CS226022B2 - Method of preparing piperidinepropyl derivatives - Google Patents
Method of preparing piperidinepropyl derivatives Download PDFInfo
- Publication number
- CS226022B2 CS226022B2 CS807703A CS770380A CS226022B2 CS 226022 B2 CS226022 B2 CS 226022B2 CS 807703 A CS807703 A CS 807703A CS 770380 A CS770380 A CS 770380A CS 226022 B2 CS226022 B2 CS 226022B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- group
- radical
- hydroxy
- acid
- propoxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- -1 piperidinopropyl Chemical class 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims 1
- 125000004755 (C2-C7) acylamino group Chemical group 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims 1
- 125000005518 carboxamido group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000004494 ethyl ester group Chemical group 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- ZXCIUTMDQLANAZ-UHFFFAOYSA-N 2-[2-nitro-6-(oxiran-2-ylmethoxy)phenyl]acetic acid Chemical compound C1=CC=C([N+]([O-])=O)C(CC(=O)O)=C1OCC1OC1 ZXCIUTMDQLANAZ-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 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 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 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
- 230000000694 effects Effects 0.000 description 3
- ZKMDEINEUKCEKN-UHFFFAOYSA-N ethyl 2-[2-nitro-6-(oxiran-2-ylmethoxy)phenyl]acetate Chemical compound C1=CC=C([N+]([O-])=O)C(CC(=O)OCC)=C1OCC1OC1 ZKMDEINEUKCEKN-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000001903 2-oxo-3-phenylpropanoic acid Substances 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- NEJMFNXZNJIROS-UHFFFAOYSA-N ethyl 2-[2-[2-hydroxy-3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]-6-nitrophenyl]acetate Chemical compound C1=CC=C([N+]([O-])=O)C(CC(=O)OCC)=C1OCC(O)CN1CCC(COC=2C=CC=CC=2)CC1 NEJMFNXZNJIROS-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- GAKLFAZBKQGUBO-UHFFFAOYSA-N 2-methyl-3-nitrophenol Chemical compound CC1=C(O)C=CC=C1[N+]([O-])=O GAKLFAZBKQGUBO-UHFFFAOYSA-N 0.000 description 1
- HUARMQNULSLANA-UHFFFAOYSA-N 2-methyl-6-(piperidin-4-ylmethoxy)pyridine Chemical compound CC1=CC=CC(OCC2CCNCC2)=N1 HUARMQNULSLANA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- YEDQERJRGLCJKY-UHFFFAOYSA-N 4-[(2-chlorophenoxy)methyl]piperidine Chemical compound ClC1=CC=CC=C1OCC1CCNCC1 YEDQERJRGLCJKY-UHFFFAOYSA-N 0.000 description 1
- CCZZNPBXUZCPEZ-UHFFFAOYSA-N 4-[(2-methoxyphenoxy)methyl]piperidine Chemical compound COC1=CC=CC=C1OCC1CCNCC1 CCZZNPBXUZCPEZ-UHFFFAOYSA-N 0.000 description 1
- IGXCLKXDHNOUIB-UHFFFAOYSA-N 4-[(3-methylphenoxy)methyl]piperidine Chemical compound CC1=CC=CC(OCC2CCNCC2)=C1 IGXCLKXDHNOUIB-UHFFFAOYSA-N 0.000 description 1
- QBVYAJIMGHTLOC-UHFFFAOYSA-N 4-[(4-phenylmethoxyphenoxy)methyl]piperidine Chemical compound C1CNCCC1COC(C=C1)=CC=C1OCC1=CC=CC=C1 QBVYAJIMGHTLOC-UHFFFAOYSA-N 0.000 description 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FHNJZIRUVFQEPH-UHFFFAOYSA-N [3-(piperidin-4-ylmethoxy)phenyl]methanol Chemical compound OCC1=CC=CC(OCC2CCNCC2)=C1 FHNJZIRUVFQEPH-UHFFFAOYSA-N 0.000 description 1
- XULBNNWZAAFEGQ-UHFFFAOYSA-N acetic acid;4-[2-hydroxy-3-[4-(phenoxymethyl)piperidin-1-yl]propoxy]-1,3-dihydroindol-2-one Chemical compound CC(O)=O.C=1C=CC=2NC(=O)CC=2C=1OCC(O)CN(CC1)CCC1COC1=CC=CC=C1 XULBNNWZAAFEGQ-UHFFFAOYSA-N 0.000 description 1
- 150000001243 acetic acids Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
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Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) Způsob přípravy piperidinopropylových derivátů(54) A method for preparing piperidinopropyl derivatives
Vynález se týká způsobu přípravy piperidinopropylových derivátů obecného vzorce IThe invention relates to a process for the preparation of piperidinopropyl derivatives of the general formula I
kdewhere
R, a Rg, které mohou být stejné nebo rozdílné, znamenají atom vodíku nebo alkylovou skupinu s 1 až 6 atomy uhlíku nebo společně elkylenový zbytek s 2 až 4 atomy uhlíku, R^ značí vodík nebo skupinu -O-R^, přičemž Rg je vodík nebo acylový zbytek se 2 až 7 atomy uhlíku, znamená vodík nebo formylový zbytek, A znamená skupinu X, = Y,, přičemž X^ a Y^ mohou být stejné nebo rozdílné a znamenají dusík nebo skupinu -C= R6 ve které Rg značí vodík, alkylovou skupinu s 1 až 6 atomy uhlíku, která jé případně substituovaná skupinou -Q-Rj, karboxylovou nebo alkoxykarbonylovou skupinou s 1 až 6 atomy uhlíku, skupinu Xg-Yg, ve které Xg značí CHg-skupinu nebo skupinu N-R?, přičemž R? značí vodík nebo alkylovou skupinu s 1 až 6 atomy uhlíku, a Yg znamená CHg-skupinu nebo skupinu C=Z, přičemž Z značí atomy kyslíku nebo síry, nebo A značí skupinu -CRg»CRg-, přičemž Rg a Rg představují dohromady -CH=CH-CH=CH- můstek, s pravidlem, že Y1 nebo Yn je spojen se zbytkem N-R^ obecného vzorce I, aR 8 and R 8, which may be the same or different, represent a hydrogen atom or a C 1 -C 6 alkyl group or together an C 2 -C 4 alkylene radical, R 6 represents hydrogen or -OR 6 wherein R 8 is hydrogen or an acyl radical having 2 to 7 carbon atoms, represents hydrogen or a formyl radical, A represents a group X, = Y, wherein X ^ and Y ^ may be the same or different and represent a nitrogen or a group -C = R skupinu in which Rg represents hydrogen C 1 -C 6 alkyl optionally substituted by -Q-R 3, carboxyl or C 1 -C 6 alkoxycarbonyl, Xg-Yg, wherein Xg is CHg, or NR 7, wherein R is ? is hydrogen or alkyl having 1 to 6 carbon atoms, and Yg represents a CH group or C = Z, wherein Z represents oxygen or sulfur, A represents -CRg »CRg-, wherein Rg and Rg together represent - CH = CH-CH = CH- bridge, with the proviso that Y 1 or Y n is linked to the radical NR 1 of formula I, and
B znamená heterocyklický zbytek so 3 až 12 atomy uhlíku a 1 až 3 heteroatomy vybranými ze skupiny dusíku nebo a/ kyslíku, nebo Jestliže A představuje Xg-Y, nebo -GH,(=Gl(q-, také B represents a heterocyclic radical having from 3 to 12 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of nitrogen and / or oxygen, or if A represents Xg-Y, or -GH, ( = Gl (q-, also
i fenylový zbytek, které jsou případně jednou nebo vícenásobně, substituovány halogene·, hydroxy-, nebo elkylovou skupinou s 1 až 6 atomy uhlíku, která případná nese hydroxy -and the phenyl radical, which is optionally mono- or polysubstituted, substituted by halogen, hydroxy- or C1-C6-alkyl, optionally bearing hydroxy-
amido-, alkylkarbonylemino-skupinou s 1 až 6 atomy uhlíku v alkylovém zbytku, acylovou skupinou se 2 až 7 atomy uhlíku nebo alkylsulfonylemino - skupinou s 1 ež 6 atomy uhlíku v alkylovém zbytku, a jejich farmakologicky nezávadných solí.an amido, alkylcarbonylemino group having 1 to 6 carbon atoms in the alkyl radical, an acyl group having 2 to 7 carbon atoms or an alkylsulfonylemino group having 1 to 6 carbon atoms in the alkyl radical, and their pharmacologically acceptable salts.
Protože mají sloučeniny vzorce I v případě, když R, není vodík, asymetrický atom uhlíku, mohou se vyskytovat v opticky aktivní formě nebo jako racemická směs. Předmětem vynálezu jsou jak racemické formy, tak také optické isomery.Since the compounds of formula I, when R 1 is not hydrogen, have an asymmetric carbon atom, they may exist in optically active form or as a racemic mixture. The invention relates to both racemic forms and optical isomers.
Acylovými skupinami, které jsou případně znázorněny substituentem R^, mohou být zbytky kyseliny přímých nebo rozvětvených alifatických karboxylových kyselin se dvěma až sedmi atomy uhlíku nebo aromatických karboxylových kyselin případně substituovaných atomy halogenu, slkylovými nebo alkoxyskupinami s 1 až 6 atomy uhlíku. Výhodný je acetylový, pivaloylový a benzoylový zbytek.The acyl groups optionally represented by R ^ may be straight or branched chain aliphatic carboxylic acids having two to seven carbon atoms or aromatic carboxylic acids optionally substituted by halogen atoms, alkyl or alkoxy groups having 1 to 6 carbon atoms. Acetyl, pivaloyl and benzoyl residues are preferred.
Alkylové nebo alkoxyskupiny, které se vyskytují v definici substituentú R, , Rg, Rj Rg, R? a B, mohou být přímé nebo rozvětvené a obsahují 1 až 6, s výhodou 1 až 4 atomy uhlíku. Výhodné je methylová, propylová a terč. butylová skupina nebo methoxy-, ethoxy-, propoxy-, a n-butoxy-skupina.Alkyl or alkoxy groups which occur in the definition of the substituents R 1, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, and B may be straight or branched and contain 1 to 6, preferably 1 to 4, carbon atoms. Preferred are methyl, propyl and target. butyl or methoxy, ethoxy, propoxy, and n-butoxy groups.
Alkylenový zbytek případně tvořený substituenty R, a Rg může obsahovat 2 až 4 atomy uhlíku.The alkylene radical optionally formed by the substituents R 1 and R 8 may contain 2 to 4 carbon atoms.
V rámci vynálezu se rozumí jako halogen fluor, chlor, brom a jod, obzvláětě fluor, chlor a brom.Within the scope of the invention, halogen is understood to mean fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.
Pod heterocyklickým zbytkem substituentu B se rozumí monocykly, např. pyridylový nebo pyrimidylový zbytek, bicykly, např. benzimidazolinonylový, benzimidazolinylový, benztriezolylový, indazolylový nebo benzodioxolanylový zbytek nebo tricykly, např. karbazolylový zbytek, s jedním, dvěma nebo třemi heteroatomy. Obzvláětě výhodný je pyridylový, pyrimidylový, benzimidazolinonylový a benzodioxolanylový zbytek.The heterocyclic radical of substituent B means monocycles, for example pyridyl or pyrimidyl, bicycles, for example benzimidazolinonyl, benzimidazolinyl, benztriezolyl, indazolyl or benzodioxolanyl or tricycles, for example carbazolyl, with one, two or three heteroatoms. Particularly preferred are the pyridyl, pyrimidyl, benzimidazolinonyl and benzodioxolanyl radicals.
Heterocyklickým zbytkem, který tvoří benzenový kruh se skupinou A, je hlavně benzimidazolinon-/2/-, benzimidazolinthion-/2/-, oxindol-, indazol-, karbazol-, benztriazol-, benzimidazol-, indolinový a indolový zbytek.The heterocyclic moiety which forms the benzene ring with group A is mainly benzimidazolinone- (2) -, benzimidazolinthione- (2) -, oxindole-, indazole-, carbazole-, benztriazole-, benzimidazole-, indoline- and indole-residues.
Sloučeniny obecného vzorce I a jejich farmakologicky nezávadné soli brzdí adrenergickéíů-receptory a současně snižují ve velké míře krevní tlak. Jsou proto vhodné k léčení nebo profylaxi srdečních onemocnění a onemocnění krevního oběhu.The compounds of formula (I) and their pharmacologically acceptable salts inhibit adrenergic receptors while lowering blood pressure to a large extent. They are therefore suitable for the treatment or prophylaxis of heart and circulatory diseases.
V DE-OS 2727630 jsou popsány a nárokovány sloučeniny podobné struktury a účinku. Změnou heterocyklických fenolových částí a zaváděním heterocyklů do postranního řetězce bylo docíleno překvapujícího zlepěení účinku.DE-OS 2727630 discloses and claims compounds of similar structure and activity. By altering the heterocyclic phenol moieties and introducing the heterocycles into the side chain, a surprising improvement in effect was achieved.
Příprava nových sloučenin obecného vzorce I se vyznačují tím, že se sloučenina obecného vzorce IIThe preparation of the novel compounds of the formula I is characterized in that the compounds of the formula II are used
(II), kde R], Rj, Rp A a B máji výše uvedený význam a Q představuje odštěpitelnou skupinu, redukuje s cyklisuje, a potom ae sloučeniny obecného vzorce I, ve kterých Rj znamená hydroxyskupinu, reaktivním derivátem kyseliny případné acylují, zbytek Rg nebo substituent ve zbytku B se případné přeméní na jiný zbytek Rg nebo jiný eubstituent ve zbytku B a získané sloučeniny obecného vzorce I se případné převedou na farmakologicky nezávadné soli.(II) wherein R 1, R 1, R p A and B are as defined above and Q is a leaving group, reduced with cyclization, and then a compound of formula I wherein R 1 is hydroxy, optionally acylated with a reactive acid derivative, or the substituent in residue B is optionally converted to another residue R 8 or another eubstitute in residue B and the compounds of formula I obtained are optionally converted into pharmacologically acceptable salts.
Q ve sloučeninách obecného vzorce II, jsou všechny zbytky, které se mohou nukleofilné substituovat. Takovými zbytky jsou např. atomy halogenu, s výhodou brom nebo chlor, skupina esteru kyseliny sulfonové, eminoimidazolylová, nízká elkoxy- nebo také merkaptoskupina.Q in the compounds of formula II are all radicals which can be nucleophilic substituted. Such radicals are, for example, halogen atoms, preferably bromine or chlorine, sulfonic acid ester group, eminoimidazolyl group, low alkoxy or mercapto group.
Způsob podle vynálezu ee výhodné provádí v inertním rozpouštédle, např. vodé, ethanolu, dioxanu nebo dimethylformamidu, případně za přítomnosti činidla vázajícího kyseliny. Reakce se mohou také uskutečnit po smíchání reakčních složek bez rozpouštědla. Reakce se provádí stáním při teplotě místnosti nebo zahříváním, popřípadě pod inertním plynem.The process according to the invention is preferably carried out in an inert solvent such as aqueous, ethanol, dioxane or dimethylformamide, optionally in the presence of an acid binding agent. The reactions can also be carried out after mixing the reactants without solvent. The reaction is carried out by standing at room temperature or by heating, optionally under an inert gas.
Redukce se s výhodou provádí katalyticky buzeným vodíkem.The reduction is preferably carried out by catalytically excited hydrogen.
Případně prováděné dodatečné acylace sloučenin obecného vzorce I, ve kterém znamená Rj hydroxylovou skupinu, se může provádět obvyklým způsobem reakcí s reaktivním derivátem kyseliny, např. halogenidem kyseliny, azidem kyseliny nebo enhydridem kyseliny, případně ca přítomnosti činidla vázajícího kyselinu, např. pyridinu, v rozpouštědle, např. acetonu, benzenu, dimethylformamidu nebo také v přebytku kyseliny.The optional additional acylations of the compounds of formula I in which R1 is a hydroxyl group can be carried out in a conventional manner by reaction with a reactive acid derivative, e.g. an acid halide, acid azide or acid anhydride, optionally in the presence of an acid binding agent such as pyridine. a solvent such as acetone, benzene, dimethylformamide or an excess of acid.
Jako dodatečná přemšna substituentu Rg na jiný substituent Rg přichází např. v úvahu redukce alkoxykarbonylové skupiny na hydroxymethylový zbytek. Tato redukce se může provádět známými způsoby. S výhodou se redukuje ester kyseliny karboxylové komplexními hydridy kovu, např. hydridem lithno-hlinitým, v neutrálním organickém rozpouštědle., např. tetrahydrofUranu.As an additional conversion of the substituent Rg to another substituent Rg, for example, reduction of the alkoxycarbonyl group to a hydroxymethyl radical is contemplated. This reduction can be carried out by known methods. Preferably, the carboxylic acid ester is reduced with complex metal hydrides, e.g., lithium aluminum hydride, in a neutral organic solvent, e.g., tetrahydrofuran.
Jako dodatečná přeměna substituentu ve zbytku se může např. uvést převedení amlnoskupiny na alkylkarbonylemido- nebo alkylsulfonylemido skupinu. Tyto reakce se provádějí rovněž podle známých způsobů obvyklými acylačními činidly, jako např. anhydridy kyseliny karboxylové, chloridy kyseliny karboxylové nebo chloridy kyseliny slkylsulfonové.An additional conversion of a substituent in a residue can be, for example, the conversion of an amino group to an alkylcarbonylemido- or alkylsulfonylemido group. These reactions are also carried out according to known methods with conventional acylating agents, such as, for example, carboxylic anhydrides, carboxylic acid chlorides or alkylsulphonic acid chlorides.
Sloučeniny podle vynálezu vzorce I se mohou získat ve formě racemické směsi. Dělení racemátu na opticky aktivní formy se provádí známými způsoby přes diastereomerní soli •ktlvních kyselin jako např. kyseliny vinné, jablečné nebo kafrsulfonové.The compounds of the invention of formula I can be obtained in the form of a racemic mixture. The resolution of the racemate into the optically active forms is carried out by known methods via diastereomeric salts of fatty acids such as tartaric, malic or camphorsulfonic acids.
Nové sloučeniny obecného vzorce I se získají za reakčních podmínek popsaných způsobů převážně jako ediční soli s kyselinou, např. jako bydrochloridy, a mohou se převést voámýffll způsoby bez dalšího na volné báze.The novel compounds of the formula (I) are obtained under the reaction conditions of the processes described above mainly as acid addition salts, e.g. as hydrochlorides, and can be converted into the free base without further purification.
K převedení sloučenin obecného vzorce I na farmakologicky nezávadné soli se nechají reagovat tyto sloučeniny, s výhodou v organickém rozpouštědle, s ekvivalentním množstvím anorganické nebo organické kyseliny, např. kyseliny solné, bromovodíkové, fosforečné, sírové, octové, citrónové, maleinové.To convert the compounds of formula I into pharmacologically acceptable salts, they are reacted, preferably in an organic solvent, with an equivalent amount of an inorganic or organic acid, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid.
Pro přípravu léčiv se smíchají látky vzorce I známým způsobem, s vhodným farmaceutickým nosičem, aromatickými chulovými látkami a barvivý a vytvarují se např. jako table-, ty nebo dražé nebo za přídavku příslušných pomocných látek se suspendují nebo rozpustí ve vodě nebo oleji, jeko např. olivovém oleji.For the preparation of medicaments, the compounds of the formula I are admixed in a known manner, with a suitable pharmaceutical carrier, flavoring substances and coloring agents, and are formed, for example, as tablets, dragees or dragees, or suspended or dissolved in water or oil such as olive oil.
Nové látky podle vynálezu vzorce I a jejleh soli se mohou aplikovat v kapalné nebo pevná formě enterálně nebo parenterálně. Jako injekční prostředí se s výhodou použije voda $ která obsahuje přísady obvyklá pro injekční roztoky jako stabilizační prostředek, prostředek usnadňující rozpouětění nebo pufr. Takovými přísadami je např. vinanový nebo citrenový pufr, ethanol, komplexotvorná látka (jako ethylendiamintetraoctová kyselina a její netoxické soli), vysokomolekulární polymery (jako kapalný polyethylenoxid) k regulaci viskosity. Jako pevné nosiče přicházející např. v úvahu škroby, laktoza, mannit, methylcelulóza, talek, vysoce disperzní kyselina křemičitá, vyskomolekulární mastné kyseliny (jako kyselina stearová) želatina, agar-agar, fosforečnan vápenatý, stearan hořečnatý, žlvočiSné a rostlinné tuky a pevné vysokomolekulární polymery (jako polyethylenglykoly). Přípravky vhodná pro orální aplikaci'mohou případně obsahovat chuíové látky a sladidla.The novel compounds of the invention of formula (I) and its salts may be administered in liquid or solid form enterally or parenterally. Preferably, water is used as the injectable medium, which contains additives customary for injectable solutions as a stabilizing agent, a dissolution aid or a buffer. Such additives are, for example, tartrate or citrate buffer, ethanol, a complexing agent (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) to control viscosity. Suitable solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids (such as stearic acid) gelatin, agar-agar, calcium phosphate, magnesium stearate, bovine and vegetable fats and solid high molecular weight. polymers (such as polyethylene glycols). Formulations suitable for oral administration may optionally contain flavoring and sweetening agents.
Podávaná dávka závisí na stáří, zdraví a hmotnosti příjemce, závažnosti onemocnění, druhu současně případně prováděných dalěích léčením častých případech léčení a druhu žádaného účinku. Obvykle je denní dávka účinné sloučeniny v rozmezí 0,1 až 50 mg/kg tělesná hmotnosti. Normálně je účinné 0,5 až 40 a s výhodou 1,0 až 20 mg/kgZden v jedné nebo více dávkách za den, aby se dosáhlo žádaných výsledků.The dose to be administered depends on the age, health and weight of the recipient, the severity of the disease, the type of concomitant therapy that may be carried out, the frequent treatment cases and the type of effect desired. Usually, the daily dose of the active compound is in the range of 0.1 to 50 mg / kg body weight. Normally, 0.5 to 40, and preferably 1.0 to 20 mg / kg Zden in one or more doses per day is effective to achieve the desired results.
Ve smyslu předloženého vynálezu je kromě sloučenin uvedených v příkladech výhodná následující sloučenina: 4-[2-hydroxy-3-/4-fenoxymethylpiperidino/-propoxy}6,7-cyklopenteno-2-benzimidazolinomFor the purposes of the present invention, the following compound is preferred in addition to the exemplified compounds: 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy} 6,7-cyclopenteno-2-benzimidazolinoma
Vynález bude blíže objasněn v následujících příkladech. Ukazují některé z četných možných variant přípravy, které se mohou použít k syntéze sloučenin podle vynálezu, aniž by omezovaly rozsah vynálezu.The following examples illustrate the invention. They show some of the many possible preparation variants that can be used to synthesize the compounds of the invention without limiting the scope of the invention.
Přiklad 1Example 1
4- f2-hydroxy-3-/4-fenoxymethyl-piperidino/-propoxy] -oxindol-acetát4- [2-hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy] -oxindole acetate
Roztok 7,8 g ethylesteru kyseliny 2-t2-hydroxy-3-/4-fenoxymethyl-piperidino/-propoXyJ-ó -nitrofenyloctové kyseliny ve 100 ml ethanolu a 100 ml kyseliny octové se hydrogenuje. při teplotě místnosti a 0,1 UPa tlaku vodíku za použití 10% paladia na uhlí. Po odsátí katalyzátoru se destiluje ve vakuu a zbytek se rozpustí ve vodě a filtruje. Přídavkem roztoku uhličitanu sodného se vyloučí báze a odsaje se. Rozpuštěním báze v asi 150 ml octanu a 5 ml kyseliny octová za horka se získá po ochlazení a odsátí 2,1 g 4-[2-hyčroxy-3-/4-fenoxyasthyl-piperidino/-propoxy]-oxindol-aoetátu (27 % teorie) o teplotě tání 125 ei 130 °C.A solution of 7.8 g of 2- [2-hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy] -6-nitrophenylacetic acid ethyl ester in 100 ml of ethanol and 100 ml of acetic acid is hydrogenated. at room temperature and 0.1 psi hydrogen pressure using 10% palladium on carbon. After suctioning off the catalyst, it is distilled under vacuum and the residue is dissolved in water and filtered. Addition of sodium carbonate solution precipitates the base and is filtered off with suction. Dissolution of the base in about 150 ml of acetate and 5 ml of hot acetic acid gave, after cooling and suction, 2.1 g of 4- [2-hydroxy-3- (4-phenoxyasthyl-piperidino) -propoxy] -oxindole-o-acetate (27%). m.p. 125 ei 130 ° C.
Analogickým způsobem, jak popsáno v příkladu 1, se získá:In an analogous manner to that described in Example 1, one obtains:
OznačeníDesignation
Výtěžek % teorieYield% of theory
Teplota tání °C (rozpouětědlo)Melting point ° C (solvent)
a) 4-<2-hydroxy-3-[4-/2-methoxyfenoxymethyl/-piperidino] propoxy>-oxindol’-acetát z ethylesteru 37 '2-<2-hydroxy-3-[4-/2methoxy-fenoxymethyl/-pi- , peridino] -propoxy>-6-nitrofenyloctové kyselinya) 4- <2-hydroxy-3- [4- (2-methoxyphenoxymethyl) -piperidino] propoxy] -oxindole acetate from ethyl ester 37 '2- <2-hydroxy-3- [4- (2-methoxy-phenoxymethyl)] - [beta] -, peridino] -propoxy-6-nitrophenylacetic acid
114 až 118 (octan)114 to 118 (acetate)
OznačeníDesignation
Výtěžek % teorieYield% of theory
Teplota tání °C (rozpouštědlo)Melting point ° C (solvent)
b) 4-<2-hydroxy-3-[4-/3-methylfenoxymethyl/-piperidino]propoxy>-oxindol-acetát 28 z ethylesterub) 4- <2-hydroxy-3- [4- (3-methylphenoxymethyl) -piperidino] propoxy] -oxindole acetate 28 from ethyl ester
2-<2-hydroxy-3-[4-/3-methylf enoxymethyl/-piperidino]propoxy>-6-nitro-fenyloctové kyseliny2- <2-hydroxy-3- [4- (3-methylphenoxymethyl) -piperidino] propoxy> -6-nitro-phenylacetic acid
c) 4-<2-hydroxy-3-[4-/4-hydroxyfenoxymethyl/-piperidino]-propoxy>-oxindol z ethylesteru 38c) 4- <2-hydroxy-3- [4- (4-hydroxyphenoxymethyl) -piperidino] -propoxy] -oxindole from ethyl ester 38
2-<2-hydroxy-3-[4-/4-benzyloxyfenoxymethyl/-piperidino]-propoxy} -ó-nitro-fenyloctové kyseliny2- <2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) -piperidino] -propoxy} -o-nitro-phenylacetic acid
d) 4-<2-hydroxy-3-[4-/2-chlor-fenoxymethyl/-piperidino] -propoxy>-oxindol z ethylesteru 33d) 4- <2-hydroxy-3- [4- (2-chloro-phenoxymethyl) -piperidino] -propoxy] -oxindole from ethyl ester 33
2-<2-hydroxy-3-[4-/2-chlor-f enoxymethyl/-piperidino]-propoxy>-6-nitrofenyloctové kyseliny2- <2-hydroxy-3- [4- (2-chloro-phenoxymethyl) -piperidino] -propoxy> -6-nitrophenylacetic acid
e) 4-<2-hydroxy-3-[4-/3-hydroxy mefhyl-f enoxymethyl/-piperidino] propoxy>-oxindol 27 z ethylesterue) 4- <2-hydroxy-3- [4- (3-hydroxymethyl-phenoxymethyl) -piperidino] -propoxy] -oxindole 27 from ethyl ester
2-<2-hydroxy-3-[4-/3-hydroxymethyl-fenoxymethyl/-piperidinq]2- <2-hydroxy-3- [4- (3-hydroxymethyl-phenoxymethyl) -piperidine]
-propoxy>-6-nitro-fenyloctové kyseliny-propoxy-6-nitro-phenylacetic acid
f) 4-<(2-hydroxy-3-[4-/2-methyl-6pyridoxymethyl/-piperidino]-propoxy>oxindol z ethylesteru 17f) 4 - <(2-hydroxy-3- [4- (2-methyl-6-pyridoxymethyl) -piperidino] -propoxy] -oxindole from ethyl ester 17
2-<2-hydroxy-3-[4-/2-methyl-6pyridoxymethyl/-piperidino]propoxy>-6-nitro-fenyloctové2- <2-hydroxy-3- [4- (2-methyl-6-pyridoxymethyl) -piperidino] propoxy> -6-nitro-phenylacetic acid
g) 4-<2-hydroxy-3-[4-/4-aminokarbony1 methy 1-f enoxyme thyl/-piperidino] propoxy)-oxindol-ac a tát z ethylesteru 46g) 4- (2-Hydroxy-3- [4- (4-aminocarbonylmethyl-phenoxymethyl) -piperidino] propoxy) oxindole-ac and ethyl ester melt 46
2-<2-hydroxy-3-[4-aminokarbonyl-methyl-fenoxymethyl/-piperidino]-propoxy>-6-nitro-fenyloctové kyseliny2- <2-hydroxy-3- [4-aminocarbonyl-methyl-phenoxymethyl / -piperidino] -propoxy> -6-nitro-phenylacetic acid
161 až 162 (octan)161 to 162 (acetate)
19; (ethanol) až 165 (methanol)19; (ethanol) to 165 (methanol)
152 až 154 (methanol)152 to 154 (methanol)
165 až 167 (methanol)165 to 167 (methanol)
173 až 175 (methanol)173 to 175 (methanol)
Ethylester 2-(2-hydroxy-3-/4-í'enoxymethyl-piperidino/-propoxyJ-6-nitro-fenyloctové — kyseliny potřebný jako výchozí látka k přípravě předchozí sloučeniny podle příkladu 1 se získá následujícím způsobem:The 2- (2-hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy) -6-nitro-phenylacetic acid ethyl ester required as a starting material for the preparation of the preceding compound of Example 1 was obtained as follows:
2-ellyloxy-6-nitro-toluen2-Elyloxy-6-nitro-toluene
K 76,6 g 2-methyl-3-nitrofenolu se přidá ve 200 ml methanolu 84,6 ml allylbromidu a přikape se 375 ml 2 N roztoku methylátu sodného. Po 18hodinovém míchání při teplotě místnosti se destiluje a zbytek se rozpustí ve vodě a etheru. Po odpaření etherové fáze se získá 95,7 g 2-sllyloxy-6-nitrotoluenu (99 % teorie).To 76.6 g of 2-methyl-3-nitrophenol, 84.6 ml of allyl bromide was added in 200 ml of methanol, and 375 ml of 2 N sodium methylate solution was added dropwise. After stirring at room temperature for 18 hours, it was distilled and the residue was dissolved in water and ether. Evaporation of the ether phase gave 95.7 g of 2-sllyloxy-6-nitrotoluene (99% of theory).
Ethylester -2-ellyloxy-6-nitro-fenylpyrohroznové kyseliny-2-Elyloxy-6-nitro-phenyl-pyruvic acid ethyl ester
0,625 molu terč. butylátu draselného, 542 ml diethylesteru kyseliny oxalové a 95,7 g 2-ellyloxy-6-nitro-toluenu se nechá míchat 3 hodiny při 60 °C, přidá se 1 N kyseliny octové a extrahuje sa etherem. Oxalový ester zbylý v etherovém zbytku se odstraní při zvýěené teplotě pomocí vodní vývěvy. Získá se 171 g ethylesteru 2-ellyloxy-6-nitro-fenylpyrohroznové kyseliny.0.625 mole target potassium butylate, 542 ml of oxalic acid diethyl ester and 95.7 g of 2-ellyloxy-6-nitro-toluene were allowed to stir for 3 hours at 60 ° C, 1 N acetic acid was added and extracted with ether. The oxal ester remaining in the ether residue is removed at elevated temperature using a water pump. 171 g of 2-ellyloxy-6-nitro-phenylpyruvic acid ethyl ester are obtained.
2-allyloxy-6-nitro-fenyloctové kyseliny2-allyloxy-6-nitro-phenylacetic acid
171 g ethylesteru 2-allyloxy-6-nitrofenyl-pyrohroznové kyseliny se oxiduje v 1 100 ml 1 N louhu sodného 6% peroxidem vodíku a získaná kyselina se čisti rozpuštěním v hydrogenuhličitanu sodném, filtrací a vysrážením kyselinou chlorovodíkovou. Pc sušení se získá 88,5 g 2-ellyloxy-6-nitro-fenyl-octové kyseliny o teplotě tání 115 až 117 °C (74 % teorie, vztaženo na 2-alloloxy-6-nitro-toluen).171 g of 2-allyloxy-6-nitrophenyl-pyruvic acid ethyl ester was oxidized in 1100 ml of 1 N sodium hydroxide solution with 6% hydrogen peroxide and the obtained acid was purified by dissolving in sodium bicarbonate, filtering and precipitating with hydrochloric acid. Drying gave 88.5 g of 2-ellyloxy-6-nitro-phenyl-acetic acid, m.p. 115 DEG-117 DEG C. (74% of theory, based on 2-alloloxy-6-nitro-toluene).
Ethylester 2-ellyloxy-6-nitro-fenyloctové kyseliny2-Ellyloxy-6-nitro-phenylacetic acid ethyl ester
23,7 g 2-ellyloxy-6-nitrofenyloctové kyseliny se př=vede '7,4 mi ethanolu v toluenu a 1 ,9 g kyseliny p-toluensulfonové na žádaný ester. Po zpracováni se získá 25,9 g ethylesteru 2-ellyloxy-6-nitrofenyloctové kyseliny (97 % teorie).23.7 g of 2-ellyloxy-6-nitrophenylacetic acid are passed through 7.4 ml of ethanol in toluene and 1.9 g of p-toluenesulfonic acid to the desired ester. After work-up, 25.9 g of 2-ellyloxy-6-nitrophenylacetic acid ethyl ester (97% of theory) are obtained.
Ethylester 2-/2,3-epoxy-propoxy/-6-nitro-fenyloctové kyseliny2- (2,3-epoxy-propoxy) -6-nitro-phenylacetic acid ethyl ester
10,6 g ethylesteru 2-sllyloxy-6-nitro-fenyloctové kyseliny ve 250 ml chloroformu se zahřívá k varu β 14,6 g m-Chlorperoxybenzoové kyseliny, sž je reakce úplná. Po obvyklém zpracování se získá 11 g ethylesteru 2-/2,3-epoxy-propoxy/-6-nitro-fenyloctové kyseliny (99 % teorie).10.6 g of 2-sllyloxy-6-nitro-phenylacetic acid ethyl ester in 250 ml of chloroform is heated to boiling β 14.6 g of m-Chloroperoxybenzoic acid, where the reaction is complete. After usual work-up, 11 g of 2- (2,3-epoxy-propoxy) -6-nitro-phenylacetic acid ethyl ester (99% of theory) are obtained.
Ethylester 2-[2-hydroxy-3-/4-fenoxymethyl-piperidino/-propoxy]-ó-nitrofenyloctové kyseliny2- [2-Hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy] -O-nitrophenylacetic acid ethyl ester
6,5 g ethylesteru 2-/2,3-epoxy-propoxy/-6-nitro-f nyloctové kyseliny a 4,4 g 4-ferioxymethyl-piperidinu se míchá 18 hodin při teplotě místnosti / o; ml n-butanolu, zahustí se ve vakuu a rozpustí se v eteru a 1 U kyseliny mléčné. Vodná fáze se zalkalizuje roztokem uhličitanu draselného a extrahuje se eterem. Po z ;5er.. z odpaření se získá 7,9 g 2-[2-hydroxy-3-/4-fenoxymethyl-piperidino/-propoxy3-ó-r.; ·. :'.’nyloctové kyseliny jako nahnědlého oleje (72 % teorie).6.5 g of 2- (2,3-epoxy-propoxy) -6-nitro-phenylacetic acid ethyl ester and 4.4 g of 4-ferioxymethyl-piperidine were stirred at room temperature for 18 hours; ml of n-butanol, concentrated in vacuo and dissolved in ether and 1 U of lactic acid. The aqueous phase was basified with potassium carbonate solution and extracted with ether. Evaporation gave 7.9 g of 2- [2-hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy-3-ol; ·. : '.' 'Acetic acids as a brownish oil (72% of theory).
Analogickým způsobem se získají výchozí látky pro sloučeniny příkladu 1a) až lg):In an analogous manner, the starting materials for the compounds of Examples 1a) to 1g) are obtained:
**
OznačeníDesignation
Výtěžek Teplota tání °C (rozpouštědlo) pro ethylester la) 2-<2-hydroxy-3-[4-/2methoxyfenoxymethyl/piperidino]-propoxy>-6nitro-fenyloctové kyseliny z ethylesteru 72Yield Melting point ° C (solvent) for ethyl ester 1a) 2- <2-Hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy> -6-nitro-phenylacetic acid from ethyl ester 72
2-/2,3-epoxy-propoxy/-6nitrofenyl-octové kyseliny a 4-/2-methoxy-fenoxymethyl/piperidinu pro ethylester lb) 2-<2-hydroxy-3-[4-/3methyl-fenoxy-methyl/piperidino]-propoxy>-6nitrofenyloctové kyseliny z ethylesteru 792- (2,3-epoxy-propoxy) -6-nitrophenyl-acetic acid and 4- (2-methoxy-phenoxymethyl) -piperidine for ethyl ester 1b) 2- <2-hydroxy-3- [4- (3-methyl-phenoxy-methyl)] piperidino] -propoxy-6-nitrophenylacetic acid from ethyl ester 79
2-/2,3-epoxy-propoxy/-6nitro-fenyl-octové kyseliny a 4-/3-methyl-fenoxymethyl/piperidinu pro ethylester lc) 2-<2-hydroxy-3-[4-benzyloxyfenoxymethyl/-piperidino]-propoxy) -6-nitro-fenylootová kyseliny z ethylesteru 872- (2,3-epoxy-propoxy) -6-nitro-phenyl-acetic acid and 4- (3-methyl-phenoxymethyl) -piperidine for ethyl ester 1c) 2- <2-hydroxy-3- [4-benzyloxy-phenoxymethyl] -piperidino] -propoxy) -6-nitro-phenylootic acid from ethyl ester 87
2-/2,3-epoxy-propoxy/-6-nitrofenyloctové kyseliny a 4-/4benzyloxy-fenoxymethyl/-piperidinu pro ethylester ld) 2-<2-hydroxy-3-[+-/2-chlor-fenoxymethyl/-piperidino]-propoxy)-6nitro-fenyloctové z ethylesteru 652- (2,3-epoxy-propoxy) -6-nitrophenylacetic acid and 4- (4-benzyloxy-phenoxymethyl) -piperidine for ethyl ester 1d) 2- (2-hydroxy-3- [+ - (2-chloro-phenoxymethyl)] - piperidino] propoxy) -6-nitro-phenylacetic acid from ethyl ester 65
2-/2,3-epoxy-propoxy/-6-nitro fenyloctové kyseliny a 4-/2-chlor-fenoxymethyl/-piperidinu pro ethylester le) 2-<2-hydroxy-3-[4-/3-hydroxymethylfenoxymethyl/-piperidino] -propoxy> -6-nitro-fenyloctové kyseliny z ethylesteru 9.02- (2,3-epoxy-propoxy) -6-nitro-phenylacetic acid and 4- (2-chloro-phenoxymethyl) -piperidine for ethyl ester 1-) 2- (2-hydroxy-3- [4- (3-hydroxymethylphenoxymethyl)] -piperidino] -propoxy-6-nitro-phenylacetic acid from ethyl ester 9.0
2-/2,3-epoxy-propoxy/-6-nitro-fenyloctová kyseliny a 4-/3-hydroxymethyl-fenoxymethyl/-piperidinu olej olej olej olej olej2- (2,3-epoxy-propoxy) -6-nitro-phenylacetic acid and 4- (3-hydroxymethyl-phenoxymethyl) -piperidine oil oil oil oil oil
OznačeníDesignation
Výtěžek Teplota tání °C (rozpouštědlo) pro ethylesterYield Melting point ° C (solvent) for ethyl ester
f) 2-<2-hydroxy-3-[4-/2-methyl-6pyridoxymethyl/-piperidino]propoxy>-6-ni tro-fenyloctové kyseliny z ethylesteru 99 olejf) 2- <2-hydroxy-3- [4- (2-methyl-6-pyridoxymethyl) -piperidino] -propoxy] -6-nitro-phenylacetic acid from ethyl ester 99 oil
2-/2,3-epoxy-propoxy/-6-nitrofenyloctové kyseliny a 4-/2-methyl6-pyridoxymethyl/-piperidinu pro ethylester2- (2,3-epoxy-propoxy) -6-nitrophenylacetic acid and 4- (2-methyl-6-pyridoxymethyl) -piperidine for ethyl ester
g) 2-<2-hydroxy-3-[4-/4-aminokarbonylmethyl-fenoxymethyl/-piperidinolpřopoxy^-ó-nitro-fenyloctová kyselina z ethylesteru 95 olejg) 2- <2-hydroxy-3- [4- (4-aminocarbonylmethyl-phenoxymethyl) -piperidinol-propoxy] -6-nitro-phenylacetic acid from ethyl ester 95 oil
2-/2,3-epoxy-propoxy/-ó-nitrofenyloctové kyseliny a 4-/4-eminokarbonyl-methyl/-piperidinu2- (2,3-epoxy-propoxy) -6-nitrophenylacetic acid and 4- (4-eminocarbonylmethyl) -piperidine
Příklad 2Example 2
4-[2-pivaloyloxy-3-/4-fenoxymethyl-piperidino/-prcpoxy]-2-2-benzimidezolinon-hydrochlorid4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -2-2-benzimidezolinone hydrochloride
5,00 g 4-[2-hydroxy-3-/4-fenoxymethyi-piperidino/-propoxy]-2-benzimid3zolinu (příprava viz příklad 1) se přťdá k 31,5 g roztavené kyseliny pivelové e přidá se 6,28 g enhydridu kyseliny pivelové. Míchá se 5 dní při teplotě místnosti, nalije se do ICO nl ledové vody, neutralizuje se zředěným amoniakem (1:10), extrahuje se dichlormethanem, suSí se síranem sodným a zahustí se. Zbytek se promyje etherem, rozpustí se v alkoholu a přidá se 2N kyselina solná.5.00 g of 4- [2-hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy] -2-benzimid3zoline (preparation see Example 1) was added to 31.5 g of molten pivelic acid and 6.28 g was added. enemic anhydride. Stir for 5 days at room temperature, pour into ice water (10 mL), neutralize with dilute ammonia (1:10), extract with dichloromethane, dry with sodium sulfate and concentrate. The residue was washed with ether, dissolved in alcohol and 2N hydrochloric acid was added.
Po zahuštění se překrystaluje z 20 ml ethanolu. Získá se 3,ú5 g <56 % teorie) žádané slouěeniny o teplotě tání 168 až 170 °C.After concentration, it is recrystallized from 20 ml of ethanol. 3.85 g (56% of theory) of the desired compound of melting point 168 DEG-170 DEG C. is obtained.
Příklad 3Example 3
4-<2-benzoyloxy-3-[4-/2-pyridyloxymethyl/piperidino]propoxy-}7-methyl-benzimidazol-hydrochlorid4- <2-Benzoyloxy-3- [4- (2-pyridyloxymethyl) piperidino] propoxy-} 7-methylbenzimidazole hydrochloride
4»37 g 4-<2-hydroxy-3-[4-/2-pyridyloxymethyl/piperidino]propoxy}-7-methyl-benzin idezolu 19,5 g kyseliny benzoové a 2,12 g anhydridu kyseliny benzoové se zahřívá 2 hodiny pod zpětným chladičem ve 100 ml benzenu a 25 ml dimethylformamidu. Po odstranění rozpouštědla se zbytek rozpustí ve 100 ml vody, zalkelizuje se koncentrovaným amoniakem a extrahuje se chloroformem. Chloroformová fáze se promyje vodou, suší se sírenem sodným a zahustí se. Rozpustí se v ethanolu a přidá se eterický roztok kyseliny chlorovodíkové. Po přídavku isopropenolu a etheru krystaluje 2,1 g (41 % teorie) žádané sloučeniny o teplotě tání 178 až 181 °C.4 »37 g of 4- <2-hydroxy-3- [4- (2-pyridyloxymethyl / piperidino] propoxy} -7-methyl-benzin idezole 19.5 g of benzoic acid and 2.12 g of benzoic anhydride are heated for 2 hours under reflux in 100 ml of benzene and 25 ml of dimethylformamide. After removal of the solvent, the residue was dissolved in 100 ml of water, basified with concentrated ammonia and extracted with chloroform. The chloroform phase is washed with water, dried with sodium sulphate and concentrated. Dissolve in ethanol and add ethereal hydrochloric acid. After addition of isopropenol and ether, 2.1 g (41% of theory) of the title compound crystallized, m.p. 178-181 ° C.
p ř i k i a a 44
4—<2-hydroxy-3-t4-/4-acetamido-fenoxymethyl/-piperidino3-propoxy)-1 -formyllndolin4- (2-hydroxy-3- [4- (4-acetamido-phenoxymethyl) -piperidino-3-propoxy) -1-formyl] indoline
3,3 g 4-<2-hydroxy-3-C4-/4-amino-fenoxymethyl/-piperidino]propoxy>-1 -formylindolinu se míchá 10 hodin při teplot® místnosti se smSsí 25 ml anhydridů kyseliny octové a 25 ml pyridinu, zahustí se ve vakuu a rozpustí se ve vodS a dichlormethanu. Po neutralizaci hydrogenuhličitanem sodným se organická fáze oddestiluje a zbytek sa převede v methanolu roztokem methylátu sodného na žádanou sloučeninu. Vytřepéním do dichlormethanu a vody a odpařením organické fáze se získá 1 ,0 g (27 % teorie) 4-<2-hydroxy-3-(4-/4-acetamidofenoxymethyl/-piperidino]-propoxy)-1 -formylindolinu o teplotě tání 177 až 179 °G.3.3 g of 4- <2-hydroxy-3-C4- (4-amino-phenoxymethyl) -piperidino] -propoxy-1-formylindoline were stirred for 10 hours at room temperature with 25 ml of acetic anhydride and 25 ml of pyridine. The reaction mixture was concentrated in vacuo and dissolved in water and dichloromethane. After neutralization with sodium bicarbonate, the organic phase is distilled off and the residue is taken up in methanol with sodium methylate solution to give the desired compound. Shaking into dichloromethane and water and evaporating the organic phase gave 1.0 g (27% of theory) of 4- <2-hydroxy-3- (4- (4-acetamidophenoxymethyl) -piperidino] -propoxy) -1-formylindoline of melting point. Mp 177-179 ° C.
Analogickým způsobem se získá:In an analogous manner there are obtained:
P'ř 1 k 1 a d 5Example 1 to 1 and d 5
4-<2-hydroxy-3-[4-/2-pyridyloxymethyl/piperidino]propoxy ) -2-hydroxymethylindol-benzoát4- <2-hydroxy-3- [4- (2-pyridyloxymethyl / piperidino] propoxy) -2-hydroxymethylindole benzoate
K suspenzi 1 g hydrodu lithno-hlinitého ve 125 ml absolutního tetrahydrofuranu se přikape roztok 4,6 g 4-< 2-hydroxy-3-[4-/2-pyridyloxymethy 1/piperidino]propoxy)-2-eth'oxykarbonylindolu ve 125 ml absolutního tetrahydrofuranu, míchá' se 30 minut, za chlazení se rozloží roztokem chloridu sodného a 10 S louhem sodným, filtruje se, promyje se tetrahydrofuranem a zahustí sa. Přídavkem ekvivalentního množství kyseliny benzoové se získá z isopropanolu 4,0 g (74 % teorie) žádaná sloučeniny o teplotě tání 76 až 78 °C.A solution of 4.6 g of 4- (2-hydroxy-3- [4- (2-pyridyloxymethyl) piperidino] propoxy) -2-ethoxycarbonylindole in 125 ml of absolute tetrahydrofuran is added dropwise to a suspension of 1 g of lithium aluminum hydride in 125 ml of absolute tetrahydrofuran. ml of absolute tetrahydrofuran, stirred for 30 minutes, quenched with sodium chloride solution and 10% sodium hydroxide solution with cooling, filtered, washed with tetrahydrofuran and concentrated. By adding an equivalent amount of benzoic acid, 4.0 g (74% of theory) of the desired compound are obtained from isopropanol, m.p. 76-78 ° C.
Příklad -21Example -21
Byly připraveny tablety:Tablets were prepared:
Každá tableta obsahuje 10 mg 4-[2-hydroxy-3-/4-fenoxymethyl-piperidino/-propoxy]-2-tienzimidazolinonu. Tablety byly připraveny podle následujícího předpisu:Each tablet contains 10 mg of 4- [2-hydroxy-3- (4-phenoxymethyl-piperidino) -propoxy] -2-thienzimidazolinone. The tablets were prepared according to the following prescription:
4-[2-hydroxy-3-(4-fenoxymethylpiperidino/- 10 g -propoxy]-2-benzimidazolinon lakto'za 80 g škrob 29 g stearan hořečnatý 1 g předchozí sloučenina se jemně rozmělní a smíchá s laktJzou a Škrobem. Smis se granuluje obvyklým způsobem. Ke granulátu se přidá stearan hořečnatý a smis se lisuje na 1 000 tablet o hmotnosti 0,12 g.4- [2-hydroxy-3- (4-phenoxymethylpiperidino) -10 g-propoxy] -2-benzimidazolinone lacto 80 g starch 29 g magnesium stearate 1 g of the previous compound is finely ground and mixed with lactose and starch. Magnesium stearate is added to the granulate and the mixture is compressed to 1000 tablets weighing 0.12 g.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS807703A CS226022B2 (en) | 1979-02-16 | 1980-11-13 | Method of preparing piperidinepropyl derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792905876 DE2905876A1 (en) | 1979-02-16 | 1979-02-16 | NEW PIPERIDINOPROPYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| CS801056A CS226008B2 (en) | 1979-02-16 | 1980-02-15 | Method of preparing piperidinopropyl derivatives |
| CS807703A CS226022B2 (en) | 1979-02-16 | 1980-11-13 | Method of preparing piperidinepropyl derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS226022B2 true CS226022B2 (en) | 1984-03-19 |
Family
ID=25745374
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS807703A CS226022B2 (en) | 1979-02-16 | 1980-11-13 | Method of preparing piperidinepropyl derivatives |
| CS814585A CS226029B2 (en) | 1979-02-16 | 1981-06-18 | Method of preparing piperidinepropyl derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS814585A CS226029B2 (en) | 1979-02-16 | 1981-06-18 | Method of preparing piperidinepropyl derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CS (2) | CS226022B2 (en) |
-
1980
- 1980-11-13 CS CS807703A patent/CS226022B2/en unknown
-
1981
- 1981-06-18 CS CS814585A patent/CS226029B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS226029B2 (en) | 1984-03-19 |
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