CS228110B2 - Production of novel derivatives of 3-/4-phenoxymethylpi - Google Patents
Production of novel derivatives of 3-/4-phenoxymethylpi Download PDFInfo
- Publication number
- CS228110B2 CS228110B2 CS785461A CS546178A CS228110B2 CS 228110 B2 CS228110 B2 CS 228110B2 CS 785461 A CS785461 A CS 785461A CS 546178 A CS546178 A CS 546178A CS 228110 B2 CS228110 B2 CS 228110B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- propoxy
- hydroxy
- group
- hydrogen
- phenoxymethylpiperidino
- Prior art date
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- -1 2-hydroxy-3- [4- (phenoxymethyl) piperidino] propoxy Chemical group 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 35
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 17
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 150000002431 hydrogen Chemical class 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 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 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
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- ZRZLIXKKYZCXKZ-UHFFFAOYSA-N 3-[4-(phenoxymethyl)piperidin-1-yl]propan-1-ol Chemical class O(C1=CC=CC=C1)CC1CCN(CC1)CCCO ZRZLIXKKYZCXKZ-UHFFFAOYSA-N 0.000 claims description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims 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
- 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
- 238000003419 tautomerization reaction Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 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 7
- 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
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 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 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- 150000008064 anhydrides Chemical class 0.000 description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- OXHUYOXGBYDMQM-UHFFFAOYSA-N 1-[(6-methyl-1h-indol-4-yl)oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C=12C=CNC2=CC(C)=CC=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 OXHUYOXGBYDMQM-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
- 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 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
- 239000011230 binding agent Substances 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
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 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
- 150000003254 radicals Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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 2
- ARFNSMYWLYZEPU-UHFFFAOYSA-N 1-(1h-indol-4-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C=1C=CC=2NC=CC=2C=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 ARFNSMYWLYZEPU-UHFFFAOYSA-N 0.000 description 2
- PFOVRLZFVUZAAA-UHFFFAOYSA-N 1-(2h-benzotriazol-4-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol;hydrochloride Chemical compound Cl.C=1C=CC=2NN=NC=2C=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 PFOVRLZFVUZAAA-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
- OYSPHZXMAJRFAZ-UHFFFAOYSA-N 1-[[6-(hydroxymethyl)-5-methyl-1H-indol-4-yl]oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound OC(COC1=C2C=CNC2=CC(=C1C)CO)CN1CCC(CC1)COC1=CC=CC=C1 OYSPHZXMAJRFAZ-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
- 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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HFYYHLKSHSXIDG-UHFFFAOYSA-N [1-(1h-indol-4-yloxy)-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-yl] 2,2-dimethylpropanoate Chemical compound C=1C=CC=2NC=CC=2C=1OCC(OC(=O)C(C)(C)C)CN(CC1)CCC1COC1=CC=CC=C1 HFYYHLKSHSXIDG-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 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
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 239000007788 liquid 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
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 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
- 239000000725 suspension 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
- 125000004169 (C1-C6) alkyl group Chemical group 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
- 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 1
- WBAXSQUIGRIDCS-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-(phenoxymethyl)piperidine Chemical compound C1CN(CC2OC2)CCC1COC1=CC=CC=C1 WBAXSQUIGRIDCS-UHFFFAOYSA-N 0.000 description 1
- RFIQLGKXBMUYIK-UHFFFAOYSA-N 1-[(2-methyl-1h-indol-4-yl)oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C1=CC=C2NC(C)=CC2=C1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 RFIQLGKXBMUYIK-UHFFFAOYSA-N 0.000 description 1
- RPPPPVYOQULVQH-UHFFFAOYSA-N 1-[(2-methyl-1h-indol-4-yl)oxy]-3-[4-[(2-methylphenoxy)methyl]piperidin-1-yl]propan-2-ol Chemical compound C1=CC=C2NC(C)=CC2=C1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1C RPPPPVYOQULVQH-UHFFFAOYSA-N 0.000 description 1
- OAAYZSLGIOZJDJ-UHFFFAOYSA-N 1-[(3-methyl-2h-indazol-4-yl)oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound C=12C(C)=NNC2=CC=CC=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 OAAYZSLGIOZJDJ-UHFFFAOYSA-N 0.000 description 1
- HJPNFCGJTPAFHE-UHFFFAOYSA-N 1-[(5,6-dimethyl-1H-indol-4-yl)oxy]-3-[4-(phenoxymethyl)piperidin-1-yl]propan-2-ol Chemical compound CC=1C(C)=CC=2NC=CC=2C=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 HJPNFCGJTPAFHE-UHFFFAOYSA-N 0.000 description 1
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- 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
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 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
- 150000003460 sulfonic acids Chemical class 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
- 229910052727 yttrium Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
(54) Způsob výroby nových derivátů 3-(4-fenoxymethylpiperidino)propanolu(54) A process for the preparation of new 3- (4-phenoxymethylpiperidino) propanol derivatives
Předložený vynález se týká způsobu výroby nových derivátů 3-(4-fenoxymethylpiperidinojpnopanolu obecného vzorce IThe present invention relates to a process for the preparation of novel 3- (4-phenoxymethylpiperidino) -opanol derivatives of the general formula I
v němž kdewhere
Ri a R2 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, alkoxyskupinu s 1 až 6 atomy uhlíku nebo skupinu vzorceZ is hydroxy, (C1-C6) alkoxy, or formula
Re /Re /
—N \—N \
R7R7
R6 a R7 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,R 6 and R 7 may be the same or different and are hydrogen, C 1 -C 6 alkyl or C 1 -C 4 hydroxyalkyl,
Rs znamená vodík nebo skupinu —O—Rs, přičemžR 5 is hydrogen or -O-R 8, wherein
Rs znamená vodík, alkanoylovou skupinu s 1 až 8 atomy uhlíku nebo benzoylovou či naftoylovou skupinu, která je popřípadě substituována halogenem, a!kylem s 1 až 6 atomy uhlíku, alkyloxyskupinou s 1 až 6 atomy uhlíku, alkoxykarbonylovou skupinou s 1 až 2 atomy uhlíku v alkoxyskupině, hydroxyskupinou, alkylthioskupinou s 1 až 6 atomy uhlíku, nitrilovou skupinou, nitroskupinou nebo trifluormethylovou skupinou,R is hydrogen, an alkanoyl group having 1-8 carbon atoms or benzoyl or naphthoyl group optionally substituted with halogen, and! (C 1 -C 6) alkyl, (C 1 -C 6) alkyloxy, (C 1 -C 2) alkoxycarbonyl, hydroxy, (C 1 -C 6) alkylthio, nitrile, nitro or trifluoromethyl group,
Rd 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 alkoxykarbonylovou skupinu s 1 až 2 atomy uhlíku v alkoxyskupině,R d and R s can 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, benzyloxycarbonyl or (C 1 -C 2) alkoxycarbonyl,
X a Y jsou stejné nebo mohou být vzájemně rozdílné a znamenají atom dusíku nebo skupinu —C= iX and Y are the same or can be different from each other and are a nitrogen atom or a group —C = i
R9 přičemžR9 where
Rg znamená vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, která je popřípadě substituována skupinou —-O—Re, 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 6 where R 8 is as defined above, or is -CO-Z wherein Z is as defined above, or a pharmacologically acceptable salt thereof , processes for their preparation and pharmaceutical compositions containing compounds of formula I.
Vzhledem k tomu, že sloučeniny vzorce I v případě, že Rs neznamená vodík, obsahují asymetrický atom uhlíku, jsou dále předmětem vynálezu opticky aktivní formy a racemické směsi těchto sloučenin.Since the compounds of formula I, when R 5 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 farmakolologicky použitelné soli mají při nízké toxicitě výrazné vasodilatační vlastnosti, které se hlavně projevují v poklesu krevního tlaku. Kromě toho bylo pozorováno potlačování adrenergických ,d-receptorů.The compounds of formula I and their pharmacologically usable salts have, at low toxicity, marked vasodilatory properties, which are mainly manifested in a decrease in blood pressure. In addition, suppression of adrenergic, d-receptors has been observed.
Alkylovými skupinami ve významu substituentů Ri, Ra, R4, Rs, Re, R7, Ra 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 a, R 4, R 5, R 6, R 7, R a 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, Ra, R6 a R7 obsahují 1 až 4 atomy uhlíku, a výhotině jsou jimi 2-hydroxyethylová a hydroxymethylová skupina.Hydroxyalkyl groups R 1, R a, R 6 and R 7 contain 1 to 4 carbon atoms and are, in particular, 2-hydroxyethyl and hydroxymethyl.
Alkoxyskupiny ve významu substituentů R.4, Rs, Rs 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 groups represented by R 4, R 5, R 5 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 methoxy- a ethoxykarbonylová skupina.Suitable alkoxycarbonyl groups R @ 4, R @ 5 and R @ 8 in particular are methoxy and ethoxycarbonyl.
Alkylthioskupinami ve významu substituentu R4, Rs a Rs jsou skupiny s 1 až 6, výhodně s 1 až 4 atomy uhlíku. Výhodná je methylmerkaptoskupina.Alkylthio groups R @ 4, R @ 5 and R @ 8 are groups having from 1 to 6, preferably from 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. Výhodný je acetylový a pivaloylový zbytek.Alkanoyl groups in the meaning of R 5 contain 1 to 8, preferably 1 to 6 carbon atoms, the alkyl groups having a straight, branched or cyclic chain. Acetyl and pivaloyl residues are preferred.
Alkanoyloxyalkylovou skupinou ve významu substituentů Ri a R2 jsou zbytky obsahující 1 až 6 atomů uhlíku, zejména acetoxymethyloivý 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 benzoylová a naftoylová, které mohou být výhodně substituovány methylem, halogenem a methoxyskupinami.Aroyl groups R @ 5 are benzoyl 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 IVThe novel compounds of the formula (I) according to the invention are prepared by the preparation of a compound of the formula (IV) in a manner known per se
v němžin which
X, Y, Ri a R2 mají shora uvedený význam, aX, Y, R 1 and R 2 are as defined above, and
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 V Ú * ,v] v němžR10 is hydrogen or the residue of acetyl, benzoyl, benzyl or tetrahydropyranyl, wherein in case indazoles capable of tautomerism can rest acetyl, benzoyl, benzyl or tetrahydropyranyl also on the second nitrogen atom of X, is reacted with a compound of the formula V U *, V] in which
A, B, Rd a Rs mají shora uvedený význam, a v případě, že symbol A znamená skupinu \A, B, Rd, and R5 are as defined above, and when A is \
0=0 /0 = 0 /
reakční produkt se poté redukuje, načež se v případě, že Ra znamená alkanoylovou skupinu s 1 až 8 atomy uhlíku nebo popřípadě substituovanou benzoylovou nebo naftoylo228110 vou skupinu, hydroxylová skupina, která je popřípadě přítomna ve významu symbolu R3, esterifikuje, nebo v případě, že Rs znamená vodík, pak se esterová skupina, která je popřípadě ve významu R3, hydrolyzuje a případně přítomná acetyiová, benzoyíová, benzylová nebo tetrahydropyranylová skupina, jakožto krycí skupina se odštěpí, nebo v případě, že jedna nebo několik skupin Ri, Rz a R9 představují hydroxymethylovou skupinu, připraví se taková skupina z hydroxymethylové, acylOxymethylové nebo alkoxykarbonylové skupiny s 1 až 2 atomy uhlíku v alkoxylové části redukcí nebo z alkanoyloxymethylové skupiny s až 6 atomy uhlíku hydrolýzou nebo se methylová skupina získá redukcí z alkoxykarbor nylové skupiny s 1 až 2 atomy uhlíku v alkoxylové části, a získané sloučeniny se popřípadě převedou na své farmakologicky použitelné soli.the reaction product is then reduced, where, when Ra is C1-C8 alkanoyl or optionally substituted benzoyl or naphthoylo228110, the hydroxyl optionally present as R3 is esterified or R 5 is hydrogen, then the ester group, which is optionally R 3, is hydrolyzed and the optionally present acetyl, benzoyl, benzyl or tetrahydropyranyl group is removed as the capping group, or when one or more of R 1, R 2 and R 9 represent hydroxymethyl, prepared from a hydroxymethyl, acyl-oxymethyl or alkoxycarbonyl group having 1 to 2 carbon atoms in the alkoxy moiety by reduction or from an alkanoyloxymethyl group having 1 to 6 carbon atoms by hydrolysis or a methyl group obtained by reduction from an alkoxycarbonyl group having 1 to 2 carbon atoms in alkoxy and the resulting compounds are optionally converted into their pharmacologically useful salts.
Reaktivními zbytky B ve sloučeninách vzorce V jsou zejména zbytky kyseliny, například kyselin halogenovodíkových a kyselin sulfonových.The reactive radicals B in the compounds of the formula V are in particular acid radicals, for example hydrohalic acids and sulfonic acids.
Postup podle vynálezu se provádí účelně v organickém rozpouštědle, které je za reakčních podmínek inertní, například v toluenu, dioxanu, ethylenglykoldimethyletheru, ethanolu, n-butanolu nebo dimethylformamidu, popřípadě v přítomnosti činidla vázajícího kyselinu.The process according to the invention is conveniently carried out in an organic solvent which is inert under the reaction conditions, for example in toluene, dioxane, ethylene glycol dimethyl ether, ethanol, n-butanol or dimethylformamide, optionally in the presence of an acid binding agent.
Reakce sloučenin vzorce IV 3 látkami vzorce V se provádí účelně za vyloučení kyslíku v přítomnosti činidla vázajícího kyselinu. Je možno používat také solí hydroxysloučenin vzorce IV s alkalickými kovy.The reaction of the compounds of formula IV with 3 with the compounds of formula V is conveniently carried out with the exclusion of oxygen in the presence of an acid binding agent. It is also possible to use alkali metal salts of the hydroxy compounds of the formula IV.
Sloučeniny vzorce IV jsou pro případ, že X a Y znamenají skupinu — C (R9]=, popsány v Helv. Chim. Acta 54, 2411 (1971), pro případ, že X znamená atom dusíku a Y znamená skupinu —C(R9) = rovněž popsány, pro případ, že Y znamená atom dusíku a X znamená skupinu —C(R9)==, popsány v Helv. Chim. Acta 35, 1740 (1952), pro případ, že X a Y znamenají atomy dusíku, popsány v J. Chem. Soc. 1956, 569.Compounds of formula (IV) are described in Helv Chim Acta 54, 2411 (1971) in case X and Y are - C (R 9) =, in case X is N and Y is - C (R 9) ) = also described, in case Y is a nitrogen atom and X is a group —C (R9) ==, described in Helv Chim Acta 35, 1740 (1952), in case X and Y are a nitrogen atom, described in J. Chem. Soc., 1956, 569.
Popřípadě prováděná redukce skupiny \Group reduction, if any \
C=O /C = O /
se provádí například pomocí komplexních hydridů kovů, jako natriumbiorhydridu, nebo katalytickou hydrogenací za použití katalyzátorů na bázi vzácných kovů.is carried out, for example, by complex metal hydrides, such as sodium hydride, or by catalytic hydrogenation using noble metal catalysts.
Případně prováděná redukce substituentů Ri, Rz a Rg ve sloučeninách vzorce I se provádí pomocí komplexních hydridů kovů, jako například lithiumaluminiumhydridu 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 R9 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 9 of the compounds of formula I can be carried out in a manner known per se under acidic or basic conditions.
Esterifikace hydroxylová skupiny ve významu symbolu Rs 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 5 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 Rio přicházejí v úvahu nižší alkanoylové skupiny, například acetylový zbytek, aroylové skupiny, například benzoylový zbytek, arylmethylové skupiny, například benzylový zbytek nebo cyklické ethery, například tetrahydpopyranylový zbytek. Odštěpení krycích skupin v substituentu Rjo se může provádět známým způsobem odpovídajícím jejich charakteru hydrolyticky nebo hydrogenclyticky.Suitable protecting groups for R 10 are lower alkanoyl groups, for example acetyl, aroyl groups, for example benzoyl, arylmethyl groups, for example benzyl or cyclic ethers, for example tetrahydopyranyl. The cleavage of the protecting groups in the substituent R10 may be carried out in a known manner corresponding to their nature, hydrolytically or by hydrogen glycol.
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 compressed, for example, tablets or dragees or suspended or dissolved in water with the addition of the appropriate excipients. or in an oil such as olive oil.
Nová sloučenina vzorce I podle vynálezu a její soli se mohou aplikovat v kapalné nebo pevné formě enterálně 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 tartrátový 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, laktozy, 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 vy228110 sokomolekulární polymery (jako- polyethylenglykoly); 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 enterally 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 regulating 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 weight polymers. (such as polyethylene glycols); 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-f enoxymethylpiperidino) propoxy ] -6-terc.butylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-tert-butylindole
4-[2-hydroxy-3-(4-fenoxymethylpiperldino)propoxy ] -6-methylbenzimidazol4- [2-hydroxy-3- (4-phenoxymethylpiperldino) propoxy] -6-methylbenzimidazole
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino') propoxy ] -6-methylbenzthiazol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylbenzthiazole
4-[2-hydroxy-3-(4-fenoxymethylpiperidino)propoxy ] -3-methylindazol.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-methylindazole.
Následující příklady blíže ilustrují syntézu sloučenin podle vynálezu. Tyto příklady však v žádném případě nepředstavují omezení předmětu vynálezu.The following examples illustrate in more detail the synthesis of 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- [ 2-hydroxy-3- (4-f enoxymethylpiperidino'j propoxy ] -2-ethoxykarbonylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole
Směs 0,9 g 2-ethoxykarbonyl-4-hydroxyinPříklad 3 dolu, 1,7 g N-(2,3-epoxypropylj-4-fenoxymethylpiperidinu, 1,2 g uhličitanu draselného a 50 ml acetonltrilu se zahřívá 10 hodin k varu pod zpětným chladičem, poté se za horka zfiltruje a filtrát se nechá přes noc vychladnout. Vykrystaluje 0,3 g 4- [ 2-hydroxy-3-(4-f enoxymethylpiperidino) propoxy j-2-ethoxykarbonylindolu (15 % teorie] o teplotě tání 168 až 170 °C.A mixture of 0.9 g of 2-ethoxycarbonyl-4-hydroxyinExample 3 below, 1.7 g of N- (2,3-epoxypropyl) -4-phenoxymethylpiperidine, 1.2 g of potassium carbonate and 50 ml of acetoniltril is heated at reflux for 10 hours. After cooling, the filtrate was allowed to cool overnight and 0.3 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole (15% of theory) crystallized, m.p. 168 to 170 ° C.
Příklad 2Example 2
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy]-2-hydroxymethylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethylindole
K suspenzi 0,95 g lithiamalticiinlunahydridu ve 45 ml absolutního tetrahydrofuranu se přikape při teplotě 0 °C roztok 4,5 g 4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxyj-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 j -2-hy droxymethylindolbenzoátu (47 % teorie] o teplotě tání 145 až 146 °C.A solution of 4.5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole in 25 ml of absolute tetrahydrofuran is added dropwise at 0 [deg.] C. to a suspension of 0.95 g of lithiamalticillin anhydride in 45 ml of absolute tetrahydrofuran, The mixture was stirred at room temperature for 1 hour, then quenched with cooling with brine, filtered, and after washing with tetrahydrofuran, 0.01 mol of benzoic acid was added to the combined filtrates. Recrystallization of the benzoate from 25 ml of ethyl acetate gave 2.5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethylindole benzoate (47% of theory), m.p. 145-146 ° C.
Analogickým způsobem jak je popsáno v příkladu 2 se získají následující sloučen’ny:In an analogous manner to that described in Example 2, the following compounds are obtained:
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-f enoxymethyl-piperldino) propoxy]-6- 174- [2-hydroxy-3- (4-phenoxymethylpiperldino) propoxy] -6-17
-methoxykarbonylindolu-methoxycarbonylindole
b) 4-[2-hydroxy-3-(4-fenoxymethylpiper idinoi) propoxy ] -6-hydroxymethyl-5-methylindol zb) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethyl-5-methylindole;
153 až 155 (ethylacetát)153 to 155 (ethyl acetate)
4- [ 2-hy droxy- 3- (4-f enoxymethyl-piperidino) propoxy J -6-methoxykarbonyl-5-methylindolu4- [2-hydroxy-3- (4-phenoxymethyl-piperidino) propoxy] -6-methoxycarbonyl-5-methylindole
Příklad 4Example 4
4-[ 2-hydroxy-3- (4-f enoxymethy lpiperidino) propoxy ]indol-2-karboxylová kyselina4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole-2-carboxylic acid
K suspenzi 2,0 g 4-[2-hydroxy-3-(4-fenoxymethylpiper idino) 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 zneutralizuje zředěnou kyselinou sírovou. Izoluje se 1,8 g 4-[2-hydroxy-3-(4-f enoxymethy lpiperidino j 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, the mixture is stirred for 16 hours at 50 DEG 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 5Example 5
4- [ 2-hydroxy-3- (4-f enoxymethylpiper idino) propoxy ] -2-methylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-methylindole
Směs 5,9 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy ] -2-hydroxymethylPříklad 6 indolu, 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% paládia na uhlí při 0,1 MPa tlaku vodíku.A mixture of 5.9 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethyl Example 6 indole, 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 (8.0 g) thus obtained was dissolved in 100 ml of methanol and hydrogenated using 2.0 g of 10% palladium on carbon at 1 atm of hydrogen pressure.
Po 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 isopropan-olu. Získá se 1,6 g 4-[2-hydroxy-3- (4-f enoxymethy] piperidino) propoxy j-2-methylindolbenzoát (28 % teorie) o teplotě tání 145 až 148 °C.After the calculated amount of hydrogen has been consumed, the mixture is filtered, the filtrate is concentrated to half its original volume, the pH is adjusted to 9 by addition of 2N sodium methoxide solution, refluxed for 10 minutes, poured into water and extracted. chloroform. After concentration of 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 were obtained 1.6 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-methylindolbenzoate (28% of theory), m.p. 145-148 ° C.
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 (rozpouštědlo)designation yield% melting point (solvent)
a) 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy ] -6-methylindol z(a) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole;
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidin-o) propoxy ] -6-hydroxymethylindolu4- [2-hydroxy-3- (4-phenoxymethylpiperidin-o) propoxy] -6-hydroxymethylindole
b) 4-(2-hydroxy-3-(4-fenoxymethy lpiperidino) propoxy ] -5,6-dimethylindol zb) 4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy) -5,6-dimethylindole;
4- [ 2-hydroxy-3- (4-f enoxymethy lpiperidino )propoxy] -6-hydroxymethyl-5-methylindol4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethyl-5-methylindole
122 až 123 (ethylacetát)122-123 (ethyl acetate)
Příklad 7Example 7
4- [ 2-pivaloyloxy-3 - (4-f enoxymethy lpiperidino)propoxy] indol4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] indole
Směs 4,4 g 4-[2-hydroxy-3-(4-fenoxymethylplperidino) propoxy ]indolacetátu, 10,2 g pivalové kyseliny a 2,0 g anhydridu pivalové kyseliny se míchá až do rozpuštění a potom 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-f enoxymethy lpiperidino) propoxy] indolu (69 % teorie) o teplotě tání 103 až 105 °C.A mixture of 4.4 g of 4- [2-hydroxy-3- (4-phenoxymethylplperidino) propoxy] indolacetate, 10.2 g of pivalic acid and 2.0 g of pivalic anhydride is stirred until dissolved and then the reaction mixture is left for 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.
Příklad 8Example 8
Analogickým způsobem jak je popsáno v příkladu 7 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 7:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-/2-pivaloyloxy-3-[4-(2-methoxyfenoxymethyl jpiperidino]propoxy/indol 66a) 4- / 2-Pivaloyloxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole 66
107 (ether) z107 (ether) 2
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl) piperidino ] propoxy/indolu a anhydridů pivalové kyseliny4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole and pivalic anhydrides
b) 4-[2-pivaloyloxy-3-(4-feno'xymethylpiperidino) propoxy ] -6-methylindolb) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ] -6-methylindolu a anhydridů pivalové kyseliny4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole and pivalic anhydrides
c) 4-[2-pivaloyloxy-3-(4-fenoxymethylpiperidino) propoxy]- 23c) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -23
-6-pivaloyloxymethylindol z-6-pivaloyloxymethylindole z
(směs Iigroinu a etheru] až 78 (ze směsi heptanu a etheru)(mixture of Igroin and ether) to 78 (from a mixture of heptane and ether)
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ] -6-hydroxymethylindolu a pivaloylchloridu4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethylindole and pivaloyl chloride
d) 4-[2-benzoyloxy-3-(4-fenoxymethylpiperidino) propoxy]- 40 indold) 4- [2-benzoyloxy-3- (4-phenoxymethylpiperidino) propoxy] -40 indole
108 až 110 (ether)108 to 110 (ether)
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidlno) propoxy ] indolu a anhydridů kyseliny benzoové4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole and benzoic anhydrides
e) 4- [ 2-pivaloyloxy-3- (4-fenoxymethylpiperidino) propoxy]- 24e) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -24
-2-pivaloyloxymethylindol z-2-pivaloyloxymethylindole z
až 95 (ze směsi heptanu a etheru)up to 95 (from a mixture of heptane and ether)
4- [ 2-hydroxy-3- (4-fenoxymethylpiper idino) propoxy ] - 2 - p i valoyloxymethylindolu a anhydridu pivalové kyseliny označení výtěžek % teplota tání°C (rozpouštědlo)4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-p-valoyloxymethylindole and pivalic anhydride designation yield% melting point ° C (solvent)
f) 4-/2-pivaloyloxy-3-[4-(2-methylfenoxymethyl) piperidino ] propOxy/-2-rnethylindiol zf) 4- [2-Pivaloyloxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] -2-methylindiol
4-/2-hydroxy-3- [ 4- (2-methylf enoxymethyl) piperidino ] propoxy/-2-methylindolu a anhydridu pivalové kyseliny4- [2-hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] -2-methylindole and pivalic anhydride
Příklad 9Example 9
4-/2-hydroxy-3- [ 4- (2-hydr oxyf enoxymethyl) piperidino ] propoxy/indol4- / 2-hydroxy-3- [4- (2-hydroxyphenoxymethyl) piperidino] propoxy / indole
13,8 g 4-/2-hydroxy-3-[4-(2-benzyloxyfenoxymethylpiperidino ] propoxy/indolu se hydrogenuje ve 250 ml methanolu při tepP ř í k 1 a d 10 lote 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-hydroxyf enoxymethyl) 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 at 10 bar of hydrogen pressure using 3 bar of hydrogen. g of 5% palladium on carbon, then the reaction mixture is filtered, the filtrate is concentrated and the residue is crystallized from ethyl acetate to give 4.7 g of 4- / 2-hydroxy-3- [4- (2-hydroxyphenoxymethyl) piperidino] propoxy / indole (42% of theory), m.p. 119-121 ° C;
Analogickým způsobem jak je popsáno v příkladu 9 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 9:
označení výtěžek % teplota tání °C (rozpouštědlo) aj 4-/2-hydroxy-3-[4-(4-hydroxyf enoxymethyl) piperidino ] propoxy/indol zdesignation yield% melting point ° C (solvent) aj 4- / 2-hydroxy-3- [4- (4-hydroxyphenoxymethyl) piperidino] propoxy / indole from
4-/2-hydroxy-3- [ 4- (4-benzyloxyf enoxymethyl) piperidino] propoxy/indolu bj 4-/2-hydroxy-3-[4-(2-karboxyf enoxymethyl j piperidino ] propoxy/indol z4- / 2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) piperidino] propoxy / indole bj 4- / 2-hydroxy-3- [4- (2-carboxyphenoxymethyl) piperidino] propoxy / indole
4-/2-hydroxy-3-[4-(2-benzyloxykarbonylf enoxymethyl j pipe- ridino ] propoxy/indolu4- / 2-hydroxy-3- [4- (2-benzyloxycarbonylphenoxymethylpiperidino) propoxy] indole
Γ ř í k 1 a cl 111 k 1 and cl 11
4-[2-pivaloxyloxy-3-( 4-f enoxymethylpiperidino )propoxy]benzimidazol4- [2-pivaloxyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole
3,8 g 4- [2-hy droxy-3-( 4-f enoxymethylpiperidino ) propoxy jbenzimidazolu a 1,3 g pivaloyichlorídu se vaří ve 25 ml pyridinu 2 hodiny pod zpětným chladičem. Po odpaření3.8 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole and 1.3 g of pivaloyl chloride are refluxed in 25 ml of pyridine for 2 hours. After evaporation
167 (isopropanol) rozpouštědla se zbytek vyjme 100 ml ch’oroformu. 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-pivaloy’oxy-3-(4-fenoxymethylpiperidino jpropoxy jbenzimidazolhydrochlorid o teplotě tání 132 až 134 °C.167 (isopropanol) of the solvent is taken up in 100 ml of chloroform. The chloroform solution is washed thoroughly with water, dried over sodium sulfate and finally 50 ml of ethereal hydrochloric acid solution are added. After concentration, 4- [2-pivaloyloxy] -3- (4-phenoxymethylpiperidino) propoxy] benzimidazole hydrochloride crystallizes from ethanol, m.p. 132-134 ° C.
teplota tání °C (rozpouštědlo)melting point ° C (solvent)
Příklad 12Example 12
Analogickým způsobem jak je popsáno v příkladu 11 se získá:In an analogous manner to that described in Example 11:
označení výtěžekdesignation yield
4-/2- (3,4,5-trimethoxybenzOyloxy)-3-(4-(2-chlorf enoxymethyl) piperidino ] propoxy/benzimidazol z4- / 2- (3,4,5-trimethoxybenzyloxy) -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 13Example 13
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) propoxy ] benztriazolhydrochloridu, 6,7 g anhydridu kyseliny pivalové a 33,3 g roztavené kyseliny pivalové se míchá po dobu 3 dnů při teplotě místnosti,A mixture of 5.1 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benztriazole hydrochloride, 6.7 g of pivalic anhydride and 33.3 g of molten pivalic acid is stirred for 3 days at room temperature,
158 až 160 (ethanol) poté se reakční směs vylije na led, zneutralizuje se roztokem amoniaku ve vodě 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-pivaloyloxy-3- (4-fenoxymethylpiperidino )propoxyjbenztriazolhydrochloridu (38 % teorie) o teplotě tání 131 až 133 °C.158-160 (ethanol) is then poured onto ice, neutralized with a solution of ammonia in water and extracted with methylene chloride. After concentrating the extract, the oily residue is taken up in methanol and the solution is slightly acidified with dilute hydrochloric acid. Evaporation of the solvent gave 2.53 g of 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride (38%), m.p. 131-133 ° C.
Příklad 14Example 14
Analogickým způsobem jak je popsáno v příkladu 13 se získají následující sloučeniny:The following compounds were obtained in an analogous manner to that described in Example 13:
označení výtěžek % teplota tání °C (rozpouštědlo)designation yield% melting point ° C (solvent)
a) 4-/2-(4-methylbenzoyloxy)-3-(4-( 2-methoxyf enoxymethyl) piperidino ] pr opoxy/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 anhydridu 4-methylbenzoové kyseliny v dioxanu4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benzotriazole and 4-methylbenzoic anhydride in dioxane
b) 4-/2-(2-chlorbenzoyloxy)-3- [ 4- (3-methylf enoxymethy 1) piperidino ] pnopoxy/benztriazol zb) 4- / 2- (2-Chlorobenzoyloxy) -3- [4- (3-methylphenoxymethyl) piperidino] pnopoxy / benztriazole from
4-/2-hydroxy-3- [ 4- (3-methyif enoxymethyl) piperidino ] propoxy/benztriazolu a anhydridu 2-chlorbenzoové kyseliny v dioxanu4- / 2-hydroxy-3- [4- (3-methyphenoxymethyl) piperidino] propoxy / benztriazole and 2-chlorobenzoic anhydride in dioxane
226116226116
Příklad 15Example 15
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy ] -3-hydroxymethylindazoldihydrochlorid4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-hydroxymethylindazole dihydrochloride
Na 3-acetoxymethyl-4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy ] 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-fenoxymethylpiperidino) propoxy ]-3-hydroxymethyli ndazoldihydrochiorid ve formě siabě žlutě zbarvených krystalů o teplotě tání 183 °C (rozklad).3-Acetoxymethyl-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-hydroxymethyldiazole dihydrochioride as pale yellow crystals of m.p. 183 DEG C. (decomposition).
Příklad 16Example 16
4- [ 2-pivaloyloxy-3- (4-f enoxymethyl piperidino )propoxy) Indazol4- [2-pivaloyloxy-3- (4-phenoxymethyl piperidino) propoxy) indazole
Směs 2,2 g 4-[2-hydroxy-3-(4-fenoxymethylpiperidino) propoxy jindazolu, 1,25 g anhydridu kyseliny pivalové a 10 g kysel ny pivaiové 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-f enoxymethylpiperidino) 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) propoxyindazole, 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 in the form of colorless crystals, 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 enoxymethy Ipiperi dino) 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-hy droxy-3- (4-f enoxymethylpiperidino)propoxy]indol, acetát, t. t. 121 až 124 stupňů Celsia, [o-)D 20 — —8,3° (1,5% roztok v methanolu).S (-) -4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole acetate, mp 121-124 degrees C, [α-] D 20 - 8.3 ° (1.5 % solution in methanol).
4- [ 2-hy droxy-3- (4-f enoxymethylpiperidino') propoxy]-2-ethoxykarbonylindol, t. t. 170 °C (isopropylalkohol).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole, m.p. 170 [deg.] C. (isopropyl alcohol).
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino)propoxy]-2-karbamoylindol, t. t. 182 °C (ethylacetát).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-carbamoylindole, m.p. 182 [deg.] C. (ethyl acetate).
4-[2-hydroxy-3-(4-fenoxymethylpiperidino)propoxyl-2-dimethylaminokarbonyUndol, 1.1. 178 °C (isopropylalkohol).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxyl-2-dimethylaminocarbonylindole, 1.1. 178 ° C (isopropyl alcohol).
4-[2-hydroxy-3-(4-f enoxymethylpiperidino') propoxy]-6-methoxykarbonylindol, t. t. 139 až 140 °C (ethylacetát).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methoxycarbonylindole, m.p. 139-140 ° C (ethyl acetate).
4-[2-hydroxy-3-(4-fenoxymethylpiperidino')propoxy]-6-methylindol, t. t. 122 až 123 °C (ethylacetát).4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole, m.p. 122-123 ° C (ethyl acetate).
2-ethoxykarhonyl-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, m.p. 189 ° C (isopropyl alcohol).
4-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino jpropoxy/indolbenzoát, t. t. 140 až 142 °C (ethylacetát).4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] indole 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-hy droxy-3- [ 4- (4-chlorf enoxymethy 1) piperidino jpropoxy/indolhenzoát, t. t. 156 až 158 °C (ethylacetát).4- [2-hydroxy-3- [4- (4-chlorophenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 156-158 [deg.] C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (2-methoxyfenoxymethyl) piperidino 1 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 jpropoxy/indolbenzoát, t. t. 128 až 129 °C (ethylacetát).4- [2-hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 128-129 [deg.] C. (ethyl acetate).
4-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidino jpropoxy/indolbenzoát, t. t. 152 až4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] indol benzoate, m.p.
154 °C (ethylacetát).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-hydr oxy-3- [ 4- (4-f luorf enoxymethyl ] piperidino ]propoxy/-6-methylindol, t. t. 137 až 139 C'C (ethylacetát).4- [2-hydroxy-3- [4- (4-fluorophenoxymethyl) piperidino] propoxy] -6-methylindole, mp 137-139 [ 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-benzyloxymethyl) -piperidino] propoxy/indol, olej.4- / 2-hydroxy-3- [4- (2-benzyloxymethyl) -piperidino] propoxy / indole, oil.
4-/2-hydroxy-3- [ 4- (4-benzyloxyfenoxymethyl)piperidino]propoxy/indol, t. t. 113 CC (ether).4- [2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) piperidino] propoxy] indole, mp 113 DEG C. (ether).
4- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxy]-2-pivaloyloxymethylindol, 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 až4- / 2-hydroxy-3- [4- (2,5-dimethylphenoxymethyl) piperidino | propoxy / indole, m.p.
155 Ál (ethylacetát).155 A1 (ethyl acetate).
5- [ 2-hydroxy-3- (4-f enoxymethylpiperidino) propoxyjindol, t. t. 121 až 123 °C (ethanol).5- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole, mp 121-123 ° C (ethanol).
1B1B
6- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy]indol, t. t. 144 až 145 °C (ethanol).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- [ 3- (4-fenoxymethylpiperidino) propoxy ] benzlmidazoldihydrochlorid, t. t. 144 až 146 stupňů Celsia.4- [3- (4-Phenoxymethyl-piperidino) -propoxy] -benzimidazole dihydrochloride, m.p. 144-146 ° C.
4- (2-hydroxy-3- (4-f enoxymethylpiperidino') propoxy]benzlmidazoldihydrochlorid, t. t. 123 až 125 °C (ethanol).4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole dihydrochloride, m.p. 123-125 ° C (ethanol).
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl) piperidino] propoxy/benzimidazoldihydrochlorid, t. t. 144 až 145 °C (ethanol).4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy] benzimidazole dihydrochloride, m.p. 144 DEG-145 DEG C. (ethanol).
4-/2-hydroxy-3- [ 4- (3-methylf enoxymethyl) piperidino ] propoxy/benzimidazoldihydr ochlorid, t. t. 118 až 120°C (ethanol).4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] benzimidazole dihydride, m.p. 118-120 [deg.] C. (ethanol).
4-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino ] propoxy/benzimidazoldihydrochlorid, t. t. 140 až 142 °C (ethanol).4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] benzimidazole dihydrochloride, m.p. 140 DEG-142 DEG C. (ethanol).
4- [2-hydroxy-3- (4-fenoxymethylpiperidino) poropoxy ] -6-methylbenzimidazoldihydrochlorid.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) poropoxy] -6-methylbenzimidazole dihydrochloride.
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy]benztriazolhydrochlorid, t. t. 187 až 189 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride, m.p. 187-189 ° C.
4-/2-hydroxy-3- [ 4- (2-methoxyf enoxymethyl) piperidino] propoxy 1 benztriazolhydrochlorid, t. t. 161 až 162 °C.4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy] benzotriazole hydrochloride, m.p. 161-162 ° C.
4-/2-hydroxy-3- [4- (3-methylf enoxymethyl) piperidino ] pr opoxy/benztriazolhydrochlorid, t. t. 206 až 208 °C.4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy / benzotriazole hydrochloride, m.p. 206 DEG-208 DEG.
4-(3-( 4-fenoxymethylpiperidino) propoxy ] benztriazolhydrochlorid, t. t. 259 až 260 °C.4- (3- (4-phenoxymethylpiperidino) propoxy) benzotriazole hydrochloride, m.p. 259-260 ° C.
4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino) propoxy Jindazol, t. t. 142 až 143 °C, hydrochlorid t. t. 220 až 222 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy Jindazole, mp 142-143 ° C, hydrochloride mp 220-222 ° C.
4-/2-hydroxy-3- [ 4- (2-chlorf enoxymethyl) piperidino Jpropoxy/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-hydroxy-3- [ 2-methylfenoxymethyl) piperidino jpropoxy/indazol, t. t. 127 až 129 stupňů Celsia (isopropylalkohol).4- (2-hydroxy-3- [2-methylphenoxymethyl) piperidino] propoxy / indazole, m.p. 127-129 degrees 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-fenoxymethylpiperidino)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 enoxymethylpiperidinoi) propoxy]indazol, t. t. 141 až 142 °C.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole, m.p. 141-142 ° C.
3- acetoxymethyl-4- [ 2-hydroxy-3- (4-fenoxymethylpiperidino )propoxy] indazolhydrochlorid, t. t. 203 až 204 °C.3-Acetoxymethyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole hydrochloride, m.p. 203-204 ° C.
4- [ 2-hydroxy-3- (4-fenoxymethyIpiperidlno )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 ] indaaol, t. t. 160 až 161 °C.4- (3- (4-phenoxymethylpiperidino) propoxy] indaol, 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, mp 130-131 degrees Celsius.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS785461A CS228110B2 (en) | 1976-11-12 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpi |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762651574 DE2651574A1 (en) | 1976-11-12 | 1976-11-12 | 3-Phenoxymethyl-piperidino 1-heterocyclyl-oxo-propane derivs. - useful as vasodilators and beta adrenergic receptor inhibitors |
| 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 |
| CS785461A CS228110B2 (en) | 1976-11-12 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpi |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS228110B2 true CS228110B2 (en) | 1984-05-14 |
Family
ID=27179547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS785461A CS228110B2 (en) | 1976-11-12 | 1978-08-21 | Production of novel derivatives of 3-/4-phenoxymethylpi |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS228110B2 (en) |
-
1978
- 1978-08-21 CS CS785461A patent/CS228110B2/en unknown
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