HUT70051A - Novel tricyclic-cyclic amines as cholinesterase inhibitors, pharmaceutical compositions containing them and process for preparing them - Google Patents
Novel tricyclic-cyclic amines as cholinesterase inhibitors, pharmaceutical compositions containing them and process for preparing them Download PDFInfo
- Publication number
- HUT70051A HUT70051A HU91406A HU40691A HUT70051A HU T70051 A HUT70051 A HU T70051A HU 91406 A HU91406 A HU 91406A HU 40691 A HU40691 A HU 40691A HU T70051 A HUT70051 A HU T70051A
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- HU
- Hungary
- Prior art keywords
- ring
- carbon
- piperidinyl
- methyl
- formula
- Prior art date
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- 239000000544 cholinesterase inhibitor Substances 0.000 title abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 247
- 125000005605 benzo group Chemical group 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 73
- -1 benzyloxy, phenoxy, hydroxy, phenyl Chemical group 0.000 claims description 64
- 229910052799 carbon Inorganic materials 0.000 claims description 56
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- 239000001301 oxygen Substances 0.000 claims description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000011593 sulfur Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 150000003951 lactams Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 150000003457 sulfones Chemical group 0.000 claims description 6
- 150000003462 sulfoxides Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 229910052711 selenium Inorganic materials 0.000 claims description 4
- 239000011669 selenium Substances 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- LOKXVDWPCSANMU-UHFFFAOYSA-N acetyloxy(hydroxy)methanesulfonic acid Chemical compound CC(=O)OC(O)S(O)(=O)=O LOKXVDWPCSANMU-UHFFFAOYSA-N 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- 125000004175 fluorobenzyl group Chemical group 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000004437 phosphorous atom Chemical group 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 5
- 206010012289 Dementia Diseases 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 112
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
- 238000002360 preparation method Methods 0.000 description 80
- 239000000203 mixture Substances 0.000 description 76
- 238000005160 1H NMR spectroscopy Methods 0.000 description 68
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 45
- 239000000243 solution Substances 0.000 description 36
- 239000002904 solvent Substances 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000002585 base Substances 0.000 description 26
- 150000002576 ketones Chemical class 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
- 239000012442 inert solvent Substances 0.000 description 20
- 238000000034 method Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000012312 sodium hydride Substances 0.000 description 14
- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- 230000008018 melting Effects 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000005909 Kieselgur Substances 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 6
- 238000003379 elimination reaction Methods 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- SGIBOXBBPQRZDM-UHFFFAOYSA-N 1-benzylpiperidine-4-carbaldehyde Chemical compound C1CC(C=O)CCN1CC1=CC=CC=C1 SGIBOXBBPQRZDM-UHFFFAOYSA-N 0.000 description 4
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- MYTYHLDSYLKPSF-UHFFFAOYSA-N 6h-thieno[2,3-b]pyrrole Chemical compound C1=CSC2=C1C=CN2 MYTYHLDSYLKPSF-UHFFFAOYSA-N 0.000 description 4
- 102000003914 Cholinesterases Human genes 0.000 description 4
- 108090000322 Cholinesterases Proteins 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229940048961 cholinesterase Drugs 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- HDMUNNPWWOBAGI-UHFFFAOYSA-N 2-[(1-benzylpiperidin-4-yl)methyl]-6-methoxy-1,2-dihydropyrrolo[1,2-a]indol-3-one Chemical compound O=C1C2=CC3=CC(OC)=CC=C3N2CC1CC(CC1)CCN1CC1=CC=CC=C1 HDMUNNPWWOBAGI-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102100033639 Acetylcholinesterase Human genes 0.000 description 3
- 108010022752 Acetylcholinesterase Proteins 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 229960004373 acetylcholine Drugs 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003638 chemical reducing 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
- 239000012043 crude product Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- HCUOEKSZWPGJIM-IYNMRSRQSA-N (e,2z)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical group COCC([N+]([O-])=O)\C(C)=C\C(=N\O)\C(N)=O HCUOEKSZWPGJIM-IYNMRSRQSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- LYKSBSFEUFSEIQ-UHFFFAOYSA-N 1,2-dihydropyrrolo[1,2-a]indol-3-one Chemical compound C1=CC=C2N3CCC(=O)C3=CC2=C1 LYKSBSFEUFSEIQ-UHFFFAOYSA-N 0.000 description 2
- PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical compound C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 description 2
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- LOLYNOUMWHSLBP-UHFFFAOYSA-N pyrrolo[1,2-a]indol-3-one Chemical compound C1=CC=C2N3C=CC(=O)C3=CC2=C1 LOLYNOUMWHSLBP-UHFFFAOYSA-N 0.000 description 1
- AIKRNPPDTQIQIZ-UHFFFAOYSA-N pyrrolo[3,4-b]indole Chemical compound C1=CC=C2C3=CN=CC3=NC2=C1 AIKRNPPDTQIQIZ-UHFFFAOYSA-N 0.000 description 1
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 description 1
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- SWZQCYSGXSDQEX-UHFFFAOYSA-N tert-butyl 4-[(6-methoxy-3-oxo-1,4-dihydrocyclopenta[b]indol-2-ylidene)methyl]piperidine-1-carboxylate Chemical compound O=C1C=2NC3=CC(OC)=CC=C3C=2CC1=CC1CCN(C(=O)OC(C)(C)C)CC1 SWZQCYSGXSDQEX-UHFFFAOYSA-N 0.000 description 1
- CJDYAJZJOFYVQW-UHFFFAOYSA-N tert-butyl 4-[(6-methoxy-3-oxo-2,4-dihydro-1h-cyclopenta[b]indol-2-yl)methyl]piperidine-1-carboxylate Chemical compound O=C1C=2NC3=CC(OC)=CC=C3C=2CC1CC1CCN(C(=O)OC(C)(C)C)CC1 CJDYAJZJOFYVQW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
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- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
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- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47692890A | 1990-02-08 | 1990-02-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HU910406D0 HU910406D0 (en) | 1991-08-28 |
| HUT70051A true HUT70051A (en) | 1995-09-28 |
Family
ID=23893824
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU91406A HUT70051A (en) | 1990-02-08 | 1991-02-07 | Novel tricyclic-cyclic amines as cholinesterase inhibitors, pharmaceutical compositions containing them and process for preparing them |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0441517A3 (en, 2012) |
| JP (1) | JPH07119214B2 (en, 2012) |
| KR (1) | KR950013562B1 (en, 2012) |
| CN (1) | CN1054600A (en, 2012) |
| AU (1) | AU631723B2 (en, 2012) |
| BR (1) | BR9100519A (en, 2012) |
| CA (1) | CA2035805C (en, 2012) |
| CS (1) | CS29991A2 (en, 2012) |
| DE (1) | DE9101348U1 (en, 2012) |
| EG (1) | EG19644A (en, 2012) |
| FI (1) | FI910592A7 (en, 2012) |
| HU (1) | HUT70051A (en, 2012) |
| IE (1) | IE910402A1 (en, 2012) |
| IL (1) | IL97140A (en, 2012) |
| NO (1) | NO177534C (en, 2012) |
| NZ (1) | NZ237040A (en, 2012) |
| PL (2) | PL167078B1 (en, 2012) |
| PT (1) | PT96681A (en, 2012) |
| TW (1) | TW197442B (en, 2012) |
| YU (1) | YU21391A (en, 2012) |
| ZA (1) | ZA91916B (en, 2012) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2807577B2 (ja) * | 1990-06-15 | 1998-10-08 | エーザイ株式会社 | 環状アミド誘導体 |
| EP0475908A1 (de) * | 1990-09-14 | 1992-03-18 | Ciba-Geigy Ag | Chromogene Lactamverbindungen und ihre Herstellung und Verwendung |
| TW263504B (en, 2012) * | 1991-10-03 | 1995-11-21 | Pfizer | |
| TW248556B (en, 2012) * | 1993-01-18 | 1995-06-01 | Takeda Pharm Industry Co | |
| US5620973A (en) * | 1993-11-30 | 1997-04-15 | Takeda Chemical Industries, Ltd. | Tetracyclic condensed heterocyclic compounds and their use |
| EP1118322A4 (en) | 1998-09-30 | 2004-10-20 | Takeda Chemical Industries Ltd | MEDICINES THAT IMPROVE BLADDER DRAINING POWER |
| PL376440A1 (en) * | 2002-10-30 | 2005-12-27 | Merck Frosst Canada Ltd. | Pyridopyrrolizine and pyridoindolizine derivatives |
| US7662831B2 (en) | 2006-07-27 | 2010-02-16 | Wyeth Llc | Tetracyclic indoles as potassium channel modulators |
| US7601856B2 (en) | 2006-07-27 | 2009-10-13 | Wyeth | Benzofurans as potassium ion channel modulators |
| WO2012038966A1 (en) | 2010-09-22 | 2012-03-29 | Tyche Industries Ltd. | Process for the preparation of donepezil intermediate |
| HUE056791T2 (hu) * | 2017-09-07 | 2022-03-28 | Eisai R&D Man Co Ltd | Pentaciklusos vegyület |
| PE20211978A1 (es) | 2019-03-05 | 2021-10-05 | Eisai Randd Man Co Ltd | Compuesto heterociclo pentaciclico |
| TWI870286B (zh) * | 2019-03-05 | 2025-01-11 | 日商衛材R&D企管股份有限公司 | 五環化合物之鹽及其等之結晶 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910947A (en) * | 1969-07-24 | 1975-10-07 | Sandoz Ag | Preparation of imidazo{8 2,1-a{9 isoindoles |
| IT1199076B (it) * | 1984-03-01 | 1988-12-30 | Consiglio Nazionale Ricerche | Derivati della fisostigmina con proprieta'di inibizione della aceticolinesterasi e relativo procedimento di produzione |
| US4563469A (en) * | 1984-07-20 | 1986-01-07 | Warner-Lambert Company | Derivatives of N-[2-(tetrahydro-3,5-dioxo-1H-pyrrolizin-7a(5H)-yl)ethyl]amine as cognition activators |
| EP0187619A3 (de) * | 1985-01-03 | 1987-08-26 | Ciba-Geigy Ag | 1,3-disubstituierte Tetrahydropyridine |
| US4791107A (en) * | 1986-07-16 | 1988-12-13 | Hoechst-Roussel Pharmaceuticals, Inc. | Memory enhancing and analgesic 1,2,3,3A,8,8A-hexahydro-3A,8 (and) 1,3A,8)-di(and tri)methylpyrrolo(2,3-B)indoles, compositions and use |
| US4778812A (en) * | 1987-06-12 | 1988-10-18 | American Home Products Corporation | 2,3-dihydro-9-methyl-1H-pyrrolo[1,2-a]indol-1-amines and derivatives thereof |
| EP0351283A1 (fr) * | 1988-07-12 | 1990-01-17 | Synthelabo | Dérivés de [(pipéridinyl-4) méthyl]-2 dihydro-2,3 1H-isoindole et tétrahydro-2,3,4,5 1H-benzazépines, leur préparation et leur application en thérapeutique |
-
1991
- 1991-01-23 TW TW080100556A patent/TW197442B/zh active
- 1991-01-29 EP EP19910300662 patent/EP0441517A3/en not_active Withdrawn
- 1991-02-03 IL IL9714091A patent/IL97140A/en not_active IP Right Cessation
- 1991-02-06 CA CA002035805A patent/CA2035805C/en not_active Expired - Fee Related
- 1991-02-06 PL PL91304632A patent/PL167078B1/pl unknown
- 1991-02-06 DE DE9101348U patent/DE9101348U1/de not_active Expired - Lifetime
- 1991-02-06 PL PL91288977A patent/PL166757B1/pl unknown
- 1991-02-06 PT PT96681A patent/PT96681A/pt unknown
- 1991-02-07 KR KR1019910002113A patent/KR950013562B1/ko not_active Expired - Lifetime
- 1991-02-07 FI FI910592A patent/FI910592A7/fi not_active Application Discontinuation
- 1991-02-07 IE IE040291A patent/IE910402A1/en unknown
- 1991-02-07 NO NO910473A patent/NO177534C/no unknown
- 1991-02-07 AU AU70879/91A patent/AU631723B2/en not_active Ceased
- 1991-02-07 CN CN91100860A patent/CN1054600A/zh active Pending
- 1991-02-07 YU YU21391A patent/YU21391A/sh unknown
- 1991-02-07 CS CS91299A patent/CS29991A2/cs unknown
- 1991-02-07 HU HU91406A patent/HUT70051A/hu unknown
- 1991-02-07 ZA ZA91916A patent/ZA91916B/xx unknown
- 1991-02-07 BR BR919100519A patent/BR9100519A/pt not_active Application Discontinuation
- 1991-02-07 NZ NZ237040A patent/NZ237040A/xx unknown
- 1991-02-07 EG EG7591A patent/EG19644A/xx active
- 1991-02-08 JP JP3103992A patent/JPH07119214B2/ja not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| NZ237040A (en) | 1993-10-26 |
| KR950013562B1 (ko) | 1995-11-09 |
| CS29991A2 (en) | 1991-09-15 |
| ZA91916B (en) | 1992-09-30 |
| FI910592A0 (fi) | 1991-02-07 |
| EP0441517A2 (en) | 1991-08-14 |
| CN1054600A (zh) | 1991-09-18 |
| JPH07119214B2 (ja) | 1995-12-20 |
| HU910406D0 (en) | 1991-08-28 |
| NO177534B (no) | 1995-06-26 |
| NO177534C (no) | 1995-10-04 |
| IL97140A0 (en) | 1992-05-25 |
| PL166757B1 (pl) | 1995-06-30 |
| FI910592L (fi) | 1991-08-09 |
| IL97140A (en) | 1995-07-31 |
| DE9101348U1 (de) | 1991-06-06 |
| BR9100519A (pt) | 1991-10-29 |
| NO910473L (no) | 1991-08-09 |
| JPH04234845A (ja) | 1992-08-24 |
| AU631723B2 (en) | 1992-12-03 |
| EP0441517A3 (en) | 1992-08-19 |
| PT96681A (pt) | 1991-10-31 |
| FI910592A7 (fi) | 1991-08-09 |
| YU21391A (sh) | 1994-01-20 |
| EG19644A (en) | 1995-08-30 |
| TW197442B (en, 2012) | 1993-01-01 |
| PL167078B1 (pl) | 1995-07-31 |
| AU7087991A (en) | 1991-08-29 |
| IE910402A1 (en) | 1991-08-14 |
| KR910015580A (ko) | 1991-09-30 |
| CA2035805C (en) | 1995-06-27 |
| NO910473D0 (no) | 1991-02-07 |
| PL288977A1 (en) | 1992-01-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DFD9 | Temporary protection cancelled due to non-payment of fee |