebo organickou kyselinou, například s kyselinou chlorovodíkovou, kyselinou bromovodíkovou, kyselinou fosforečnou, kyselinou sírovou, kyselinou octovou, kyselinou citrónovou, kyselinou maleinovou nebo kyselinou benzoovou.In order to convert the compounds of formula I into their pharmacologically acceptable salts, the compounds are reacted preferably in an organic solvent with an inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
Sloučeniny vzorce I podle vynálezu mohou vznikat ve formě racemické směsi. Dělení racemátu na opticky aktivní formy se daří o sobě známými metodami přes diastereomerní soli. Jako aktivní kyseliny se mohou používat převážně kyselina vinná, kyselina jablečná, kyselina kafrová a kyselina kafrsulfonová.The compounds of the formula I according to the invention can be formed in the form of a racemic mixture. The resolution of the racemate into the optically active forms is accomplished by known methods via diastereomeric salts. As the active acids, predominantly tartaric acid, malic acid, camphoric acid and camphorsulfonic acid can be used.
Za účelem přípravy léčiv se sloučenina vzorce I mísí o sobě známým způsobem s vhodnými farmaceutickými nosnými látkami, aromatickými látkami, chuťovými přísadami a barvivý, a ze získané směsi se lisují například tablety nebo dražé nebo se za přidání příslušných pomocných látek suspendují nebo rozpouštějí ve vodě nebo v oleji, jako například v olivovém oleji.For the preparation of medicaments, the compound of the formula I is admixed in a manner known per se with suitable pharmaceutical carriers, flavoring agents, flavoring agents and coloring agents, and the resulting mixture is compressed, for example, tablets or dragees or suspended or dissolved in water with the appropriate excipients; in an oil such as olive oil.
Nová sloučenina vzorce I podle vynálezu a její soli se mohou aplikovat v kapalné nebo pevné formě enetrálně nebo parenterálně. Jako injekční prostředí přichází v úvahu výhodně voda, která v případě injekčních roztoků obsahuje obvyklé přísady jako stabilizátory, pomocná rozpouštědla nebo pufry. Takovýmito přísadami jsou například tartrátcvý a citrátový pufr, ethanol, komplexotvorné látky (jako ethylendiamintetraoctová kyselina a její netoxické soli), vysokomolekulární polymery (jako kapalný polyethylenoxid) za účelem regulace vyskozity. Pevnými nosnými látkami jsou například škroby, laktóza, mannit, methylcelulóza, mastek, vysoce disperzní kyselina křemičitá, vysokomolekulární mastné kyseliny (jako kyselina stearová), želatina, agar-agar, fosforečnan vápenatý, stearan horečnatý, živočišné a rostlinné tuky a pevné vysokomolekulární polymery (jako polyethylenglykolyj; pro orální aplikaci jsou vhodnými přípravky například takové, které mohou obsahovat popřípadě chuťové přísady a sladidla.The novel compound of the formula I according to the invention and its salts can be administered in liquid or solid form enetrally or parenterally. Suitable injectable media are preferably water which, in the case of injectable solutions, contains conventional additives such as stabilizers, co-solvents or buffers. Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and non-toxic salts thereof), high molecular weight polymers (such as liquid polyethylene oxide) for the purpose of controlling obesity. Solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular polymers ( For oral administration, suitable preparations are, for example, those which may optionally contain flavoring and sweetening agents.
Ve smyslu předloženého vynálezu jsou kromě sloučenin uvedených v příkladech výhodné následující sloučeniny:For the purposes of the present invention, the following compounds are preferred in addition to the compounds exemplified:
4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy ] -6-terc. butylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-tert. butylindole
4-[2-hydroxy-3-(4-fenoxymethylpiperidino j propoxy j-6-methylbenzimidazol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylbenzimidazole
4-[2-hydroxy-3-(4-fenoxymethylpiperidino j propoxy j -6-methylbenzthiazol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylbenzthiazole
4-[2-hydroxy-3-(4-fenoxymethylpiperidino) priopoxy 1 -3-methylindazol.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-3-methylindazole.
Následující příklady blíže ilustrují synté228109 zu sloučenin podle vynálezu. Tyto příklady však v žádném případě nepředstavují omezení předmětu vynálezu.The following examples illustrate in more detail the synthesis of 228109 from the compounds of the invention. However, these examples are not intended to limit the scope of the invention in any way.
Příklad 1Example 1
4- [ 3- (4-f enoxy methylpiperidino) propoxy | benzimidazol4- [3- (4-Phenoxymethylpiperidino) propoxy | benzimidazole
Směs 7,0 g 2,3-diamino-l-[3-(4-f enoxymethylpiperidino ) propoxy ] benzentrihy drocliloridu a 100 ml kyseliny mravenčí se zahřívá dny k varu pod zpětným chladičem, potom se reakční směs zahustí ve vakuu a zbytek se překrystaluje z ethanolu. Získá se 3,34 g 4-[3-(4-f enoxymethylpiperidi.no) propoxy ]benzlmidazoldihydrochloridu (50 % teorie) o teplotě tání 144 až 145 °C.A mixture of 7.0 g of 2,3-diamino-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene trichloride and 100 ml of formic acid is refluxed for days, then the reaction mixture is concentrated in vacuo and the residue is concentrated in vacuo. recrystallized from ethanol. There were obtained 3.34 g of 4- [3- (4-phenoxymethylpiperidino) propoxy] benzimidazole dihydrochloride (50% of theory), m.p. 144-145 ° C.
2,3-diamino-l- [ 3- (4-f enoxymethy Ipiperidino) propoxy] benzentrihydrochlorid, používaný jako výchozí látka, se může vyrobit následujícím způsobem:The 2,3-diamino-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene trihydrochloride used as starting material can be prepared as follows:
1- (2-amino-3-nitrof enoxy) -3-chlorpropan1- (2-Amino-3-nitrophenoxy) -3-chloropropane
Směs 21,0 g 2-amino-3-nitrofenolu, 20,1 g uhličitanu draselného a 750 ml butanonu se zahřívá 1 hodinu k varu pod zpětným chladičem, potom se přidá 64,0 g 1-bnom-3-chlorpropanu, směs se dále zahřívá ještě hodiny k varu pod zpětným chladičem, zfiltruje se a zahustí.A mixture of 2-amino-3-nitrophenol (21.0 g), potassium carbonate (20.1 g) and butanone (750 ml) was heated at reflux for 1 hour, then 1-bromo-3-chloropropane (64.0 g) was added. The mixture is heated at reflux for a further hour, filtered and concentrated.
Izoluje se 29,0 g 1- (2-amino-3-nitrofenoPříklad 2 xy)-3-chlorpropanu (90 % teorie) ve formě amorfní látky.29.0 g of 1- (2-amino-3-nitrophenoxexample 2 xy) -3-chloropropane (90% of theory) are isolated as an amorphous substance.
2-amino-3-nitro-l- [ 3- (4-f enoxymethylpiperidino)propoxy]benzenhydrochlorid2-Amino-3-nitro-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene hydrochloride
Směs 17,5 g 1- (2-amino-3-nitrof enoxy )-3-chtorpropanu, 31,0 g 4-fenoxymethylpiperidinu a 500 ml ethanolu se zahřívá 7 dnů k varu pod zpětným chladičem. Po zahuštění se směs extrahuje 500 ml etheru, extrakt se okyselí zředěnou kyselinou chlorovodíkovou a odpaří se. Získá se 29,7 g 2-amino~3-nitro-1- [ 3- (4-f enoxymethylpiperidino) propoxy ]benzenhydrochloridu (86 % teorie) ve formě amorfní soli.A mixture of 17.5 g of 1- (2-amino-3-nitrophenoxy) -3-chloropropane, 31.0 g of 4-phenoxymethylpiperidine and 500 ml of ethanol is heated to reflux for 7 days. After concentration, the mixture is extracted with 500 ml of ether, the extract is acidified with dilute hydrochloric acid and evaporated. 29.7 g of 2-amino-3-nitro-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene hydrochloride (86% of theory) are obtained in the form of an amorphous salt.
2,3-diamino-l- [ 3- (4-f enoxymethylpiperidino ) propoxy ] benzentrihydrochlorid2,3-diamino-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene trihydrochloride
Roztok 28,0 g 2-amino-3-nitro-l-[3-(4-fenoxymethy lpi peridi no) propoxy ] benzenhydrochloridu v 600 ml ethanolu a 200 ml vody se hydrogenuje při teplotě místnosti a atmosférickém tlaku za použití 0,4 g kysličníku platičitého. Po filtraci se filtrát okyselí zředěnou kyselinou chlorovodíkovou, zahustí se a zbytek se rozpustí ze směsi ethanolu a ethylacetátu. Získá se 21,4 g 2,3-diamino-l- (3- (4-f enoxymethylpiperidino) propoxy jbenzentrihydrochloridu (70 % teorie) ve formě amorfní soli.A solution of 28.0 g of 2-amino-3-nitro-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene hydrochloride in 600 ml of ethanol and 200 ml of water is hydrogenated at room temperature and atmospheric pressure using 0.4 g of platinum oxide. After filtration, the filtrate was acidified with dilute hydrochloric acid, concentrated, and the residue was dissolved from a mixture of ethanol and ethyl acetate. 21.4 g of 2,3-diamino-1- (3- (4-phenoxymethylpiperidino) propoxybenzene trihydrochloride (70% of theory) are obtained in the form of an amorphous salt.
Analogickým způsobem jak je popsáno v příkladu 1 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 1:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-[2-hydroxy-3-( 4-f enoxymethylpiperidino) propoxy ] benzimidazoldihydrochlorid 47 123 až 125 (ethanol) za) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole dihydrochloride 47 123 to 125 (ethanol) from
2.3- diamino-l- [ 2-hydr oxy-3- (4-f enoxymethylpiperidino) propoxy ] benzentrihydrochloridu a kyseliny mravenčí2,3-diamino-1- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzene trihydrochloride and formic acid
b) 4-/2-hydroxy-3-[4-(2-methoxyf enoxymethyl jpiperidino ] propoxy/benzimidazoldihydrochlorid 39 144 až 145 (ethanol) zb) 4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benzimidazole dihydrochloride 39 144-145 (ethanol) from
2.3- dlamino-l-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl) piperidino ] propoxy/benzentrihydrochloridu a kyseliny mravenčí označení výtěžek % teplota tání °C (rozpouštědlo)2,3-dlamino-1- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benzene trihydrochloride and formic acid designation yield% melting point ° C (solvent)
c) 4-/2-hydroxy-3-[ 4-(3-methylf enoxymethyl )-piperidino ] propoxy/benzimidazoldihydrochlorid 22 zc) 4- / 2-hydroxy-3- [4- (3-methylphenoxymethyl) -piperidino] propoxy / benzimidazole dihydrochloride 22 of
2,3-diamino-l-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidino ] propoxy/benzen-trihydrochioridu a kyseliny mravenčí2,3-diamino-1- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] benzene trihydrochioride and formic acid
d) 4-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino ] propoxy/benzimidazoldihydrochlorid 39 zd) 4- / 2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy / benzimidazole dihydrochloride 39 z
2.3- diamino-l-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino ] propoxy/benzentrihydrochloridu a kyseliny mravenčí2,3-diamino-1- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] benzene trihydrochloride and formic acid
e) 4-[2-hydroxy-3-(4-fenoxymethylpiper idino) propoxy)-6-methylbenzimidazoldihydrochlorid ze) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy) -6-methylbenzimidazole dihydrochloride from
2.3- diamino-l- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy ] -5-methylbenzentrihydrochloridu a kyseliny mravenčí2,3-diamino-1- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -5-methylbenzene trihydrochloride and formic acid
2,3-diamino-l- [ 2-hydroxy-3-fenoxymethylpiperidino) propoxy) benzentrihydrochlorid, který se používá jako' výchozí látka, se může vyrobit následujícím způsobem:The 2,3-diamino-1- [2-hydroxy-3-phenoxymethylpiperidino) propoxy) benzene trihydrochloride used as starting material can be prepared as follows:
Směs 40,0 g l-(2-amino-3-nitrofenoxy )-2,3-epoxypropanu, 36,2 g 4-fenoxymethylpiperidinu a 450 ml ethanolu se míchá 18 hodin při teplotě místnosti a přitom vzniklý roztok 2-amino-l- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy ] -3-nitr obenzenu (teplota tání 117 až 118 °C) se potom hydrogenuje za použití 1,0 g kysličníku platičitého při teplotě místnosti. Po filtraci se filtrát okyselí zředěnou kyselinou chlorovodíkovou, okyselený filtrát se zahustí a překrystaluje se ze směsi ethanolu a ethylacetátu. Izoluje se 72,3 g 2,3-diamino-l-[2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy Jbenzentrihydrochloridu (81 % teorie) ve formě amorfní látky.A mixture of 40.0 g of 1- (2-amino-3-nitrophenoxy) -2,3-epoxypropane, 36.2 g of 4-phenoxymethylpiperidine and 450 ml of ethanol is stirred at room temperature for 18 hours while the resulting 2-amino-1 solution is formed. The [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-nitro-benzene (m.p. 117-118 ° C) is then hydrogenated using 1.0 g of platinum oxide at room temperature. After filtration, the filtrate is acidified with dilute hydrochloric acid, the acidified filtrate is concentrated and recrystallized from a mixture of ethanol and ethyl acetate. 72.3 g of 2,3-diamino-1- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzene trihydrochloride (81% of theory) are isolated as an amorphous substance.
1- (2-amino-3-nitrof enoxy) -2,3-epoxypropan je známou látkou.1- (2-Amino-3-nitrophenoxy) -2,3-epoxypropane is a known substance.
118 až 120 (ethanol)118 to 120 (ethanol)
140 až 142 (ethanol)140 to 142 (ethanol)
Odpovídajícím způsobem se mohou vyrobit ostatní meziprodukty uvedené v příkladu 2.The other intermediates listed in Example 2 can be prepared accordingly.
P ř í k 1 a d 3Example 1 a d 3
4- [ 2-hydroxy-3- (4-f enoxymethylpipsridino) propoxy ] benztriazol4- [2-hydroxy-3- (4-phenoxymethylpipsridino) propoxy] benzotriazole
K suspenzi 23,0 g 2,3-diaroinoi-l-[2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy ] benzentrihydrochloridu ve 150 mi vody a 8,8 ml koncentrované kyseliny chlorovodíkové se přikape při teplotě 0 °C roztok 3,3 gramu dusitanu sodného v 37 ml vody. Reakční směs se ponechá v klidu přes noc a poté se zfiltruje a získaná sraženina se překrystaluje z methanolu. Izoluje se 9,5 g 4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy] benztriazolhydrochloridu (47 % teorie) o teplotě tání 187 až 189 °C.To a suspension of 23.0 g of 2,3-diaroino-1- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzene trihydrochloride in 150 ml of water and 8.8 ml of concentrated hydrochloric acid is added dropwise a solution of 3 at 0 ° C. 3 g of sodium nitrite in 37 ml of water. The reaction mixture is left overnight and then filtered and the precipitate obtained is recrystallized from methanol. 9.5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride (47% of theory) are isolated, m.p. 187-189 ° C.
Příklad 4Example 4
Analogickým způsobem jak je popsáno v příkladu 3 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 3:
označení výtěžek °/o teplota tání °C (rozpouštědlo j aj 4-/2-hydroxy-3-[4-(2-methoxyf enoxymethyl jpiperidino ] pr opoxy) benztriazolhydr ochlorid zdesignation yield ° / o melting point ° C (solvent is also 4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy) benztriazole hydride
2.3- diamino-l-/2-hydroxy-3-[4- (2-methoxyf enoxymethyl j piperidino ] propoxy/benzentrihydrochloridu a dusitanu sodného bj 2-/2-hydroxy-3-[4-(3-methylf enoxymethyl j piperidino ] propoxy/benztriazolhydrochlorid z2,3-diamino-1- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benzene trihydrochloride and sodium nitrite bj 2- / 2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino propoxy / benztriazole hydrochloride from
2.3- diamino-l-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl j piperidino] propoxy/benzentrihydrochloridu a dusitanu sodného2,3-diamino-1- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy / benzene trihydrochloride and sodium nitrite
c) 4-[3-(4-fenoxymethylpiperidino) propoxy ] benztriazolhydrochlorid zc) 4- [3- (4-Phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride z
2.3- diamino-l-[ 3- (4-fenoxymethylpiperidino j propoxy ] benzentrihydrochloridu a dusitanu sodného2,3-diamino-1- [3- (4-phenoxymethylpiperidino) propoxy] benzene trihydrochloride and sodium nitrite
161 až 162161 to 162
206 až 208206 to 208
259 až 260259 to 260
Příklad 5Example 5
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy j -2-hydr oxymethyl indol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethylindole
K suspenzi 0,95 g lithiumaluminiumhydridu ve 45 ml absolutního tetrahydrofuranu se přikape při teplotě 0 °C roztok 4,5 g 4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino j propoxy ]-2-ethoxykarbonylindolu v 25 ml absolutního tetrahydrofuranu, směs se míchá 1 hodinu při teplotě místnosti, poté se za chlazení roztokem chloridu sodného rozloží, směs se zfiltruje, a po promytí tetrahydrofuranem se ke spojeným filtrátům přidá 0,01 mol benzoové kyseliny. Po překrystalování benzoátu z 25 ml ethylacetátu se získá 2,5 g 4-[2-hydroxy-3-( 4-f enoxymethylpiperidino j propoxy ] -2-hydroxymethy lindolbenzoátu (47 % teorie) o teplotě tání 145 až 146 °C.A solution of 4.5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidinopropoxy) -2-ethoxycarbonylindole in 25 ml of absolute tetrahydrofuran is added dropwise at 0 ° C to a suspension of 0.95 g of lithium aluminum hydride in 45 ml of absolute tetrahydrofuran. The mixture is stirred for 1 hour at room temperature, then quenched with cooling with brine, filtered, and after washing with tetrahydrofuran, 0.01 mol of benzoic acid is added to the combined filtrates, after crystallization of the benzoate from 25 ml of ethyl acetate. 5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethylindole benzoate (47% of theory), m.p. 145-146 ° C.
Příklad 6Example 6
Analogickým způsobem jak je popsáno v příkladu 5 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 5:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-(2-hydroxy-3-(4-f enoxymethylpiperidino ) propoxy ] -6-hydroxymethylindolbenzoát z(a) 4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy) -6-hydroxymethylindole benzoate
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidinio) propoxy ] -6-methoxykarbonylindolu4- [2-hydroxy-3- (4-phenoxymethylpiperidinio) propoxy] -6-methoxycarbonylindole
b) 4-[2-hydroxy-3-(4-fenoxymethylpiperidino j propoxy ] -6-hydroxymethyl-5-methylindoil zb) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethyl-5-methylindoil;
4- [ 2-hydr oxy-3- (4-fenoxymethylpiperidino) propoxy ] -6-methoxykarbony]-5-methylindolu4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methoxycarbonyl-5-methylindole
153 až 155 (ethylacetát)153 to 155 (ethyl acetate)
Příklad 7Example 7
4- [ 2-hydroxy-3- (3-fenoxymethylpiperidino) propoxy ] indol-2-karboxylová kyselina4- [2-hydroxy-3- (3-phenoxymethylpiperidino) propoxy] indole-2-carboxylic acid
K suspenzi 2,0 g 4-[2-hydroxy-3-( 4-fenoxymethylpiperidino ) propoxy ] -2-ethoxykarbonylindolu v 50 ml dioxanu se přidá roztok 0,5 g hydroxidu draselného ve 25 ml vody, směs se míchá 16 hodin při 50 °C, zahustí se, zbytek se vyjme vodou a vodný roztok se /neutralizuje zředěnou kyselinou sírovou. Izoluje se 1,8 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy ]indol-2-karboxylové kyseliny (96 % teorie) o teplotě tání 218 až 220°C (rozklad).To a suspension of 2.0 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole in 50 ml of dioxane is added a solution of 0.5 g of potassium hydroxide in 25 ml of water, and the mixture is stirred for 16 hours at 50 ° C, concentrated, the residue is taken up in water and the aqueous solution is neutralized with dilute sulfuric acid. 1.8 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole-2-carboxylic acid (96% of theory) is isolated, m.p. 218 DEG-220 DEG C. (decomposition).
Příklad 8Example 8
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy) -2-methylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy) -2-methylindole
Směs 5,9 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy ] -2-hydroxymethylindolu, 114 ml acetanhydridu a 55 ml pyridinu se míchá 4 hodiny při teplotě místnosti a poté se zahustí ve vakuu. Zbytek se vyjme ethylacetátem, ethylacetátový roztok se promyje vodou a zahustí se. Přitom získaná bisacetylová sloučenina (8,0 g) se rozpustí ve 100 ml methanolu a hydrogenuje se za použití 2,0 g 10% paládía na uhlí při 0,1 MPa tlaku vodíku.A mixture of 5.9 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethylindole, 114 ml of acetic anhydride and 55 ml of pyridine was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is taken up in ethyl acetate, the ethyl acetate solution is washed with water and concentrated. The bisacetyl compound thus obtained (8.0 g) was dissolved in 100 ml of methanol and hydrogenated using 2.0 g of 10% palladium on carbon at 1 atm of hydrogen pressure.
Pc spotřebování vypočteného množství vodíku se směs zfiltruje, filtrát se zahustí na polovinu původního objemu, přidáním 2N roztoku methoxidu sodného se hodnota pH upraví na 9, směs se zahřívá 10 minut k varu pod zpětným chladičem, vylije se do vody a provede se extrakce chloroformem. Po zahuštění extraktu se zbytek vyjme ethylacetátem, přidá se 0,01 mol benzoové kyseliny a vyloučený benzoát se překrystaluje z 25 ml isopropanolu. Získá se 1,6 g 4-[2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ]-2-methylindolbenzoát (28 % teorie] o teplotě tání 145 až 148 °C.When the calculated amount of hydrogen is consumed, the mixture is filtered, the filtrate is concentrated to half its original volume, adjusted to pH 9 by addition of 2N sodium methoxide solution, refluxed for 10 minutes, poured into water and extracted with chloroform. After concentrating the extract, the residue is taken up in ethyl acetate, 0.01 mol of benzoic acid is added and the precipitated benzoate is recrystallized from 25 ml of isopropanol. There was obtained 1.6 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-methylindolbenzoate (28% of theory), m.p. 145-148 ° C.
1S1S
Příklad 9Example 9
Analogickým způsobem jak je popsáno v příkladu 8 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 8:
označení výtěžek % teplota tání °C (rozpouštědlo) označenídesignation yield% melting point ° C (solvent) designation
a) 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) pnopoxy ] -6-methylindol z(a) 4- [2-Hydroxy-3- (4-phenoxymethylpiperidino) pnopoxy] -6-methylindole;
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy ] -6-hydroxymethylindolu4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethylindole
b) 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propyl ] -5,6-dimethylindol zb) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propyl] -5,6-dimethylindole;
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy) -6-hydroxymethyl-5-methylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy) -6-hydroxymethyl-5-methylindole
122 až 123 (ethylacetát)122-123 (ethyl acetate)
Příklad 10Example 10
4- [ 2-piva!oyloxy-3- (4-f enoxymethylpiperidino)propoxy(indol4- [2-pivoyloxy-3- (4-phenoxymethylpiperidino) propoxy (indole
Směs 4,4 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy] indolacetátu, 10,2 g pivalové kyseliny a 2,0 g anhydridu pivalové kyseliny se míchá až do rozpuštění a poPříklad 11 tom se reakční směs ponechá 2 dny v klidu při teplotě místnosti. Reakční směs se potom vylije na led, hodnota pH se upraví pomocí vodného roztoku amoniaku na 9, provede se extrakce methylenchloridem, extrakt se zahustí a zbytek se rozetře s etherem. Izoluje se 3,2 g 4-[2-pivaloyloxy-3-(4-fenoxymethylpiperidino)propoxy]indolu (69 % teorie) o teplotě tání 103 až 105 °C.A mixture of 4.4 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indolacetate, 10.2 g of pivalic acid and 2.0 g of pivalic anhydride is stirred until dissolved, and for example 11 the reaction mixture is left therein. 2 days at room temperature. The reaction mixture is then poured onto ice, adjusted to pH 9 with aqueous ammonia solution, extracted with methylene chloride, concentrated and the residue triturated with ether. 3.2 g of 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] indole (69% of theory) are isolated, m.p. 103-105 ° C.
Analogickým způsobem jak je popsáno v příkladu 10 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 10:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-/2-pivaloyloxy-3-[4-(2-methoxyf enoxymethyl) piperldino ] propoxy/indol z 66 107 (ether)a) 4- / 2-Pivaloyloxy-3- [4- (2-methoxyphenoxymethyl) piperldino] propoxy / indole from 66 107 (ether)
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl) piperidino ] propoxy/indolu a anhydridu pivalové kyseliny4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole and pivalic anhydride
b) 4-[2-pivaloyloxy-3-(4-fenoxymethylpiperidino) propoxy) -6-methylindol (směs ligroinu a etheru) výtěžek % teplota tání °C (rozpouštědlo) označeníb) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy) -6-methylindole (ligroin / ether mixture) yield% melting point ° C (solvent) designation
4- [ 2-hydroxy-3- (4f enoxymethylpiperidino)propoxy]-6-methylindolu a anhydridu pivalové kyseliny4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole and pivalic anhydride
c) 4-[2-pivaloyloxy-3-(4-fenoxymethylpiperidino) propoxy]- 23c) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -23
-6-pivaloyloxymethylindol z-6-pivaloyloxymethylindole z
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy ] -6-hydroxymethylindolu a pivalo-ylchloridu4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethylindole and pivaloyl chloride
d) 4-[2-benzoyloxy-3-(4-fenoxymethylpiperidino) propoxy ] indol 40 zd) 4- [2-benzoyloxy-3- (4-phenoxymethylpiperidino) propoxy] indole 40 z
4- (2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ] indolu a anhydridu kyseliny benzoové4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole and benzoic anhydride
e) 4-[2-pivaloyloxy-3-(4-feno- 24 xymethylpiperidino) propoxy ] -2-pivaloyloxymethylindol ze) 4- [2-pivaloyloxy-3- (4-pheno-24-xymethylpiperidino) propoxy] -2-pivaloyloxymethylindole;
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ] -2-pivaloyloxymethylindolu a anhydridu pivalové kyseliny4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-pivaloyloxymethylindole and pivalic anhydride
f) 4-/2-pival)oyloxy-3-[4-(2-methylf enoxymethyl) piperidino ] propoxy/-2-methylindol zf) 4- [2-pivaloyloxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] -2-methylindole;
4-/2-hydroxy-3-[ 4-(2-methylf enoxy-methyl) plperidino ] propoxy/-2-methylindolu a anhydridu pivalové kyseliny až 78 (ze směsi heptanu a etheru)4- / 2-hydroxy-3- [4- (2-methylphenoxymethyl) plperidino] propoxy / -2-methylindole and pivalic anhydride up to 78 (from heptane / ether)
108 až 110 (ether) až 95 (ze směsi heptanu a etheru)108 to 110 (ether) to 95 (from a mixture of heptane and ether)
Příklad 12Example 12
4-/2-hydroxy-3- [ 4- (2-hydroxyfenoxymethyl) piperidino ] propoxy/indol4- / 2-hydroxy-3- [4- (2-hydroxyphenoxymethyl) piperidino] propoxy / indole
13,8 g 4-/2-hydroxy-3-[4-(2-benzyloxyfenoxymethylpiperidinojpropoxy/indolu se hydrogenuje ve 250 ml methanolu při teplotě místnosti a tlaku vodíku 0,1 MPa za použití 3 g 5% paládia na uhlí, potom se reakční směs zfiltruje, filtrát se zahustí a zbytek se nechá vykrystalovat z ethylacetátu. Získá se 4,7 g 4-/2-hydroxy-3-( 4- (2-hydroxyfenoxymethyl) piperidino ] propoxy/indolu (42 % teorie) o teplotě tání 119 až 121 °C.13.8 g of 4- (2-hydroxy-3- [4- (2-benzyloxyphenoxymethylpiperidino) propoxy / indole) are hydrogenated in 250 ml of methanol at room temperature and 1 bar of hydrogen using 3 g of 5% palladium on carbon, then The reaction mixture was filtered, the filtrate was concentrated and the residue was crystallized from ethyl acetate to give 4.7 g of 4- / 2-hydroxy-3- (4- (2-hydroxyphenoxymethyl) piperidino] propoxy) indole (42%). mp 119-121 ° C.
1B1B
P ř í k 1 a d 13Example 1 a d 13
Analogickým způsobem jak je popsáno v příkladu 12 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 12:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-/2-hydroxy-3-[4-(4-hydr oxyf enoxymethyl jpiperidlnojpropoxy/indol za) 4- / 2-Hydroxy-3- [4- (4-hydroxyphenoxymethyl) piperidinylpropoxy / indole;
4-/2-hydr oxy-3- [ 4- (4-benzyloxyfenoxymethyl jpiperidino j propoxy/indolu bj 4-/2-hydroxy-3-[4-(2-karboxyf enoxymethy 1) piperidino ] propoxy/indiol z4- / 2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) -piperidino] propoxy / indole bj 4- / 2-hydroxy-3- [4- (2-carboxyphenoxymethyl) piperidino] propoxy / indiol
4-/2-hydr oxy-3- [ 4- (2-benzy loxykarbonylf enoxymethyl) piperidino ] propoxy/indolu4- / 2-Hydroxy-3- [4- (2-benzyloxycarbonylphenoxymethyl) piperidino] propoxy / indole
Příklad 14Example 14
4- [ 2-pivaloyloxy-3- (4-fenOxymetliylpiperidino) propoxy ] benzimidazol4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole
3,8 g 4-[2-hydroxy-3-(4-fenioxymethylplperidino) propoxy jbenzimidazolu a 1,3 g pivaloylchloridu se vaří ve 25 ml pyridinu 2 hodiny pod zpětným chladičem. Po odpaře39 167 (isopropanol) ní rozpouštědla se zbytek vyjme 100 ml chloroformu. Chloroformový roztok se důkladně promyje vodou, vysuší se síranem sodným a konečně se k němu přidá 50 ml etherického roztoku kyseliny chlorovodíkové. Po zahuštění krystaluje z ethanolu 4-[2-pivaloyloxy-3- (4-f enoxymethylpiperidino) propoxy ] benzimidazolhydrochlorid o teplote tání 132 až 134 °C.3.8 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole and 1.3 g of pivaloyl chloride were refluxed in 25 ml of pyridine for 2 hours. After evaporation of the solvent (isopropanol), the residue is taken up in 100 ml of chloroform. The chloroform solution was washed well with water, dried over sodium sulfate and finally 50 ml of ethereal hydrochloric acid was added. After concentration, 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole hydrochloride crystallizes from ethanol, m.p. 132-134 ° C.
Příklad 15Example 15
Analogickým způsobem jak je popsáno v příkladu 14 se získá:In an analogous manner to that described in Example 14:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
4-/2- (3,4,5-trimethoxybenzoyloxy )-3-(4-( 2-chlorf enoxymethyl j piperidino ] propoxy/benzimidazol z4- / 2- (3,4,5-trimethoxybenzoyloxy) -3- (4- (2-chlorophenoxymethyl) piperidino] propoxy / benzimidazole
4-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino ] propoxy/benzimidazolu a 3,4,5-trimethoxybenzoylchloridu4- / 2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy / benzimidazole and 3,4,5-trimethoxybenzoyl chloride
Příklad 16Example 16
4- [ 2-pivaloyloxy-3- (4-f enoxymethylpiperidino ) propoxy ] benztriazol4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole
Směs 5,1 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino j propoxy ] benztrlazolhydrochloridu, 6,7 g anhydridu kyseliny pivalové a 33,3 g roztavené kyseliny pivalové se míchá po dobu 3 dnů při teplotě místnosti, poi32 158 až 160 (ethanol) té se reakční směs vylije na led, zneutralizuje se roztokem amoniaku ve viodě a provede se extrakce methylenchloridem. Po zahuštění extraktu se vyjme olejovitý zbytek methanolem a roztok se zředěnou kyselinou chlorovodíkovou slabě okyselí. Při odpařování rozpouštědla se získá 2,53 g 4-[2-plvaloyloxy-3- (4-f enoxymethylpiperidino j propoxy jbenztriazolhydrochloridu (38 % teorie) o teplotě tání 131 až 133 °C,A mixture of 5.1 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benztrlazole hydrochloride, 6.7 g of pivalic anhydride and 33.3 g of molten pivalic acid is stirred for 3 days at room temperature. The reaction mixture was poured onto ice, neutralized with a solution of ammonia in water and extracted with methylene chloride, and the extract was concentrated, the oily residue was taken up in methanol, and the solution was slightly acidified with dilute hydrochloric acid. g of 4- [2-plvaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride (38% of theory), m.p.
Příklad 17Example 17
Analogickým způsobem jak je popsáno v příkladu 16 se získají následující sloučeniny:In an analogous manner to that described in Example 16, the following compounds were obtained:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-/2-(4-methylbenzoyloxy)-3- [ 4- (2-methoxyf enoxymethyl ) piper idino ] propoxy/benztriazol za) 4- / 2- (4-Methylbenzoyloxy) -3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benztriazole from
4-/2-hydroxy-3- [ 4- (2-methoxyfenoxymethyl) piperidino ] propoxy/benztriazolu a anhydrldu 4-methylbenzoové kyseliny v dioxanu bj 4-/2-(2-chlorbenzoyloxy)-3-(4-( 3-methylf enoxymethyl) piperidino j pr opoxy/benztriazol z4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benzotriazole and 4-methylbenzoic acid anhydride in dioxane bj 4- / 2- (2-chlorobenzoyloxy) -3- (4- (3- methylphenoxymethyl) piperidinopropoxy / benztriazole z
4-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidino j pr opoxy/benztriazolu a anhydridu 2-chlorbenzoové kyseliny v dioxanu4- / 2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy / benztriazole and 2-chlorobenzoic anhydride in dioxane
Příklad 18Example 18
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy]-3-hydroxymethylindazoldihydrochlorid4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-hydroxymethylindazole dihydrochloride
Na 3-ačetoxymethyl-4-[2-hydroxy-3-(4-f enoxymethylpiperidino) pr opoxy ] indazol se nechá působit ethanolický chlorovodík v nadbytku, poté se produkt vysráží etherem a překrystaluje se z ethanolu. Izoluje se v 48% výtěžku 4-[2-hydroxy-3-( 4-f enoxymethylpiperidino ) propoxy j -3-hydroxymethylindazoldihydrochlorid ve formě slabě žlutě zbarvených krystalů o teplotě tání 183 °C (rozklad).3-Acethoxymethyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole is treated with excess ethanolic hydrogen chloride, then the product is precipitated with ether and recrystallized from ethanol. It is isolated in 48% yield of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-hydroxymethylindazole dihydrochloride as pale yellow crystals of m.p. 183 DEG C. (decomposition).
Příklad 19Example 19
4- [ 2-pivaloyloxy-3- (4-f enoxymethylpiperidino )propoxy] indazol4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] indazole
Směs 2,2 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino )propoxyjindazolu, 1,25 g anhydridu kyseliny pivalové a 10 g kyseliny pivalové se zahřívá na 40 °C. Potom se reakční směs vylije do 2N roztoku hydroxidu sodného, provede se extrakce methylenchloridem, extrakt se zahustí a zbytek se překrystaluje ze směsi isopropanolu a vody. Získá se 1,3 g 4-[2-pivaloyloxy-3-(4-fenoxymethylpiperidino) propoxy jindazolu (48 % teorie) ve formě bezbarvých krystalů o teplotě tání 116 až 118 °C.A mixture of 2.2 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole, 1.25 g of pivalic anhydride and 10 g of pivalic acid is heated to 40 ° C. The reaction mixture was poured into 2N sodium hydroxide solution, extracted with methylene chloride, the extract was concentrated and the residue was recrystallized from isopropanol / water. 1.3 g of 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxyindazole (48% of theory) are obtained as colorless crystals of m.p. 116 DEG-118 DEG.
Analogickým způsobem jako je popsán ve shora uvedených příkladech se vyrobí také následující sloučeniny:The following compounds were also prepared in an analogous manner to those described above:
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino') propoxy]indol, acetát, t. t. 127 až 129 °C, benzoát, t. t. 146 až 147 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino ') propoxy] indole, acetate, mp 127-129 ° C, benzoate, mp 146-147 ° C.
S (—) -4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy] indol, acetát, t. t. 121 až 124 °C,[a]D 20 — —8,3° (1,5% roztok v methanolu).S (-) -4- [2-hydroxy-3- (4-f enoxymethylpiperidino) -propoxy] -indole acetate, mp 121-124 ° C, [?] D20 - -8.3 ° (1.5% solution in methanol).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ]-2-ethoxykarbonylindol, t. t. 170 °C (isopropanol).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole, m.p. 170 [deg.] C. (isopropanol).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino j propoxy ]-2-karbamoylindol, t. t. 182 “C (ethylacetát j.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-carbamoylindole, m.p. 182 DEG C. (ethyl acetate i.
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidinopr opoxy j-2-dimethylamínokarbonylindol, t. t. 178 °C (isopropylalkohol).4- [2-hydroxy-3- (4-phenoxymethylpiperidinopropoxy) -2-dimethylaminocarbonylindole, m.p. 178 [deg.] C. (isopropyl alcohol).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ]-6-methoxykarbonylindol, t. t. 139 až 140 °C (ethylacetátj.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methoxycarbonylindole, m.p. 139-140 ° C (ethyl acetate).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino j propoxy ]-6-methylindoil, t. t. 122 až 123 °C (ethylacetátj.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindoil, m.p. 122-123 ° C (ethyl acetate).
2-ethoxykarbonyl-4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino] propoxy ] -6-methylindolbenzoát, t. t. 189 °C (isopropylalkohol).2-ethoxycarbonyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino] propoxy] -6-methylindole benzoate, mp 189 ° C (isopropyl alcohol).
4-/2-hy droxy-3- [ 4- (2-chlorf enoxymethyl) piperidino] propoxyindolbenzoát/, t. t. 140 až 142 °C (ethylacetát).4- (2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxyindole benzoate), m.p. 140-142 ° C (ethyl acetate).
4-/2-hydroxy-3- [ 4- (3-chlorf enoxymethyl) piperidino Jpropoxy/indolbenzoát, t. t. 149 až 151 °C (ethylacetát).4- [2-hydroxy-3- [4- (3-chlorophenoxymethyl) piperidino] propoxy / indole benzoate, m.p. 149-151 [deg.] C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (4-chlorf enoxymethyl) piperidino ]propoxy/indolbenzoát, t. t. 156 až 158 °C (ethylacetát).4- [2-hydroxy-3- [4- (4-chlorophenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 156-158 ° C (ethyl acetate).
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl } piperidino] propoxy/indolbenzoát, t. t. 115 až 117°C (ethylacetát).4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 115 DEG-117 DEG C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (2-methylf enoxymethyl) piperidino] propoxy/indolbenzoát, t. t. 128 až 129°C (ethylacetát).4- [2-hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 128 DEG-129 DEG C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidino] propoxy/indolbenzoát, t. t. 152 až 154°C, (ethylacetát).4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 152-154 ° C, (ethyl acetate).
4-/2-hydroxy-3- [ 4- (2-methylmerkaptof enoxymethyl )piperidino]propoxy/indol, t. t. 108 až 110 °C (ethylacetát).4- / 2-hydroxy-3- [4- (2-methylmercaptophenoxymethyl) piperidino] propoxy / indole, m.p. 108-110 ° C (ethyl acetate).
4-/2-hydroxy-3- [ 4- (4-f luorf enoxymethyl)piperidino]propoxy/-6-methylindol, t. t. 137 až 139°C (ethylacetát).4- [2-hydroxy-3- [4- (4-fluorophenoxymethyl) piperidino] propoxy] -6-methylindole, m.p. 137 DEG-139 DEG C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidino ] propoxy/-6-methylindolbenzoát, t. t. 138 až 140 °C (ethylacetát).4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] -6-methylindole benzoate, m.p. 138-140 [deg.] C. (ethyl acetate).
4-/2-hydroxy-3-[ 4-(2-benzyloxyf enoxymethyl )piperidino] propoxy/indol, olej.4- / 2-hydroxy-3- [4- (2-benzyloxyphenoxymethyl) piperidino] propoxy / indole, oil.
4-/2-hydroxy-3- [ 4- (4-benzyloxyf enoxymethyl) piperidino] propoxy/indol, t. t. 113 °C (ether).4- [2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) piperidino] propoxy] indole, m.p. 113 [deg.] C. (ether).
4- [ 2-hydroxy-3- (4-f enoxymethy lpiperidino) propoxy]-2-pivaloyloxymethylindoi, t. t. 130 až 132 °C (ethylacetát).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-pivaloyloxymethylindole, m.p. 130 DEG-132 DEG C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethy 1) piperidino ]propoxy/-2-methylindol, t. t. 137 až 138°C (ethylacetát).4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy] -2-methylindole, m.p. 137 DEG-138 DEG C. (ethyl acetate).
4-/2-hydroxy-3-[4-(2-chlorf enoxymethyl )piperidino ] propoxy/-2-methylindol.4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] -2-methylindole.
4-/2-hydroxy-3- [ 4- (2,5-dimethylf enoxymethyl) piperidino] propoxy/indol, t. t. 153 až 155 °C (ethylacetát).4- (2-hydroxy-3- [4- (2,5-dimethylphenoxymethyl) piperidino] propoxy / indole, m.p. 153-155 ° C (ethyl acetate).
5- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy]indol, t. t. 121 až 123 °C (ethaniol).5- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole, mp 121-123 ° C (ethanol).
6- [ 2-hydroxy-3-(4-f enoxymethylpiperidino)propoxy]indol, t. t. 144 až 145 °C (ethanolj.6- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole, m.p. 144-145 ° C (ethanol);
4- (3-( 4-f enoxymethylpiperidino;) propoxy ] Indol, t. t. 118 až 119 °C.4- (3- (4-phenoxymethylpiperidino) propoxy) indole, mp 118-119 ° C.
5- (3-( 4-f enoxymethylpiperidino) propoxy ] indol, t. t. 107 až 108 °C (ethylacetát).5- (3- (4-phenoxymethylpiperidino) propoxy] indole, m.p. 107-108 ° C (ethyl acetate).
6- (3-( 4-f enoxymethylpiperidino) propoxy ] indol, t. t. 123 až 124 °C (isopropylalkohol).6- (3- (4-phenoxymethylpiperidino) propoxy] indole, m.p. 123-124 ° C (isopropyl alcohol).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ]-2-ethoxykarbonylindol, t. t. 168 až 170 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole, m.p. 168-170 ° C.
4- [ 2-hydr oxy-3- (4-f enoxymethylpiperidino) propoxyjlndazol, t. t. 142 až 143 °C, hydrochlorid, t. t. 220 až 222 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole, mp 142-143 ° C, hydrochloride mp 220-222 ° C.
4-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino ]-propoxy/indazol, t. t. 154 °C (isopropylalkohol).4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy / indazole, m.p. 154 [deg.] C. (isopropyl alcohol).
4-/2-hydr oxy-3- [ 4- (2-methylf enoxymethyl) piperidino jpropoxy/indazol, t. t. 127 až 129 stupňů Celsia (isopropylalkohol).4- [2-Hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy / indazole, m.p. 127 DEG-129 DEG C. (isopropyl alcohol).
4-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidinojpropoxy/indazol, t. t. 158 až 159 stupňů Celsia (isopropylalkohol).4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidin] propoxy / indazole, m.p. 158-159 DEG C. (isopropyl alcohol).
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl) piperidino] propoxy/indazol, t. t. 151 až 153 stupňů Celsia (isopropylalkohol).4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indazole, m.p. 151-153 degrees C (isopropyl alcohol).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino ] propoxy]-5-methylindazol, t. t. 156 až 157 °C (isopropylalkohol).4- [2-hydroxy-3- (4-phenoxymethylpiperidino] propoxy] -5-methylindazole, m.p. 156-157 ° C (isopropyl alcohol).
4- [ 2-hydroxy-3- (4-f enoxymethy lpiperidino} propoxy ]-6-methylindazol, t. t. 152 až 153 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino} propoxy] -6-methylindazole, m.p. 152-153 ° C.
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy]indazol, t. t. 141 až 142 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole, m.p. 141-142 ° C.
3- aceťoxymethyl-4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy ] indazolhydr ochlorid, t. t. 203 až 204 °C.3-Acethoxymethyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole hydride, m.p. 203-204 ° C.
4- [2-hydroxy-3-(4-fenoxymethylpiperidino)propoxy]-7-methylindazol, t. t. 132 až 135 °C (isopropylalkohol ].4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -7-methylindazole, m.p. 132-135 ° C (isopropyl alcohol).
4-(3-( 4-f enoxymethylpiperidino) propoxy ] indazol, t. t. 160 až 161 °C.4- (3- (4-phenoxymethylpiperidino) propoxy] indazole, m.p. 160-161 ° C.
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy]-6-terc.butylindazol, t. t. 130 až 131 stupňů Celsia.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-tert-butylindazole, m.p. 130-131 ° C.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS785460A CS228109B2 (en) | 1977-08-20 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpi |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772737630 DE2737630A1 (en) | 1977-08-20 | 1977-08-20 | 3-Phenoxymethyl-piperidino 1-heterocyclyl-oxo-propane derivs. - useful as vasodilators and beta adrenergic receptor inhibitors |
| CS777291A CS228106B2 (en) | 1976-11-12 | 1977-11-08 | Production of novel derivatives of 3-/4-phenoxymethylpiperidino/-propanol |
| CS785460A CS228109B2 (en) | 1977-08-20 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpi |
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| Publication Number | Publication Date |
|---|---|
| CS228109B2 true CS228109B2 (en) | 1984-05-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS785459A CS228108B2 (en) | 1977-08-20 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpiperidino/propanol |
| CS785460A CS228109B2 (en) | 1977-08-20 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpi |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS785459A CS228108B2 (en) | 1977-08-20 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpiperidino/propanol |
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| Country | Link |
|---|---|
| CS (2) | CS228108B2 (en) |
-
1978
- 1978-08-21 CS CS785459A patent/CS228108B2/en unknown
- 1978-08-21 CS CS785460A patent/CS228109B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS228108B2 (en) | 1984-05-14 |
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