CA2042860A1 - Bicyclic 1-aza-cycloalkanes - Google Patents
Bicyclic 1-aza-cycloalkanesInfo
- Publication number
- CA2042860A1 CA2042860A1 CA002042860A CA2042860A CA2042860A1 CA 2042860 A1 CA2042860 A1 CA 2042860A1 CA 002042860 A CA002042860 A CA 002042860A CA 2042860 A CA2042860 A CA 2042860A CA 2042860 A1 CA2042860 A1 CA 2042860A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- formula
- compounds
- substituted
- unsubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 125000002619 bicyclic group Chemical group 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 25
- 230000008569 process Effects 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 21
- -1 alkali metal alkoxides Chemical class 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 11
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical group C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000006267 biphenyl group Chemical group 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000468 ketone group Chemical group 0.000 claims description 5
- 150000003222 pyridines Chemical class 0.000 claims description 5
- 229930192474 thiophene Natural products 0.000 claims description 5
- STHHLVCQSLRQNI-UHFFFAOYSA-N 1-azabicyclo[3.2.1]octane Chemical group C1C2CCN1CCC2 STHHLVCQSLRQNI-UHFFFAOYSA-N 0.000 claims description 4
- VGCNQTVSNYXLSG-UHFFFAOYSA-N 2-(prop-2-ynoxymethyl)-1-azabicyclo[2.2.2]octane Chemical compound C1CN2C(COCC#C)CC1CC2 VGCNQTVSNYXLSG-UHFFFAOYSA-N 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010039966 Senile dementia Diseases 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 230000001713 cholinergic effect Effects 0.000 claims description 4
- 208000010877 cognitive disease Diseases 0.000 claims description 4
- 230000006870 function Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000005595 deprotonation Effects 0.000 claims description 3
- 238000010537 deprotonation reaction Methods 0.000 claims description 3
- 230000007334 memory performance Effects 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- JVCBVWTTXCNJBJ-UHFFFAOYSA-N 1-azabicyclo[2.2.1]heptane Chemical compound C1CC2CCN1C2 JVCBVWTTXCNJBJ-UHFFFAOYSA-N 0.000 claims 1
- FMEHIMDNLRASDU-UHFFFAOYSA-N 1-azabicyclo[3.3.1]nonane Chemical compound C1CCN2CCCC1C2 FMEHIMDNLRASDU-UHFFFAOYSA-N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 230000006993 memory improvement Effects 0.000 claims 1
- 230000000718 cholinopositive effect Effects 0.000 abstract description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 32
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000013543 active substance Substances 0.000 description 16
- 229910001868 water Inorganic materials 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- GUAWHSHTXVVCLZ-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-ylmethanol Chemical compound C1CC2C(CO)CN1CC2 GUAWHSHTXVVCLZ-UHFFFAOYSA-N 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229910052757 nitrogen Chemical group 0.000 description 4
- 229940039748 oxalate Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- 229940072033 potash Drugs 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- RWPSJZPTQVRQJL-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-ylmethyl acetate Chemical compound N12CC(C(CC1)CC2)COC(C)=O RWPSJZPTQVRQJL-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical class OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- RZKSECIXORKHQS-UHFFFAOYSA-N Heptan-3-ol Chemical compound CCCCC(O)CC RZKSECIXORKHQS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 2
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 238000009492 tablet coating Methods 0.000 description 2
- 239000002700 tablet coating Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
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- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- 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
- C07D487/08—Bridged systems
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Abstract
Abstract The invention relates to bicyclic 1-aza-cycloalkanes, processes for preparing them and their use as pharmaceutical compositions with cholinomimetic properties.
Description
56651.19 Bicyclic 1-aza-cYcloalkanes The present invention relates to novel bicyclic 1-aza-cycloalkanes of general fo:rmula I, to processes for their preparation and to their use as pharmaceutical compositions.
According to the present invention we provide compounds of general formula I
0 ~ "(CH2)n X--R
A h-C
wherein R represents a Cl6-alkyl group, a C36-alkenyl group or a C36-alkynyl group, the alkyl, alkenyl or alkynyl group being optionally substituted by a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted oxetan ring or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group; or R represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group;
X represents oxygen or sulphur;
A, B and C independently of one another represent CH2 or a single bond;
n represents 0, 1 or 2;
. ' ' , ' ., . ;
According to the present invention we provide compounds of general formula I
0 ~ "(CH2)n X--R
A h-C
wherein R represents a Cl6-alkyl group, a C36-alkenyl group or a C36-alkynyl group, the alkyl, alkenyl or alkynyl group being optionally substituted by a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted oxetan ring or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group; or R represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group;
X represents oxygen or sulphur;
A, B and C independently of one another represent CH2 or a single bond;
n represents 0, 1 or 2;
. ' ' , ' ., . ;
2 ~
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof; with the proviso that i) for a compound of formula I wherein the bicyclic ring system is quinuclidine, R may not represent an unsubstituted alkyl, alkenyl or alkynyl group; ii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo~3,2,1]octane, the group -(CH2)n-X-R may not represent a propoxy group; and iii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo[2,2,2]octane, the group -(CH2~n-X-R may not represent a 3-(2-pyridinyloxy)- group.
Examples of alkyl groups for the purposes of this invention are branched or unbranched C16-alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl groups as well as the branched isomers thereof such as isopropyl, isobutyl, tert.-butyl, sec.-butyl etc.; the C36-alkenyl groups are branched or unbranched C36-alkenyl groups - such as propenyl, butenyl, pentenyl and hexenyl groups - having a single double bond; C36-alkynyl groups are branched or unbranched C36-alkynyl groups - such as propynyl, butynyl and pentynyl - having a single triple bond. Alkenyl or alkynyl groups in which a double or triple bond respectively is in a terminal position are preferred.
The term "substituted phenyl" indicates, unless otherwise stated, phenyl groups which are mono-, di- or trisubstituted by a halogen atom, or by a hydroxy, a branched or unbranched C15-alkyl, a substituted or unsubstituted C36-cycloalkyl, a C15-hydroxyalkyl, an amino or a mono- or disubstituted-C~4-alkylamino group.
The terms "substituted cycloalkyl" and "substituted biphenyl" indicate cycloalkyl and biphenyl groups in which the cycloalkyl ring and either of the phenyl rings in a biphenyl group may be substituted as specified ~2~
above for a substituted phenyl group. Examples of substituted phenyl groups include:
2-chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-tert.-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyph~nyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl.
The term "heterocyclic group" indicates a 5- to 7-membered ring which contains one or more heteroatoms selected from oxygen, sulphur and nitrogen and onto which another aromatic ring, preferably a phenyl group, may optionally be fused.
Examples of saturated heterocyclic 6-membered rings include: 1,4- and 1,3-dioxan, morp~oline, thiomorpholine, piperidine, piperazine, 4-C14-alkylpiperazine, N-hydroxy-Cl4-alkylpiperazine, 2,5-diketopiperazine and tetrahydropyran. Examples of saturated heterocyclic 5-membered rings include:
tetrahydropyrrole, tetrahydrofuran, proline, tetrahydropyrazole, imidazolidine, hydroxyproline, pyrrolidine, pyrazolidine, pyrrolidone, thiolan, butyrolactone and 1,2-oxathiolan.
Examples of 5-, 6--and 7-membered mono- and polyunsaturated heterocyclic rings include:
pyrrole, imidazole, imidazoline, 1,2,4- and 1~2,3-triazole, tetrazole, isothiazole, furan, dihydrofuran, thiophene, pyridine, pyrimidine, pyran, 2,5-dihydropyrrole, thiazole, thiadiazine, azepine, 1,2-oxathiepan, pyrazoline, dimethylpyrrole, 2-acylfuran and dihydrothiophene. Examples of other heteroaryl groups include pyrazinyl, quinolyl, isoquinolyl, quinazolyl, -- a, --quinoxalyl, thia~olyl, be~zothiazolyl, isothiazolyl, oxazolyl, b~nzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, and indolyl. A pre~erred heterocyclic group is the pyridine group which may be mono- to tetrasubstituted, preferably mono- to disubstituted, with identical or different substituents, selecte~ from hydroxy, Cl4-alkyl, C14-alkoxy, NH2, mono-or di-(C~4)-alkylamino, halogen, CF3, CN or nitro.
Examples of 5, 6 or 7-membered heterocyclic rings bound via a nitrogen atom also include:
phenanthridin-6-one, quinolin-2-one, isoquinolin-1,3-dione, benz[c,d]indole, 1,4-benzoxazin-3-onP, indol-2,3-dione, indol-2-one, 1,2,4-triazolo[4,3-a]pyridin-3-one, 1,2-benzisothia201-3-one, lH-indazole, lH-benzimidazole, lH-benztriazole, benzothiazin-3-one, isoindol-1,3-dione, benz[d,e]isoquinolin-1,3-dione, 4-quinazolinone, isoindol-l-one, pyrrolo[l,2-c]imidazol-1,3-dione, 1,3-dihydro-2H-indol-2-one, tetrahydro-lH-isoindol-1,3-dione, 3,7-dihydro-lH-purin-2,6-dione, indole, indazole, benzimidazole, benzimidazol-2-one-,-1,4-benzothiazin-3-one and lH-isoindol-1,3-dione.
The heterocyclic group may be mono- or polysubstituted by a halogen atom, or a hydroxy, a branched or unbranched C14-alkyl, a Cl4-hydroxyalkyl or a C14-alkoxy group. The heterocyclic group may additionally contain a keto-function as in e.g.
dihydrotetrafuranone.
Preferred compounds according to the present invention are compounds of general formula I as defined above wherein X represents oxygen; n represents 0 or 1;
the substituent -(CHz)n-X-R is in the ~- or ~-position relative to the carbocyclic bridgehead; and R represents an optionally substituted C13-alkyl, C34-alkenyl, or C3 4-alkynyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group.
Particularly preferred compounds according to the 6 ~
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof; with the proviso that i) for a compound of formula I wherein the bicyclic ring system is quinuclidine, R may not represent an unsubstituted alkyl, alkenyl or alkynyl group; ii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo~3,2,1]octane, the group -(CH2)n-X-R may not represent a propoxy group; and iii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo[2,2,2]octane, the group -(CH2~n-X-R may not represent a 3-(2-pyridinyloxy)- group.
Examples of alkyl groups for the purposes of this invention are branched or unbranched C16-alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl groups as well as the branched isomers thereof such as isopropyl, isobutyl, tert.-butyl, sec.-butyl etc.; the C36-alkenyl groups are branched or unbranched C36-alkenyl groups - such as propenyl, butenyl, pentenyl and hexenyl groups - having a single double bond; C36-alkynyl groups are branched or unbranched C36-alkynyl groups - such as propynyl, butynyl and pentynyl - having a single triple bond. Alkenyl or alkynyl groups in which a double or triple bond respectively is in a terminal position are preferred.
The term "substituted phenyl" indicates, unless otherwise stated, phenyl groups which are mono-, di- or trisubstituted by a halogen atom, or by a hydroxy, a branched or unbranched C15-alkyl, a substituted or unsubstituted C36-cycloalkyl, a C15-hydroxyalkyl, an amino or a mono- or disubstituted-C~4-alkylamino group.
The terms "substituted cycloalkyl" and "substituted biphenyl" indicate cycloalkyl and biphenyl groups in which the cycloalkyl ring and either of the phenyl rings in a biphenyl group may be substituted as specified ~2~
above for a substituted phenyl group. Examples of substituted phenyl groups include:
2-chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-tert.-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyph~nyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl.
The term "heterocyclic group" indicates a 5- to 7-membered ring which contains one or more heteroatoms selected from oxygen, sulphur and nitrogen and onto which another aromatic ring, preferably a phenyl group, may optionally be fused.
Examples of saturated heterocyclic 6-membered rings include: 1,4- and 1,3-dioxan, morp~oline, thiomorpholine, piperidine, piperazine, 4-C14-alkylpiperazine, N-hydroxy-Cl4-alkylpiperazine, 2,5-diketopiperazine and tetrahydropyran. Examples of saturated heterocyclic 5-membered rings include:
tetrahydropyrrole, tetrahydrofuran, proline, tetrahydropyrazole, imidazolidine, hydroxyproline, pyrrolidine, pyrazolidine, pyrrolidone, thiolan, butyrolactone and 1,2-oxathiolan.
Examples of 5-, 6--and 7-membered mono- and polyunsaturated heterocyclic rings include:
pyrrole, imidazole, imidazoline, 1,2,4- and 1~2,3-triazole, tetrazole, isothiazole, furan, dihydrofuran, thiophene, pyridine, pyrimidine, pyran, 2,5-dihydropyrrole, thiazole, thiadiazine, azepine, 1,2-oxathiepan, pyrazoline, dimethylpyrrole, 2-acylfuran and dihydrothiophene. Examples of other heteroaryl groups include pyrazinyl, quinolyl, isoquinolyl, quinazolyl, -- a, --quinoxalyl, thia~olyl, be~zothiazolyl, isothiazolyl, oxazolyl, b~nzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, and indolyl. A pre~erred heterocyclic group is the pyridine group which may be mono- to tetrasubstituted, preferably mono- to disubstituted, with identical or different substituents, selecte~ from hydroxy, Cl4-alkyl, C14-alkoxy, NH2, mono-or di-(C~4)-alkylamino, halogen, CF3, CN or nitro.
Examples of 5, 6 or 7-membered heterocyclic rings bound via a nitrogen atom also include:
phenanthridin-6-one, quinolin-2-one, isoquinolin-1,3-dione, benz[c,d]indole, 1,4-benzoxazin-3-onP, indol-2,3-dione, indol-2-one, 1,2,4-triazolo[4,3-a]pyridin-3-one, 1,2-benzisothia201-3-one, lH-indazole, lH-benzimidazole, lH-benztriazole, benzothiazin-3-one, isoindol-1,3-dione, benz[d,e]isoquinolin-1,3-dione, 4-quinazolinone, isoindol-l-one, pyrrolo[l,2-c]imidazol-1,3-dione, 1,3-dihydro-2H-indol-2-one, tetrahydro-lH-isoindol-1,3-dione, 3,7-dihydro-lH-purin-2,6-dione, indole, indazole, benzimidazole, benzimidazol-2-one-,-1,4-benzothiazin-3-one and lH-isoindol-1,3-dione.
The heterocyclic group may be mono- or polysubstituted by a halogen atom, or a hydroxy, a branched or unbranched C14-alkyl, a Cl4-hydroxyalkyl or a C14-alkoxy group. The heterocyclic group may additionally contain a keto-function as in e.g.
dihydrotetrafuranone.
Preferred compounds according to the present invention are compounds of general formula I as defined above wherein X represents oxygen; n represents 0 or 1;
the substituent -(CHz)n-X-R is in the ~- or ~-position relative to the carbocyclic bridgehead; and R represents an optionally substituted C13-alkyl, C34-alkenyl, or C3 4-alkynyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group.
Particularly preferred compounds according to the 6 ~
present invention are quinuclidine compounds of general formula I as defined above wherein n represents o or l;
X represents oxygen; R represents a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; the side chain -(CH2)n-X-R being in the 3-position of the quinuclidine system.
Further particularly preferred compounds according to the present invention are l-azabicyclo[2,2,1]heptanes of general formula I as defined above wherein X
represents oxygen; n represents 0 or 1; R represents an optionally substituted C13-alkyl, C34-alkenyl or C3 4-alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group;
the side chain -(CH2)n-X-R being in the 3-position of the bicyclic system.
Further particularly preferred compounds according to the present invention are 1-aza-bicyclo[3,2,1]octanes of general formula I as defined above wherein X
represents oxygen; n represents 0 or 1; R represents an optionally substituted C13-alkyl, C34-alkenyl group or ~ 4-alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group; the side chain -(CHz)n-X-R
being in the 3- or 6-position of the bicyclic group.
Further particularly preferred compounds according to the present invention are l-aza-bicyclo[3,3,13nonanes of general formula I as defined above wherein X
represents oxyger.; n represents 0 or 1; R represents an optionally substituted C13-alkyl, C34-alXenyl or C34-alkynyl group, a substituted or unsubstituted pyridine, thiophen~, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxol~n group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group;
the side chain -(CH2)n-X-R being in the 3-position of the bicyclic group.
Especially preferred compounds according to the present invention are compounds of general formula ~ ~CH2 )n - R
J
N
wherein n represents o or l; R represents a group of formula -CH2~ I Rl)k -~ RlJk -CH2 ~ (R1lk ~ (~1)k -CH2 ~I R2)l _~( R2) -CH2~ IR2 ), ~ (R2 )I - .
-CH2 ~ R2JI ~1 R2), - 7 - 2~
,~,CH2 ,~, R`--N_~,N R --~ N
Q~N J~
-CH2/ 1 ~
-C~2 ~ ~F~2) 15-CH2 ~ (R2)l ~ (R2 20-CH2 ~ (R2~ 2) -CH2 ~ ~ ( R 2 ) in which 30 Rl represents a hydrogen atom, a C14-alkyl group, preferably methyl, a C14-alkoxy group, preferably methoxy, an amino, C14-alkylamino, C14-dialkylamino, hydroxy, or C36-cycloalkyl group, a substituted or unsubstituted phenyl group or a keto-function; 5 k represents 1, 2 or 3, whilst if k is greater-than 1 the R1 groups may be identical or different, R2 represents a hydrogen or halogen atom, a C14-alkyl - : - .
.
2~2~
group, preferably methyl, a C14-alkoxy yroup, preferably methoxy or a keto-function;
1 represents 1 or 2, preferably 1, whilst when 1 represents 2 the groups R2 may be identical or different;
R3 represents a hydrogen atom or a C~ 4 alkyl group, preferably methyl;
and all racemic and tauto:meric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
Further especially preferred compounds according to the present invention are those of general formula (C~2 )n- O - R
N ~ ( CH2)n- 0 - R
~ ~CH2)n 0- R
N
wherein n represents 0 or 1, preferably zero;
R represents a C3-alkynyl group, a C3-alkenyl group, or a group of formula 2 $ ~
_ 9 _ -CU ~-(Rl)k ~(Rl)k -CH ~ ~ I R ~ ~ k --~ ~ R ~ ~ k -CH2 ~(R2~1 ` ~(R2Jt -CH2 ~ (R2)l ~ (R2 2 0 - CH2 ~ ( R 2 ) I N~ N
in which R1, R2, k and l are as hereinbefore defined; and all racsmic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
Further especially preferred compounds according to the present invention are those of general formula ~J--(CH2)n- O- R
wherein n represents O or l;
R represents a C3-alkynyl group, a C3-alkenyl group, or a methyl, ethyl or propyl group, or a group of formula -cH2~(R1~k ~Rl~k -CH2 ~ ~ R ~ ~ < ` ~ ( R 1 J k -C~12 ~( R2~l ~( ~; N N~ N
-CH ~( R2~l ~ ~( R2 2t~ ~ (R2 )l wherein R1, ~, k and 1 are as hereinbefore defined; and 30 all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and the acid addition salts thereof and additionally the quaternary salts thereof.
Certain compounds analogous to compounds of general 35 formula I are described in the prior art. Thus, for example, EP 370415 discloses compounds of formula Ia ~(CHz1",- X- R (Ia) wherein Rl represents an unsubstituted C16-alkyl, C36-alkenyl or C36-alkynyl group; X' represents an oxygen or sulphur atom; and m represents 0, 1 or 2.
UK Patent No. 2208385 discloses compounds of general formula Ib ~
N (Ib) ~ - -wherein R" represents a 3-(2-pyridinyloxy)- group.
However these compounds are described as 5-HT-antagonists. European Patent No. 257741 discloses compounds of formula Ic R " ' ~ (Ic) wherein R"' represents a propyloxy group.
However certain of the optically active compounds of formulae Ia, Ib and Ic are not specifically mentioned by name in EP 370415, GB 2208385 and EP 257741.
.
.. . . .
, ~ lence according to a further feature of the present invention there are pro~ided compounds of formulae Ia, Ib and Ic as defined above in the form of individual enantiomers and acid addition salts thereof and additionally the quaternary salts thereof, collectively termed the compounds of formula (Id); with the proviso that in the compounds of formula Ia when X' represents oxygen and m represents 0, R' cannot represent a C3-alkynyl group or an ethyl group.
A most especially preferred compound according to the present invention is (+)-(propargyloxymethyl)-l-azabicyclo[2,2,2]octane and acid addition salts thereof and additionally the quaternary salts thereof.
When in the compounds of general formula I, R
represents an aliphatic group such compounds may be prepared analogously to the methods described by L.
Stotter et al. in Heterocycles, Vol. 25 (1987), page 25.
Hence, according to a further feature of the present invention we provide a process ~or the preparation of a compound of formula I as defined above wherein R represents an aliphatic group, characterised in that a corresponding optionally N-protected derivative of general formula I (in which R represents H
and the nitrogen atom of the bicyclic group is bloc~ed by a protecting group Z, e.g. BH3) is deprotonated, for example with a strong base, and is subsequently reacted with an alkylating reagent of general formula Y-R, wherein R is as defined hereinbefore and Y represents a readily removable leaving group such as halogen or p~
toluenesulphonate. The reaction is carried out in polar inert organic solvents such as dimethylformamide, tetrahydrofuran, dioxan.
Whereas the deprotonation and conversion of the hydroxy compound into a metal salt is pre~erably carried out at ambient or slightly elevated temperature, the subsequent alkylation is carried out whilst cooling with ice. A~ter the reaction has ended the protecting group is cleaved and the compounds are optionall~ con~erted into their acid addition salts or quaternary compounds using known reaction conditions; the pre~erred quaternary compounds are the methoiodides and methobromides.
Preferred reagents for the deprotonation step are sodium hydride, sodium amide and alkali metal alkoxides such as potassium tert.-butoxide.
Preferred acid addition salts are physiologically acceptable acid addition salts and include, for example salts with hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, ethanesulphonic, toluenesulphonic, benzenesulphonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric and benzoic acid.
The starting compounds required for the synthesis, namely the corresponding hydroxyazabicycloalkanes, are Xnown from the prior art, being of formula 1CH2~nH~ C }~CH2~
IIa II b IV
Thus, for example, for those wherein n represents O from JACS 74, 2215 (1952) (IIa), J. Org. Chem. 33, 4376 (1968) (IIb), European Patent Application 307 140 (III) and J. Pharm. Science 52, 331 (1954) (IV). Starting com~ounds (R = H) wherein n represents 1 or 2 can be obtained by reduction of the corresponding alkylesters (X-R = COOalkyl). Starting from the corresponding ketones the thiols of general formulae II and III may be prepared analogously to the method described in J. Chem.
43, 1965.
~2~
When the group R in the compounds of general formula I is an aromatic or heteroaromatic group, the compounds of general formula I may be obtained using the Mitsunobu reaction (O. Mitsunobu in Synthesis, 1, 1981, Georg Thieme Verlag, Stuttgart; J. C. S. Perkin I, page 462, 1975).
Hence, according to a yet further feature of the present invention is provided a process for the preparation of compounds of formula I as defined above wherein R represents an aromatic or a heterocyclic group, characterised in that a compound of the formula ~Sy(CH2Jn X--H
A -~ ~C
I
z wherein A, B, C, n and X are as hereinbefore defined, is reacted with a compound of formula HOR (in which R
represents an aromatic or heterocyclic group as hereinbefore defined) in the presence of triphenyl-phosphine and alkylazodicarboxylate. The reaction is generally carried out in inert organic solvents at ambient temperature.
The novel individual enantiomers of formula Id may be prepared by a separation process, as is now described for the first time in Example 3, starting from the corresponding racemic compounds using optically active salts e.g. (+)- or (-)- tartaric acid, by methods known E~_ se. This process comprises a further feature of the present invention. The corresponding racemate may be prepared by a process analogous to that for the preparation of the compounds of formula I as hereinbefore described using appropriate starting materials.
The novel compounds of general formulae I and Id 2 ~ a according to the present invention have valuable pharmacological properties as do the known compounds of formulae Ia, Ib and Ic. Thus, in bonding studies, the compounds showed affinities for muscarinic receptors and muscarin-agonistic GTP ~hifts (GTP = guanosine triphosphate). (Birdsall, N.I.M., E.C. Hulme and I.M.
Stockton 1984 in T.I.P.S. Supp:Lement, Proc. Internat.
Symposium on Subtypes of Muscarinic Receptors, Ed.
Hirschowitz, Hammer, Giacchetti, Klirns, Levine;
Elsevier p. 4 - 8).
The receptor binding stud:ies were carried out in accordance with the following literary reference [A.
Closs~, H. Bittiger, D. Langenegger and A. Wahner;
Naunyn-Schmiedeberg's Arch. Pharmacol. 335, 372 - 377 (1987)].
Table A: Receptor bindinq studies Radioliq~a~: L(~)cis-[2-methyl-3H~-N,N,N-trimethyl-1,3-dioxolan-4-methanammonium-iodide-NET-647, Messrs. NEN
(New England Nuclear DU PONT).
orqan: Cerebral cortex (rat) Table A:
Example R* Ki [nMol/l]
1 ~ ~ 120 4 -O-CH2-phenyl 229 9 -O-C6~5 89 As muscarinic agonists (cholinomimetics) the compounds of formulae I, Id, Ib and Ic are therefore therapeutically useful for the treatment of diseases caused by the reduced function of the cholinergic system.
In the light of the studies on binding to the ^
, muscarine subtypes M1, M2 and M3 (rat) and ~he stimulation of the phosphatidyl inositol turnover (CHO
cell cultures with human M1 receptor subtype), ~he compound (+)-(propargyloxymethyl)-l-aza-bicyclo[2.2.2]octane was found to be more effective thanthe racemate and the (-)-enantiomer in vitro and this (+)-enantiomer is thus particularly preferred for use in therapy. The cholinomimetic in-vivo efficacy o~ (+)-(propargyloxymethyl)-l-aza-bicyclo-[2.2.2]octane was demonstrated in the rabbit by EEG (theta wave increase).
Surprisingly the (~)-enantiomer has less than half the toxicity of the racemate.
In the light of the pharmacological findings the compounds of general formulae I, Id, Ib and Ic as defined above are therefore useful for treatment of, for example, the following diseases: Alzheimer's disease, senile dementia and cognitive disorders; the compounds may also be used to improve memory performance.
Quaternary compounds of general formulae I, Id, Ib and Ic are particularly suitakle ~or peripheral application, e.g. for treating glaucoma.
According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I or Id, as defined above, or a physiologically acceptable acid addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
The compounds of general formula I or Id may be used on their own or in conjunction with other active substances according to the invention, possibly in conjunction with other pharmacologically active substances, e.g. cerebroactivators and/or a peripheral cholinergic blocker. Suitable preparations include, for example, tablets, capsules, suppositories, solutionsr syrups, emulsions or dispersible powders.
Corresponding tablets may be made for example by .
2 ~
mixing the active substance or substances with known excipients, e.g. inert diluents such as calcium carbonate, calcium phosphate or lactose, disinkegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for achieving delayed release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate. The tablets may also consist of several layers.
A yet further feature of the present invention is a method of treatment of diseases or conditions in a subject which arise from the reduced function of the cholinergic system which comprises administering to said subject an ~ffective amount of a compound of formula I, Id, Ib or Ic as hereinbefore defined above or a physiologically acceptable acid addition salt thereof or a quaternary salt thereof, in particular wherein the disease or condition is Alzheimers disease, senile dementia, a cognitive disorder, glaucoma or reduced memory performance.
Coated tablets may be produced in the same way by coating cores made analogously to the tablets with agents conventionally used in tablet coating, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or avoid incompatibilities the core may also consist of several layers. Similarly, the tablet coating may be made of several layers in order to achieve delayed release, using the excipients mentioned for the tablets above.
Syrups of the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract.
They also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with 2~6~
ethylene oxide or preservatives such as p-hydroxy-benzoates.
Injectable solutions are produced in the usual way, e.g. by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediaminetetraacetic acid and trans~erring them into in~ection vials or ampoules. The capsules containing one or more active substances or combinations thereof may be produced for example by mixing the active substances with inert carriers such as lactose or sorbitol and encapsulating the mixture in gelatine capsules.
Suitable suppositories can be produced for example by mixing with carriers provided for this purpose such as neutral fats or polyethyleneglycol or derivatives thereof.
The therapeutically effective single dose is in the range from 1 to 100 mg.
The following non-limiting Examples serve to illustrate the present invention: -~ ~ ~ 2 $ ~ ~!
Examples of Pharmaceutical Formulations A) Tablets Per tablet Active substance 80 mg Lactose 1~0 mg Corn starch 240 mg Polyvinylpyrrolidone15 mg Magnesium stearate__~_~g 480 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, moist-granulated and dried. The granules, the remaining corn starch and magnesium stearate are screened and mixed together. The mixture is compressed to form tablets of suitable shape and size.
B) Tablets per tablet Active substance 60 mg Corn starch 190 mg Lactose 55 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone15 mg Sodium carboxymethyl starch 23 mg Magnesium stearate 2 ma 380 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and processed with the remainder of the corn starch and water to form granules which are dried and screened. The sodium carboxymethyl starch and the (s ~ ~
magnesium stearate are added thereto and mixed and the mixture is compressed to form tablets of a suitable size.
C) Ampoules Active substance 20 mg Sodium chloride 10 mg Twice distilled water q.s. to 1.0 ml Preparation:
The active substance and sodium chloride are dissolved in twice distilled water and the solution is transferred under sterile conditions into ampoules.
D) Drops Active substance 5.0 g Methyl p-hydroxybenzoate0.1 g Propyl p-hydroxybenzoate0.1 g Demineralised water q.s. to lO0.0 ml Preparation:
The active substance and preservatives are dissolved in demineralised water and the solution is filtered and transferred into 100 ml vials.
Example 1 .
3-Proparqyloxy-l-azabicyclo~2~2~1]heptane 5.6 g (0.05 mol) of 1 azabicyclot2,2,1]heptan-3-ol are dissolved in 150 ml of absolute tetrahydrofuran under a nitrogen atmosphere and at 0C 50 ml of lM
boran-THF-complex are added. After it has all been added the resulting mixture is stirred for one hour at ambient temperature, evaporated to dryness, the residue is taken up in saturated saline solution and extracted with dichloromethane. The combined organic phases are dried and concentrated by evaporation, ~he residue is dissolved in 120 ml of absolute THF and 2.08 g (0.052 mol) of sodium hydride are added in batches under a nitrogen atmosphere. After one hour the mixture is cooled to 0C and at this temperature 17.55 g of propargyl bromide are added dropwise as a 50% solution in THF. The mixture is stirred for 12 hours at ambient temperature, then the excess hydride is decomposed with ethanol, the mixture is evaporated down, the residue is taken up in saturated saline solution and extracted with dichloromethane. After drying and evaporation of the combined organic phases, an oil is obtained which is distilled under a high vacuum (BP1 ~ar = 45-46C). The fumarate is prepared with one equivalent of fumaric acid, recrystallised from ethanol/ether and dried in vacuo. 2.1 g of colourless crystals of the title compound are obtained, m.p. 121-123C.
1H-NMR(250 MHz, CD30D, TMS): ~ = 6.68 (2H, s, fumaric acid); 4.47 (lH, m, H-3); 4.21 (2H, m, CH2-8); 3.73-2.86 (7H, m, CH2-2, 6, 7; H-4); 2.95 (lH, t, J=3Hz, H-9);
2.30; 1.96 (2H, m, CH2-5).
2 ~
Example 2:
3-Phenoxy-l-azabicyclo[2 t 2~2]octane 3.82 g (0.03 mol) of 3-hydroxyquinuclidine, 2.82 g t0.03 mol) of phenol and 7.96 g (0.03 mol) of triphenylphosphine and 5.22 g (0.03 mol) of diethylazo-dicarboxylate are dissolved in 150 ml of absolute THF
and stirred for 2 days at ambient temperature. The mixture is evaporated to dryness, the residue is taken up in 20 ml of 6N HCl and 50 ml of H20 and extracted with ether. The aqueous phase is made alkaline and extracted with ethyl acetate, the combined ethyl acetate phases are dried and concentrated by evaporation. After distillation, 3.6 g of colourless oil are obtained (Bpo 1 ~ar = 104-105C~
,~0 C6H5 1H-NMR (250 MHz, CDCl3, TMS): ~=7.26; 6.87 (5H, ~, aryl-H); 4.36 (lH, m, H-3); 3.34-2.63 (6H, m, CH2-2, 6, 7); 2.19-1.27 (5H, m, CH-4); CH2 5, 8).
The base is converted in an ethanolic solution into the fumarate, which is precipitated with ether and recrystallised from acetonitrile.
4.1 g of colourless crystals are obtained, m.p.
122-124C.
~ac2~
Example 3:
(+)- and (-)-3-(ProparavloxYmethyl)-1-azabicyclo-r 2,2,2loctane +-(3-quinuclidinylmethyl)-acetate Racemic 3-quinuclidinylmethanol is prepared by methods known from the literature, e.g. using cyanohydrin synthesis from quinuclidin-3-one according to Helv. Chim. Acta 37, 1695 (1954) and acylated with acetylchloride and triethylamine in chloroform as solvent at ambient temperature, the racemic (3-quinuclidinylmethyl)-acetate being obtained in an 82%
yield and with a boiling point of 130 to 134 at 30 mbar.
(-)-3-quinuclidinylmethanol 26.5 g of (3-quinuclidinylmethyl)-+-acetate and 21.7 g of L-(+)-tartaric acid are heated to boiling in 275 ml of 95% ethanol; during the subsequent slow cooling, crystalline tartaric acid salt is obtained which is recrystallised from ~5% ethanol about 5 times until the angle of rotation is constant. The 13.5 g of salt thus obtained, with a rotational value [~]20=
-16.93 (c = 2, H2O) are stirred in 80 ml of 2N sodium hydroxide solution for 2 hours at ambient temperature, then 80 g of potash are added to the solution and the mixture is worked up extractively with chloroform. In this way, with simultaneous ester saponification, 5.6 g of (-)-3-quinuclidinylmethanol are liberated as a light coloured oil with [~]20= -66 (c = 1, 2, in lN HCl).
Analytical checking of the enantiomeric purity was carried out after derivatisation with phenylisocyanate using HPLC on a chiracel-OD column and yielded an enantiomer distribution of 98.6% (-) : 1O4% (+)-- 2~ -enantiomer.
~ 3-quinuclidinylmethanol The accumulated mother liquors obtained during the production of (-)-3-quinuclidinylmethanol are evaporated down in vacuo. The residue is taken up in a little water, made alkaline with potash and extracted with chloroform. The resulting 19.5 g of optically enriched 3-quinuclidinylmethyl acetate are converted into the diastereomeric salt with 16.0 g of D-(+)-tartaric acid in 200 ml of 95% ethanol. After 5 recrystallisations from 95% ethanol, 12.7 g of salt are obtained, with a rotary value [~]2~ = 16.8 (c = 2, H20), from which 4.7 g of (+)-3-quinuclidinylmethanol are liberated as a light coloured oil with [~]20= +66.5 (c = 1, in lN HCl), analogously to the (-)-enantiomer, using 75 ml of 2N
sodium hydroxide solution.
After derivatisation with phenylisocyanate, the enantiomeric purity was determined by HPLC on a chiracel-OD column with 97.4% (+)- : 2.6% (-)-enantiomer.
3a: (+)-3-(propargyloxymethyl)-l-azabicyclo[2~2~2]
octane 5.6 g of (+)-3-quinuclidinylmethanolhydrochloride, 1.32 g of sodium borohydride and 100 ml of tetrahydrofuran are stirred overnight. The solvent is removed from the filtrate, the residue is taken up in ethyl acetate and the resulting solution is washed with saturated saline solution. After drying and removal of the solvent, 3.4 g of (+)-3-quinuclidinylmethanol-boran complex remain in the form of a light coloured oil.
3.4 g of the boran complex are stirred in 100 ml of tetrahydrofuran for 30 minutes with 2.63 g of 60% sodium hydride at an)bient temperature, then reacted with 4.89 g of 80% propargyl bromide and stirred for a further 6 ~12~
hours. The reaction mixture is carefully decomposed with alcohol, the solvent is eliminatecl, the residue is taken up in 150 ml of ethylacetate, the solution is washed with saturated saline solution and the solvent is removed once more. In order to destroy the boran protecting group the residue is taken up in 50 ml of acetone and stirred overnight with 20 ml of 3N HCl.
After the acetone has evaporated off the aqueous phase is washed with ethylacetate, made alkaline with potash and extracted with ethylacetate. The extraction residue is flash-chromatographed on silica gel using ethylacetate:methanol:NH3 = 85:15:1 as eluant and yields 4.3 g of propargylether, which is converted in alcohol, with the calculated quantity of fumaric acid, into the fumaric salt which is re-precipitated from alcohol-ether and is obtained in a 3.9 g yield with a melting point of 132-133C and [~]20= + 28.47 (c = 1, methanol).
3b: (-)-3-(Propargyloxymethyl)-1-azabicyclo[2,2,2]octane Analogously to 3a, the boran protecting group is introduced into (-)-3-quinuclidinylmethanol, etherification is carried out with propargyl bromide and after the boran protecting group has been split off the free base is converted into the fumarate, m.p. 132-133C
and [~]Z= -28.42 (c = 1, methanol).
.
, 6~,~3 I'~f. 2~
The following compounds of general formula I may be prepared by analogous methods of synthesis to those described in the Examples above.
TABLE I R
Compounds of formula ~ ~
Example R* M.P. C
I - 0~-2HC1 236 tdecomp.) N
-O~N 164 - 16 Fumarate 3 -0 ~ 160 - 161 N Fumarate 4 -0-CH2 ~ 135-136 Fumarate 4a (+)Enantiomer -0-CH2 ~ ~ 27,5 tC = 1, H20) .
Example R* M.~. oc 4b (-)Enantiomer [a]D =
- 25.6 --O-CH2~g) (C= 1, H20) - O-CH ~CI lo (Decomp.) 6 - 0-cH2 ~ 110-112 Fumarate 7 --C~2 ~ 112-114 Fumarate 8 ~=~ 108-110 -0-CH2 ~ S Fumarate 9 ~ 122-124 - 0 ~ Fumarate 2 ~
Example R* M.P. C
/~\
9a (+)-Enantiomer~ -O ~ + 22.2 (c = 2, H20) 9b (-)-Enantiomer~ -O ~ [~]D =
- 22.9 (c = 2, H20 ) /==~ 147 - 149 ~ 3 Fumarate lOa - o ~ CH2 -CH ~CH3) 2 /~ /=\
lOb -O ~ \\ ~ ) 10C - --/~{>
~ ~ ~ C~3 126 - 129 Fumarate The reaction takes place with inversion.
' :
.
, 2 o ~ ~
Exam~le R* M.~. C
lla ,, CH3 (+) -Enantiomer -O~CH~
llb_O ~ ~ (-)-Enantiomer .
12 ~ 125 - 126 C~ Fumarate Cl 13- O ~ 147 - 149 Cl Fumarate 14 0 ~ 128-131 ~ Fumarate 5 -O~) 16 -S~3 .' ' ~ .
. . .
. .
.
Example R* M. p. C
.
17 -O~\S
8 -o~3 o ~ 3 Fumarate N
N~
--0~/ ~CH3 N
~N
-S~ ~
N
22 /~N
--O--CH2--N~
23 . N
C~2~_~
24 C~2~N3 --O ¢~,N
N
, ~ ' ' ' : .:
. , . . ~: . .
- , .. , . `
'- :` .' ' - 3 1 ~
Example R* M . p . C
-26 0-CH2 ~0 27 --O--CH2~
H I
28 --O--CH2~
Lo 29 --O--CH2 ~\o ~ 0--CH
N
31----CH2~'N ~N
32-CH:2-- ~3 117 - 18 33 -CH2--Y/ =~ 189 - 191 Fumarate - ' , - , -:
- . . .
2~6~
Example R* a~
33a -CH2-O ~7 158 - 160 Fumarate .
2 l3 ~
TABLE II
Compounds of formula ~ R
Example R* M.p. C
- O - CH2 - C - CH Fumarate -0-cH2-cH-cH2 N
36 -O ~
37 ~O ~ 114 - 116 Oxalate 38 - 0 - CH2 ~
N=\
39 -0 ~\ ~
- S ~ \) ',~ S~
TABLE III
Compounds of formula ( ~J
Example R*
41 endo -O-CH2- C--CH 121-124 Oxal ate exo -O-CH2- C--CH
42 Oil Oxalate 43 - O -CH2- C-CH 93~95 2 oxalate ~0 -CH2 -~
46 -0~3 N
47 ~~\S
N~
48 -o4N ~) , .
TABLE IV
Compounds o~ formula ~ ) R~
Example R* M.p. C
49 endo -O-CH2- C-CH 148-149 Fumarate 49a 147 - 148 exo -O-CH2- C-CH Fumarate exo -o-cH2-cH=cH2 Fumarate 50a endo -o-cH2-cH=cH2 113-114 Fumarate 51 exo -0-CH2-CH3 147 148 Fumarate 51a endo 0-CH2-CH3 115-117 Fumarate 52 -0-C6Hs -O-CH2- C6Hs J ~
ExampleR* M . p . C
N=\
5~ -0~\ ~
-o~3 N
, TABLE V , Compounds o~ formula ( ~) R~
~N
Exp. R* M.p. C
56 -0-CH2-GH= CH~ :
58 ~ O- C6H5 N
- O ~\ ~
61 - O-C~- C6H5 62 0-CH2-cH3
X represents oxygen; R represents a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; the side chain -(CH2)n-X-R being in the 3-position of the quinuclidine system.
Further particularly preferred compounds according to the present invention are l-azabicyclo[2,2,1]heptanes of general formula I as defined above wherein X
represents oxygen; n represents 0 or 1; R represents an optionally substituted C13-alkyl, C34-alkenyl or C3 4-alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group;
the side chain -(CH2)n-X-R being in the 3-position of the bicyclic system.
Further particularly preferred compounds according to the present invention are 1-aza-bicyclo[3,2,1]octanes of general formula I as defined above wherein X
represents oxygen; n represents 0 or 1; R represents an optionally substituted C13-alkyl, C34-alkenyl group or ~ 4-alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group; the side chain -(CHz)n-X-R
being in the 3- or 6-position of the bicyclic group.
Further particularly preferred compounds according to the present invention are l-aza-bicyclo[3,3,13nonanes of general formula I as defined above wherein X
represents oxyger.; n represents 0 or 1; R represents an optionally substituted C13-alkyl, C34-alXenyl or C34-alkynyl group, a substituted or unsubstituted pyridine, thiophen~, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxol~n group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group;
the side chain -(CH2)n-X-R being in the 3-position of the bicyclic group.
Especially preferred compounds according to the present invention are compounds of general formula ~ ~CH2 )n - R
J
N
wherein n represents o or l; R represents a group of formula -CH2~ I Rl)k -~ RlJk -CH2 ~ (R1lk ~ (~1)k -CH2 ~I R2)l _~( R2) -CH2~ IR2 ), ~ (R2 )I - .
-CH2 ~ R2JI ~1 R2), - 7 - 2~
,~,CH2 ,~, R`--N_~,N R --~ N
Q~N J~
-CH2/ 1 ~
-C~2 ~ ~F~2) 15-CH2 ~ (R2)l ~ (R2 20-CH2 ~ (R2~ 2) -CH2 ~ ~ ( R 2 ) in which 30 Rl represents a hydrogen atom, a C14-alkyl group, preferably methyl, a C14-alkoxy group, preferably methoxy, an amino, C14-alkylamino, C14-dialkylamino, hydroxy, or C36-cycloalkyl group, a substituted or unsubstituted phenyl group or a keto-function; 5 k represents 1, 2 or 3, whilst if k is greater-than 1 the R1 groups may be identical or different, R2 represents a hydrogen or halogen atom, a C14-alkyl - : - .
.
2~2~
group, preferably methyl, a C14-alkoxy yroup, preferably methoxy or a keto-function;
1 represents 1 or 2, preferably 1, whilst when 1 represents 2 the groups R2 may be identical or different;
R3 represents a hydrogen atom or a C~ 4 alkyl group, preferably methyl;
and all racemic and tauto:meric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
Further especially preferred compounds according to the present invention are those of general formula (C~2 )n- O - R
N ~ ( CH2)n- 0 - R
~ ~CH2)n 0- R
N
wherein n represents 0 or 1, preferably zero;
R represents a C3-alkynyl group, a C3-alkenyl group, or a group of formula 2 $ ~
_ 9 _ -CU ~-(Rl)k ~(Rl)k -CH ~ ~ I R ~ ~ k --~ ~ R ~ ~ k -CH2 ~(R2~1 ` ~(R2Jt -CH2 ~ (R2)l ~ (R2 2 0 - CH2 ~ ( R 2 ) I N~ N
in which R1, R2, k and l are as hereinbefore defined; and all racsmic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
Further especially preferred compounds according to the present invention are those of general formula ~J--(CH2)n- O- R
wherein n represents O or l;
R represents a C3-alkynyl group, a C3-alkenyl group, or a methyl, ethyl or propyl group, or a group of formula -cH2~(R1~k ~Rl~k -CH2 ~ ~ R ~ ~ < ` ~ ( R 1 J k -C~12 ~( R2~l ~( ~; N N~ N
-CH ~( R2~l ~ ~( R2 2t~ ~ (R2 )l wherein R1, ~, k and 1 are as hereinbefore defined; and 30 all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and the acid addition salts thereof and additionally the quaternary salts thereof.
Certain compounds analogous to compounds of general 35 formula I are described in the prior art. Thus, for example, EP 370415 discloses compounds of formula Ia ~(CHz1",- X- R (Ia) wherein Rl represents an unsubstituted C16-alkyl, C36-alkenyl or C36-alkynyl group; X' represents an oxygen or sulphur atom; and m represents 0, 1 or 2.
UK Patent No. 2208385 discloses compounds of general formula Ib ~
N (Ib) ~ - -wherein R" represents a 3-(2-pyridinyloxy)- group.
However these compounds are described as 5-HT-antagonists. European Patent No. 257741 discloses compounds of formula Ic R " ' ~ (Ic) wherein R"' represents a propyloxy group.
However certain of the optically active compounds of formulae Ia, Ib and Ic are not specifically mentioned by name in EP 370415, GB 2208385 and EP 257741.
.
.. . . .
, ~ lence according to a further feature of the present invention there are pro~ided compounds of formulae Ia, Ib and Ic as defined above in the form of individual enantiomers and acid addition salts thereof and additionally the quaternary salts thereof, collectively termed the compounds of formula (Id); with the proviso that in the compounds of formula Ia when X' represents oxygen and m represents 0, R' cannot represent a C3-alkynyl group or an ethyl group.
A most especially preferred compound according to the present invention is (+)-(propargyloxymethyl)-l-azabicyclo[2,2,2]octane and acid addition salts thereof and additionally the quaternary salts thereof.
When in the compounds of general formula I, R
represents an aliphatic group such compounds may be prepared analogously to the methods described by L.
Stotter et al. in Heterocycles, Vol. 25 (1987), page 25.
Hence, according to a further feature of the present invention we provide a process ~or the preparation of a compound of formula I as defined above wherein R represents an aliphatic group, characterised in that a corresponding optionally N-protected derivative of general formula I (in which R represents H
and the nitrogen atom of the bicyclic group is bloc~ed by a protecting group Z, e.g. BH3) is deprotonated, for example with a strong base, and is subsequently reacted with an alkylating reagent of general formula Y-R, wherein R is as defined hereinbefore and Y represents a readily removable leaving group such as halogen or p~
toluenesulphonate. The reaction is carried out in polar inert organic solvents such as dimethylformamide, tetrahydrofuran, dioxan.
Whereas the deprotonation and conversion of the hydroxy compound into a metal salt is pre~erably carried out at ambient or slightly elevated temperature, the subsequent alkylation is carried out whilst cooling with ice. A~ter the reaction has ended the protecting group is cleaved and the compounds are optionall~ con~erted into their acid addition salts or quaternary compounds using known reaction conditions; the pre~erred quaternary compounds are the methoiodides and methobromides.
Preferred reagents for the deprotonation step are sodium hydride, sodium amide and alkali metal alkoxides such as potassium tert.-butoxide.
Preferred acid addition salts are physiologically acceptable acid addition salts and include, for example salts with hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, ethanesulphonic, toluenesulphonic, benzenesulphonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric and benzoic acid.
The starting compounds required for the synthesis, namely the corresponding hydroxyazabicycloalkanes, are Xnown from the prior art, being of formula 1CH2~nH~ C }~CH2~
IIa II b IV
Thus, for example, for those wherein n represents O from JACS 74, 2215 (1952) (IIa), J. Org. Chem. 33, 4376 (1968) (IIb), European Patent Application 307 140 (III) and J. Pharm. Science 52, 331 (1954) (IV). Starting com~ounds (R = H) wherein n represents 1 or 2 can be obtained by reduction of the corresponding alkylesters (X-R = COOalkyl). Starting from the corresponding ketones the thiols of general formulae II and III may be prepared analogously to the method described in J. Chem.
43, 1965.
~2~
When the group R in the compounds of general formula I is an aromatic or heteroaromatic group, the compounds of general formula I may be obtained using the Mitsunobu reaction (O. Mitsunobu in Synthesis, 1, 1981, Georg Thieme Verlag, Stuttgart; J. C. S. Perkin I, page 462, 1975).
Hence, according to a yet further feature of the present invention is provided a process for the preparation of compounds of formula I as defined above wherein R represents an aromatic or a heterocyclic group, characterised in that a compound of the formula ~Sy(CH2Jn X--H
A -~ ~C
I
z wherein A, B, C, n and X are as hereinbefore defined, is reacted with a compound of formula HOR (in which R
represents an aromatic or heterocyclic group as hereinbefore defined) in the presence of triphenyl-phosphine and alkylazodicarboxylate. The reaction is generally carried out in inert organic solvents at ambient temperature.
The novel individual enantiomers of formula Id may be prepared by a separation process, as is now described for the first time in Example 3, starting from the corresponding racemic compounds using optically active salts e.g. (+)- or (-)- tartaric acid, by methods known E~_ se. This process comprises a further feature of the present invention. The corresponding racemate may be prepared by a process analogous to that for the preparation of the compounds of formula I as hereinbefore described using appropriate starting materials.
The novel compounds of general formulae I and Id 2 ~ a according to the present invention have valuable pharmacological properties as do the known compounds of formulae Ia, Ib and Ic. Thus, in bonding studies, the compounds showed affinities for muscarinic receptors and muscarin-agonistic GTP ~hifts (GTP = guanosine triphosphate). (Birdsall, N.I.M., E.C. Hulme and I.M.
Stockton 1984 in T.I.P.S. Supp:Lement, Proc. Internat.
Symposium on Subtypes of Muscarinic Receptors, Ed.
Hirschowitz, Hammer, Giacchetti, Klirns, Levine;
Elsevier p. 4 - 8).
The receptor binding stud:ies were carried out in accordance with the following literary reference [A.
Closs~, H. Bittiger, D. Langenegger and A. Wahner;
Naunyn-Schmiedeberg's Arch. Pharmacol. 335, 372 - 377 (1987)].
Table A: Receptor bindinq studies Radioliq~a~: L(~)cis-[2-methyl-3H~-N,N,N-trimethyl-1,3-dioxolan-4-methanammonium-iodide-NET-647, Messrs. NEN
(New England Nuclear DU PONT).
orqan: Cerebral cortex (rat) Table A:
Example R* Ki [nMol/l]
1 ~ ~ 120 4 -O-CH2-phenyl 229 9 -O-C6~5 89 As muscarinic agonists (cholinomimetics) the compounds of formulae I, Id, Ib and Ic are therefore therapeutically useful for the treatment of diseases caused by the reduced function of the cholinergic system.
In the light of the studies on binding to the ^
, muscarine subtypes M1, M2 and M3 (rat) and ~he stimulation of the phosphatidyl inositol turnover (CHO
cell cultures with human M1 receptor subtype), ~he compound (+)-(propargyloxymethyl)-l-aza-bicyclo[2.2.2]octane was found to be more effective thanthe racemate and the (-)-enantiomer in vitro and this (+)-enantiomer is thus particularly preferred for use in therapy. The cholinomimetic in-vivo efficacy o~ (+)-(propargyloxymethyl)-l-aza-bicyclo-[2.2.2]octane was demonstrated in the rabbit by EEG (theta wave increase).
Surprisingly the (~)-enantiomer has less than half the toxicity of the racemate.
In the light of the pharmacological findings the compounds of general formulae I, Id, Ib and Ic as defined above are therefore useful for treatment of, for example, the following diseases: Alzheimer's disease, senile dementia and cognitive disorders; the compounds may also be used to improve memory performance.
Quaternary compounds of general formulae I, Id, Ib and Ic are particularly suitakle ~or peripheral application, e.g. for treating glaucoma.
According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I or Id, as defined above, or a physiologically acceptable acid addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
The compounds of general formula I or Id may be used on their own or in conjunction with other active substances according to the invention, possibly in conjunction with other pharmacologically active substances, e.g. cerebroactivators and/or a peripheral cholinergic blocker. Suitable preparations include, for example, tablets, capsules, suppositories, solutionsr syrups, emulsions or dispersible powders.
Corresponding tablets may be made for example by .
2 ~
mixing the active substance or substances with known excipients, e.g. inert diluents such as calcium carbonate, calcium phosphate or lactose, disinkegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for achieving delayed release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate. The tablets may also consist of several layers.
A yet further feature of the present invention is a method of treatment of diseases or conditions in a subject which arise from the reduced function of the cholinergic system which comprises administering to said subject an ~ffective amount of a compound of formula I, Id, Ib or Ic as hereinbefore defined above or a physiologically acceptable acid addition salt thereof or a quaternary salt thereof, in particular wherein the disease or condition is Alzheimers disease, senile dementia, a cognitive disorder, glaucoma or reduced memory performance.
Coated tablets may be produced in the same way by coating cores made analogously to the tablets with agents conventionally used in tablet coating, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or avoid incompatibilities the core may also consist of several layers. Similarly, the tablet coating may be made of several layers in order to achieve delayed release, using the excipients mentioned for the tablets above.
Syrups of the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract.
They also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with 2~6~
ethylene oxide or preservatives such as p-hydroxy-benzoates.
Injectable solutions are produced in the usual way, e.g. by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediaminetetraacetic acid and trans~erring them into in~ection vials or ampoules. The capsules containing one or more active substances or combinations thereof may be produced for example by mixing the active substances with inert carriers such as lactose or sorbitol and encapsulating the mixture in gelatine capsules.
Suitable suppositories can be produced for example by mixing with carriers provided for this purpose such as neutral fats or polyethyleneglycol or derivatives thereof.
The therapeutically effective single dose is in the range from 1 to 100 mg.
The following non-limiting Examples serve to illustrate the present invention: -~ ~ ~ 2 $ ~ ~!
Examples of Pharmaceutical Formulations A) Tablets Per tablet Active substance 80 mg Lactose 1~0 mg Corn starch 240 mg Polyvinylpyrrolidone15 mg Magnesium stearate__~_~g 480 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, moist-granulated and dried. The granules, the remaining corn starch and magnesium stearate are screened and mixed together. The mixture is compressed to form tablets of suitable shape and size.
B) Tablets per tablet Active substance 60 mg Corn starch 190 mg Lactose 55 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone15 mg Sodium carboxymethyl starch 23 mg Magnesium stearate 2 ma 380 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and processed with the remainder of the corn starch and water to form granules which are dried and screened. The sodium carboxymethyl starch and the (s ~ ~
magnesium stearate are added thereto and mixed and the mixture is compressed to form tablets of a suitable size.
C) Ampoules Active substance 20 mg Sodium chloride 10 mg Twice distilled water q.s. to 1.0 ml Preparation:
The active substance and sodium chloride are dissolved in twice distilled water and the solution is transferred under sterile conditions into ampoules.
D) Drops Active substance 5.0 g Methyl p-hydroxybenzoate0.1 g Propyl p-hydroxybenzoate0.1 g Demineralised water q.s. to lO0.0 ml Preparation:
The active substance and preservatives are dissolved in demineralised water and the solution is filtered and transferred into 100 ml vials.
Example 1 .
3-Proparqyloxy-l-azabicyclo~2~2~1]heptane 5.6 g (0.05 mol) of 1 azabicyclot2,2,1]heptan-3-ol are dissolved in 150 ml of absolute tetrahydrofuran under a nitrogen atmosphere and at 0C 50 ml of lM
boran-THF-complex are added. After it has all been added the resulting mixture is stirred for one hour at ambient temperature, evaporated to dryness, the residue is taken up in saturated saline solution and extracted with dichloromethane. The combined organic phases are dried and concentrated by evaporation, ~he residue is dissolved in 120 ml of absolute THF and 2.08 g (0.052 mol) of sodium hydride are added in batches under a nitrogen atmosphere. After one hour the mixture is cooled to 0C and at this temperature 17.55 g of propargyl bromide are added dropwise as a 50% solution in THF. The mixture is stirred for 12 hours at ambient temperature, then the excess hydride is decomposed with ethanol, the mixture is evaporated down, the residue is taken up in saturated saline solution and extracted with dichloromethane. After drying and evaporation of the combined organic phases, an oil is obtained which is distilled under a high vacuum (BP1 ~ar = 45-46C). The fumarate is prepared with one equivalent of fumaric acid, recrystallised from ethanol/ether and dried in vacuo. 2.1 g of colourless crystals of the title compound are obtained, m.p. 121-123C.
1H-NMR(250 MHz, CD30D, TMS): ~ = 6.68 (2H, s, fumaric acid); 4.47 (lH, m, H-3); 4.21 (2H, m, CH2-8); 3.73-2.86 (7H, m, CH2-2, 6, 7; H-4); 2.95 (lH, t, J=3Hz, H-9);
2.30; 1.96 (2H, m, CH2-5).
2 ~
Example 2:
3-Phenoxy-l-azabicyclo[2 t 2~2]octane 3.82 g (0.03 mol) of 3-hydroxyquinuclidine, 2.82 g t0.03 mol) of phenol and 7.96 g (0.03 mol) of triphenylphosphine and 5.22 g (0.03 mol) of diethylazo-dicarboxylate are dissolved in 150 ml of absolute THF
and stirred for 2 days at ambient temperature. The mixture is evaporated to dryness, the residue is taken up in 20 ml of 6N HCl and 50 ml of H20 and extracted with ether. The aqueous phase is made alkaline and extracted with ethyl acetate, the combined ethyl acetate phases are dried and concentrated by evaporation. After distillation, 3.6 g of colourless oil are obtained (Bpo 1 ~ar = 104-105C~
,~0 C6H5 1H-NMR (250 MHz, CDCl3, TMS): ~=7.26; 6.87 (5H, ~, aryl-H); 4.36 (lH, m, H-3); 3.34-2.63 (6H, m, CH2-2, 6, 7); 2.19-1.27 (5H, m, CH-4); CH2 5, 8).
The base is converted in an ethanolic solution into the fumarate, which is precipitated with ether and recrystallised from acetonitrile.
4.1 g of colourless crystals are obtained, m.p.
122-124C.
~ac2~
Example 3:
(+)- and (-)-3-(ProparavloxYmethyl)-1-azabicyclo-r 2,2,2loctane +-(3-quinuclidinylmethyl)-acetate Racemic 3-quinuclidinylmethanol is prepared by methods known from the literature, e.g. using cyanohydrin synthesis from quinuclidin-3-one according to Helv. Chim. Acta 37, 1695 (1954) and acylated with acetylchloride and triethylamine in chloroform as solvent at ambient temperature, the racemic (3-quinuclidinylmethyl)-acetate being obtained in an 82%
yield and with a boiling point of 130 to 134 at 30 mbar.
(-)-3-quinuclidinylmethanol 26.5 g of (3-quinuclidinylmethyl)-+-acetate and 21.7 g of L-(+)-tartaric acid are heated to boiling in 275 ml of 95% ethanol; during the subsequent slow cooling, crystalline tartaric acid salt is obtained which is recrystallised from ~5% ethanol about 5 times until the angle of rotation is constant. The 13.5 g of salt thus obtained, with a rotational value [~]20=
-16.93 (c = 2, H2O) are stirred in 80 ml of 2N sodium hydroxide solution for 2 hours at ambient temperature, then 80 g of potash are added to the solution and the mixture is worked up extractively with chloroform. In this way, with simultaneous ester saponification, 5.6 g of (-)-3-quinuclidinylmethanol are liberated as a light coloured oil with [~]20= -66 (c = 1, 2, in lN HCl).
Analytical checking of the enantiomeric purity was carried out after derivatisation with phenylisocyanate using HPLC on a chiracel-OD column and yielded an enantiomer distribution of 98.6% (-) : 1O4% (+)-- 2~ -enantiomer.
~ 3-quinuclidinylmethanol The accumulated mother liquors obtained during the production of (-)-3-quinuclidinylmethanol are evaporated down in vacuo. The residue is taken up in a little water, made alkaline with potash and extracted with chloroform. The resulting 19.5 g of optically enriched 3-quinuclidinylmethyl acetate are converted into the diastereomeric salt with 16.0 g of D-(+)-tartaric acid in 200 ml of 95% ethanol. After 5 recrystallisations from 95% ethanol, 12.7 g of salt are obtained, with a rotary value [~]2~ = 16.8 (c = 2, H20), from which 4.7 g of (+)-3-quinuclidinylmethanol are liberated as a light coloured oil with [~]20= +66.5 (c = 1, in lN HCl), analogously to the (-)-enantiomer, using 75 ml of 2N
sodium hydroxide solution.
After derivatisation with phenylisocyanate, the enantiomeric purity was determined by HPLC on a chiracel-OD column with 97.4% (+)- : 2.6% (-)-enantiomer.
3a: (+)-3-(propargyloxymethyl)-l-azabicyclo[2~2~2]
octane 5.6 g of (+)-3-quinuclidinylmethanolhydrochloride, 1.32 g of sodium borohydride and 100 ml of tetrahydrofuran are stirred overnight. The solvent is removed from the filtrate, the residue is taken up in ethyl acetate and the resulting solution is washed with saturated saline solution. After drying and removal of the solvent, 3.4 g of (+)-3-quinuclidinylmethanol-boran complex remain in the form of a light coloured oil.
3.4 g of the boran complex are stirred in 100 ml of tetrahydrofuran for 30 minutes with 2.63 g of 60% sodium hydride at an)bient temperature, then reacted with 4.89 g of 80% propargyl bromide and stirred for a further 6 ~12~
hours. The reaction mixture is carefully decomposed with alcohol, the solvent is eliminatecl, the residue is taken up in 150 ml of ethylacetate, the solution is washed with saturated saline solution and the solvent is removed once more. In order to destroy the boran protecting group the residue is taken up in 50 ml of acetone and stirred overnight with 20 ml of 3N HCl.
After the acetone has evaporated off the aqueous phase is washed with ethylacetate, made alkaline with potash and extracted with ethylacetate. The extraction residue is flash-chromatographed on silica gel using ethylacetate:methanol:NH3 = 85:15:1 as eluant and yields 4.3 g of propargylether, which is converted in alcohol, with the calculated quantity of fumaric acid, into the fumaric salt which is re-precipitated from alcohol-ether and is obtained in a 3.9 g yield with a melting point of 132-133C and [~]20= + 28.47 (c = 1, methanol).
3b: (-)-3-(Propargyloxymethyl)-1-azabicyclo[2,2,2]octane Analogously to 3a, the boran protecting group is introduced into (-)-3-quinuclidinylmethanol, etherification is carried out with propargyl bromide and after the boran protecting group has been split off the free base is converted into the fumarate, m.p. 132-133C
and [~]Z= -28.42 (c = 1, methanol).
.
, 6~,~3 I'~f. 2~
The following compounds of general formula I may be prepared by analogous methods of synthesis to those described in the Examples above.
TABLE I R
Compounds of formula ~ ~
Example R* M.P. C
I - 0~-2HC1 236 tdecomp.) N
-O~N 164 - 16 Fumarate 3 -0 ~ 160 - 161 N Fumarate 4 -0-CH2 ~ 135-136 Fumarate 4a (+)Enantiomer -0-CH2 ~ ~ 27,5 tC = 1, H20) .
Example R* M.~. oc 4b (-)Enantiomer [a]D =
- 25.6 --O-CH2~g) (C= 1, H20) - O-CH ~CI lo (Decomp.) 6 - 0-cH2 ~ 110-112 Fumarate 7 --C~2 ~ 112-114 Fumarate 8 ~=~ 108-110 -0-CH2 ~ S Fumarate 9 ~ 122-124 - 0 ~ Fumarate 2 ~
Example R* M.P. C
/~\
9a (+)-Enantiomer~ -O ~ + 22.2 (c = 2, H20) 9b (-)-Enantiomer~ -O ~ [~]D =
- 22.9 (c = 2, H20 ) /==~ 147 - 149 ~ 3 Fumarate lOa - o ~ CH2 -CH ~CH3) 2 /~ /=\
lOb -O ~ \\ ~ ) 10C - --/~{>
~ ~ ~ C~3 126 - 129 Fumarate The reaction takes place with inversion.
' :
.
, 2 o ~ ~
Exam~le R* M.~. C
lla ,, CH3 (+) -Enantiomer -O~CH~
llb_O ~ ~ (-)-Enantiomer .
12 ~ 125 - 126 C~ Fumarate Cl 13- O ~ 147 - 149 Cl Fumarate 14 0 ~ 128-131 ~ Fumarate 5 -O~) 16 -S~3 .' ' ~ .
. . .
. .
.
Example R* M. p. C
.
17 -O~\S
8 -o~3 o ~ 3 Fumarate N
N~
--0~/ ~CH3 N
~N
-S~ ~
N
22 /~N
--O--CH2--N~
23 . N
C~2~_~
24 C~2~N3 --O ¢~,N
N
, ~ ' ' ' : .:
. , . . ~: . .
- , .. , . `
'- :` .' ' - 3 1 ~
Example R* M . p . C
-26 0-CH2 ~0 27 --O--CH2~
H I
28 --O--CH2~
Lo 29 --O--CH2 ~\o ~ 0--CH
N
31----CH2~'N ~N
32-CH:2-- ~3 117 - 18 33 -CH2--Y/ =~ 189 - 191 Fumarate - ' , - , -:
- . . .
2~6~
Example R* a~
33a -CH2-O ~7 158 - 160 Fumarate .
2 l3 ~
TABLE II
Compounds of formula ~ R
Example R* M.p. C
- O - CH2 - C - CH Fumarate -0-cH2-cH-cH2 N
36 -O ~
37 ~O ~ 114 - 116 Oxalate 38 - 0 - CH2 ~
N=\
39 -0 ~\ ~
- S ~ \) ',~ S~
TABLE III
Compounds of formula ( ~J
Example R*
41 endo -O-CH2- C--CH 121-124 Oxal ate exo -O-CH2- C--CH
42 Oil Oxalate 43 - O -CH2- C-CH 93~95 2 oxalate ~0 -CH2 -~
46 -0~3 N
47 ~~\S
N~
48 -o4N ~) , .
TABLE IV
Compounds o~ formula ~ ) R~
Example R* M.p. C
49 endo -O-CH2- C-CH 148-149 Fumarate 49a 147 - 148 exo -O-CH2- C-CH Fumarate exo -o-cH2-cH=cH2 Fumarate 50a endo -o-cH2-cH=cH2 113-114 Fumarate 51 exo -0-CH2-CH3 147 148 Fumarate 51a endo 0-CH2-CH3 115-117 Fumarate 52 -0-C6Hs -O-CH2- C6Hs J ~
ExampleR* M . p . C
N=\
5~ -0~\ ~
-o~3 N
, TABLE V , Compounds o~ formula ( ~) R~
~N
Exp. R* M.p. C
56 -0-CH2-GH= CH~ :
58 ~ O- C6H5 N
- O ~\ ~
61 - O-C~- C6H5 62 0-CH2-cH3
Claims (24)
1. Compounds of general formula I
I
wherein R represents a C1-6-alkyl group, a C3-6-alkenyl group or a C3-6-alkynyl group, the alkyl, alkenyl or alkynyl group being optionally substituted by a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted oxetan ring or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group; or R represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group;
X represents oxygen or sulphur;
A, B and C independently of one another represent CH2 or a single bond;
n represents 0, 1 or 2;
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof; with the proviso that i) for a compound of formula I wherein the bicyclic ring system is quinuclidine, R may not represent an unsubstituted alkyl, alkenyl or alkynyl group; ii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo[3,2,1]octane, the group -(CH2)n-X-R may not represent a propoxy group; and iii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo[2,2,2]octane, the group -(CH2)n-X-R may not represent a 3-(2-pyridinyloxy)- group.
I
wherein R represents a C1-6-alkyl group, a C3-6-alkenyl group or a C3-6-alkynyl group, the alkyl, alkenyl or alkynyl group being optionally substituted by a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted oxetan ring or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group; or R represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic group;
X represents oxygen or sulphur;
A, B and C independently of one another represent CH2 or a single bond;
n represents 0, 1 or 2;
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof; with the proviso that i) for a compound of formula I wherein the bicyclic ring system is quinuclidine, R may not represent an unsubstituted alkyl, alkenyl or alkynyl group; ii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo[3,2,1]octane, the group -(CH2)n-X-R may not represent a propoxy group; and iii) for a compound of formula I wherein the bicyclic ring system is 1-azabicyclo[2,2,2]octane, the group -(CH2)n-X-R may not represent a 3-(2-pyridinyloxy)- group.
2. Compounds of general formula I as claimed in claim 1 wherein X represents oxygen; n represents 0 or 1; the substituent (CH2)n-X-R is in the .alpha.- or .beta.-position relative to the carbocyclic bridgehead; and R represents an optionally substituted C1-3-alkyl, C3-4-alkenyl or C3-4-alkynyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group.
3. Compounds of general formula I as claimed in claim 1 or claim 2 wherein the ring system is selected from a group comprising quinuclidine, 1-azabicyclo[2,2,1]heptane, 1-azabicyclo[3,2,1]octane or 1-azabicyclo[3,3,1]nonane; X represents oxygen; n represents 0 or 1; R represents an optionally substituted C1-3-alkyl, C3-4-alkenyl or C3-4-alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group; the side chain (CH2)n-X-R being in the 3-position of the bicyclic group and in the case of 1-azabicyclo[3,2,1]octane optionally in the 6-position.
4. Compounds as claimed in any of claims 1 to 3 of general formula wherein n represents 0 or 1;
R represents a group of formula in which R1 represents a hydrogen atom, a C1-4-alkyl group, a C1-4-alkoxy group, an amino, C1-4-alkylamino, C1-4-dialkylamino, hydroxy or C3-6-cycloalkyl group, a substituted or unsubstituted phenyl group or a keto-function;
k represents 1, 2 or 3, whilst if k is greater than 1 the R1 groups may be identical or different, R2 represents a hydrogen or halogen atom, a C1-4-alkyl group, a C1-4-alkoxy group or a keto-function;
l represents 1 or 2, whilst when 1 represents 2 the groups R2 may be identical or different;
R3 represents a hydrogen atom or a C1-4-alkyl group;
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
R represents a group of formula in which R1 represents a hydrogen atom, a C1-4-alkyl group, a C1-4-alkoxy group, an amino, C1-4-alkylamino, C1-4-dialkylamino, hydroxy or C3-6-cycloalkyl group, a substituted or unsubstituted phenyl group or a keto-function;
k represents 1, 2 or 3, whilst if k is greater than 1 the R1 groups may be identical or different, R2 represents a hydrogen or halogen atom, a C1-4-alkyl group, a C1-4-alkoxy group or a keto-function;
l represents 1 or 2, whilst when 1 represents 2 the groups R2 may be identical or different;
R3 represents a hydrogen atom or a C1-4-alkyl group;
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
5. Compounds as claimed in any one of claims 1 to 3 of general formula wherein n represents 0 or 1;
R represents a C3-alkynyl group, a C3-alkenyl group, or a group of formula in which R1, R2, k and 1 are as defined in claim 4;
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
R represents a C3-alkynyl group, a C3-alkenyl group, or a group of formula in which R1, R2, k and 1 are as defined in claim 4;
and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.
6. Compounds as claimed in any one of claims 1 to 3 of general formula wherein n represents 0 or 1;
R represents a C3-alkynyl group, a C3-alkenyl group, or a methyl, ethyl or propyl group, or a group of formula wherein R1, R2, k and l are as defined in claim 4; and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and the acid addition salts thereof and additionally the quaternary salts thereof.
R represents a C3-alkynyl group, a C3-alkenyl group, or a methyl, ethyl or propyl group, or a group of formula wherein R1, R2, k and l are as defined in claim 4; and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and the acid addition salts thereof and additionally the quaternary salts thereof.
7. Compounds of general formula Ia, Ib or Ic, (Ia) (Ib) (Ic) wherein R' represents an unsubstituted C1-6-alkyl, C3-6-alkenyl or C3-6-alkynyl group; X' represents an oxygen or sulphur atom; and m represents 0, 1 or 2; R" represents a 3-(2-pyridinyloxy)- group and R''' represents a propyloxy group; in the form of individual enantiomers, and acid addition salts thereof and additionally the quaternary salts thereof, collectively termed the compounds of formula Id; with the proviso that in the compounds of formula Ia wherein X' represents oxygen and m represents 0, R' cannot represent a C3-alkynyl group or an ethyl group.
8. (+)-(Propargyloxymethyl)-1-azabicyclo[2,2,2]octane;
and acid addition salts thereof and additionally the quaternary salts thereof.
and acid addition salts thereof and additionally the quaternary salts thereof.
9. Compounds as claimed in any one of the preceding claims as herein specifically disclosed in any one of the Examples.
10. A process for the preparation of compounds of general formula I as claimed in any one of claims 1 to 6 and 9 wherein R represents an aliphatic group, characterised in that a compound of general formula wherein A, B, C, n and X are as defined in claim 1 and Z
represents a protecting group (where X=S the protecting group Z can be omitted) is deprotonated and reacted with an alkylating reagent of the formula Y - R
wherein R represents an aliphatic group as indicated in claim 1 and Y represents a readily removable leaving group, the protecting group is then cleaved and, if desired, the compound thereby obtained is converted into an acid addition salt or a quaternary salt thereof and/or, if desired, separated into the optically active isomers thereof by methods known per se.
represents a protecting group (where X=S the protecting group Z can be omitted) is deprotonated and reacted with an alkylating reagent of the formula Y - R
wherein R represents an aliphatic group as indicated in claim 1 and Y represents a readily removable leaving group, the protecting group is then cleaved and, if desired, the compound thereby obtained is converted into an acid addition salt or a quaternary salt thereof and/or, if desired, separated into the optically active isomers thereof by methods known per se.
11. A process as claimed in claim 10 wherein the deprotonation is effected by means of a strong base, the reaction being effected in a polar inert organic solvent.
12. A process as claimed in claim 11 wherein the strong base is selected from sodium hydride, sodium amide and alkali metal alkoxides and the solvent is selected from dimethylformamide, tetrahydrofuran and dioxan.
13. A process for the preparation of compounds of general formula I as claimed in any one of claims 1 to 6 and 9, wherein R represents an aromatic or a heterocyclic group, characterised in that a compound of the formula wherein A, B, C, n and X are as defined in claim 1, is reacted with a compound of formula HOR (in which R
represents an aromatic or heterocyclic group as indicated in claim 1) in the presence of triphenyl-phosphine and alkylazodicarboxylate.
represents an aromatic or heterocyclic group as indicated in claim 1) in the presence of triphenyl-phosphine and alkylazodicarboxylate.
14. A process for the preparation of compounds of formula Id as defined in claim 7 wherein the corresponding racemate is resolved using an optically active salt by a method known per se.
15. A process as claimed in any of claims 10 to 14 substantially as hereinbefore described with reference to the Examples.
16. Compounds as claimed in any one of claims 1 to 9 whenever prepared by a process as claimed in any one of claims 10 to 14.
17. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I or Id, as claimed in claim 1 or claim 7, or a physiologically acceptable acid addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
18. Compositions as claimed in claim 17 substantially as herein defined and with reference to the Examples.
19. Compounds of general formula I or Id as claimed in claim 1 or claim 7 for use in therapy.
20. The use of a compound of general formula I or Id as claimed in claim 1 or claim 7; or the use of a compound of formula Ib or Ic as defined in claim 7 and all racemic forms, diastereomers and mixtures thereof and physiologically acceptable acid addition salts thereof and additionally the quaternary salts thereof;
for the preparation of a medicament for use in the treatment of diseases or conditions caused by the reduced function of the cholinergic system.
for the preparation of a medicament for use in the treatment of diseases or conditions caused by the reduced function of the cholinergic system.
21. The use as claimed in claim 20 wherein the medicament is used in the treatment of Alzheimers disease, senile dementia, cognitive disorders or glaucoma and in the improvement of memory performance.
22. A method of treatment of diseases or conditions in a subject which arise from the reduced function of the cholinergic system which comprises administering to said subject an effective amount of a compound of formula I
or Id, as claimed in claim 1 or claim 7, or an effective amount of a compound of formula Ib or Ic as defined in claim 7 and all racemic forms, diastereomers and mixtures thereof and physiologically acceptable acid addition salts thereof and additionally the quaternary salts thereof.
or Id, as claimed in claim 1 or claim 7, or an effective amount of a compound of formula Ib or Ic as defined in claim 7 and all racemic forms, diastereomers and mixtures thereof and physiologically acceptable acid addition salts thereof and additionally the quaternary salts thereof.
23. A method as claimed in claim 22 wherein the disease or condition is Alzheimers disease, senile dementia, a cognitive disorder, glaucoma or reduced memory performance.
24. Each and every novel compound, process, method, composition and use herein disclosed.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4016212 | 1990-05-19 | ||
DEP4016212.5 | 1990-05-19 | ||
DE4018886 | 1990-06-13 | ||
DEP4018886.8 | 1990-06-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2042860A1 true CA2042860A1 (en) | 1991-11-20 |
Family
ID=25893382
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002042860A Abandoned CA2042860A1 (en) | 1990-05-19 | 1991-05-17 | Bicyclic 1-aza-cycloalkanes |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0458214A1 (en) |
JP (1) | JP2853837B2 (en) |
KR (1) | KR910020009A (en) |
AU (1) | AU648789B2 (en) |
CA (1) | CA2042860A1 (en) |
CZ (1) | CZ281837B6 (en) |
FI (1) | FI912409A (en) |
HU (1) | HUT58091A (en) |
IE (1) | IE911688A1 (en) |
IL (1) | IL98176A0 (en) |
NO (1) | NO911934L (en) |
PT (1) | PT97703A (en) |
SK (1) | SK279168B6 (en) |
YU (1) | YU84791A (en) |
Cited By (8)
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US5731323A (en) * | 1992-12-21 | 1998-03-24 | Zeneca Limited | Quinuclidine derivatives as squalene synthase inhibitors |
US6030966A (en) * | 1994-10-24 | 2000-02-29 | Eli Lilly And Company | Heterocyclic compound and their use |
US8048885B2 (en) | 2005-12-16 | 2011-11-01 | Novartis Ag | Organic compounds |
US8173667B2 (en) | 2005-10-21 | 2012-05-08 | Novartis Ag | 1-aza-bicycloalkyl derivatives |
US8236803B2 (en) | 2002-09-04 | 2012-08-07 | Novartis Ag | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US8609662B2 (en) | 2004-07-14 | 2013-12-17 | Novartis Ag | 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases |
US8759346B2 (en) | 2005-12-16 | 2014-06-24 | Novartis Ag | Organic compounds |
US8933090B2 (en) | 2004-06-18 | 2015-01-13 | Novartis Ag | 1-aza-bicyclo[3.3.1]nonanes |
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DK0456519T3 (en) * | 1990-05-11 | 1994-11-07 | Sankyo Co | Piperidyloxy and quinuclidinyloxyisoxazole derivatives, their preparation and their therapeutic use |
GB9122988D0 (en) * | 1991-10-30 | 1991-12-18 | Ici Plc | Heterocyclic compounds |
GB9127279D0 (en) * | 1991-12-23 | 1992-02-19 | Ici Plc | Heterocyclic derivatives |
AU3901393A (en) * | 1992-04-10 | 1993-11-18 | Zeneca Limited | Biphenylylquinuclidine derivatives as squalene synthase inhibitors |
GB9211796D0 (en) * | 1992-06-04 | 1992-07-15 | Ici Plc | Heterocyclic derivatives |
IT1255179B (en) * | 1992-06-26 | 1995-10-20 | Enzo Cereda | AZACICLO AND AZABICICLO ALCHILIDEN IDROSSILAMINE |
GB9216721D0 (en) * | 1992-08-06 | 1992-09-23 | Ici Plc | Therapeutic heterocyclic derivatives |
GB9218334D0 (en) * | 1992-08-28 | 1992-10-14 | Ici Plc | Heterocyclic compounds |
IL107184A (en) * | 1992-10-09 | 1997-08-14 | Abbott Lab | Heterocyclic ether compounds that enhance cognitive function |
DE4236331A1 (en) * | 1992-10-28 | 1994-05-05 | Boehringer Ingelheim Kg | Synergistic combination |
IL109451A0 (en) * | 1993-04-29 | 1994-07-31 | Zeneca Ltd | Heterocyclic derivatives |
US5512574A (en) * | 1994-12-21 | 1996-04-30 | American Home Products Corporation | Quinuclidine and azabicyclo 2.2.1! heptane pyrazinyl ethers as muscarinic agonists |
US5859004A (en) * | 1995-02-17 | 1999-01-12 | Novo Nordisk A/S | Use of heterocyclic compounds for the treatment of conditions caused by malfunctioning of the nicotinic cholinergic system |
US6040442A (en) * | 1995-06-01 | 2000-03-21 | Eli Lilly And Company | Process for preparing 1,2,5-thiadiazole containing ethers |
EP0874828A4 (en) * | 1995-12-06 | 1999-09-01 | Lilly Co Eli | Composition for treating pain |
WO1997039753A1 (en) * | 1996-04-23 | 1997-10-30 | Eli Lilly And Company | Heterocyclic compounds |
KR20050055711A (en) * | 2002-08-14 | 2005-06-13 | 뉴로서치 에이/에스 | Novel quinuclidine derivatives and their use |
WO2005016923A1 (en) | 2003-08-13 | 2005-02-24 | Neurosearch A/S | Novel quinuclidine derivatives and their pharmaceutical use |
US7160876B2 (en) | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137203A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-quinuclidinyl amino-substituted biaryl derivatives |
US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
JP2008523058A (en) * | 2004-12-10 | 2008-07-03 | アボット・ラボラトリーズ | Fused bicycloheterocyclic substituted quinuclidine derivatives |
TW202322824A (en) | 2020-02-18 | 2023-06-16 | 美商基利科學股份有限公司 | Antiviral compounds |
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WO2022221514A1 (en) | 2021-04-16 | 2022-10-20 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
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SE321933B (en) * | 1967-10-05 | 1970-03-23 | Astra Ab | |
FR2014831A1 (en) * | 1968-08-01 | 1970-04-24 | Sogeras | Quinuclidinyl and quinuclidinylalkyl ethers with cholino - lytic, antihistaminic and neurosedative activity |
GB8615785D0 (en) * | 1986-06-27 | 1986-08-06 | Beecham Group Plc | Compounds |
NZ224237A (en) * | 1987-04-15 | 1991-04-26 | Beecham Group Plc | Bicyclic compounds (n bridged compounds) |
GB8718445D0 (en) * | 1987-08-04 | 1987-09-09 | Wyeth John & Brother Ltd | Pyridyl-ethers |
CA1307790C (en) * | 1987-08-04 | 1992-09-22 | Ian Anthony Cliffe | Ethers |
DE3839385A1 (en) * | 1988-11-22 | 1990-05-23 | Boehringer Ingelheim Kg | NEW QUINUCLIDINES, THEIR MANUFACTURE AS A MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF |
-
1991
- 1991-05-15 YU YU84791A patent/YU84791A/en unknown
- 1991-05-16 NO NO91911934A patent/NO911934L/en unknown
- 1991-05-16 SK SK1448-91A patent/SK279168B6/en unknown
- 1991-05-16 CZ CS911448A patent/CZ281837B6/en not_active IP Right Cessation
- 1991-05-17 JP JP3113418A patent/JP2853837B2/en not_active Expired - Lifetime
- 1991-05-17 PT PT97703A patent/PT97703A/en not_active Application Discontinuation
- 1991-05-17 EP EP91108054A patent/EP0458214A1/en not_active Ceased
- 1991-05-17 HU HU911663A patent/HUT58091A/en unknown
- 1991-05-17 CA CA002042860A patent/CA2042860A1/en not_active Abandoned
- 1991-05-17 IE IE168891A patent/IE911688A1/en unknown
- 1991-05-17 FI FI912409A patent/FI912409A/en not_active Application Discontinuation
- 1991-05-17 IL IL98176A patent/IL98176A0/en unknown
- 1991-05-18 KR KR1019910008106A patent/KR910020009A/en not_active Application Discontinuation
- 1991-05-20 AU AU77130/91A patent/AU648789B2/en not_active Ceased
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US5731323A (en) * | 1992-12-21 | 1998-03-24 | Zeneca Limited | Quinuclidine derivatives as squalene synthase inhibitors |
US6030966A (en) * | 1994-10-24 | 2000-02-29 | Eli Lilly And Company | Heterocyclic compound and their use |
US6071900A (en) * | 1994-10-24 | 2000-06-06 | Eli Lilly And Company | Heterocyclic compounds and their use |
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US9567343B2 (en) | 2002-09-04 | 2017-02-14 | Novartis Ag | Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists |
US9849117B2 (en) | 2002-09-04 | 2017-12-26 | Novartis Ag | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US8933090B2 (en) | 2004-06-18 | 2015-01-13 | Novartis Ag | 1-aza-bicyclo[3.3.1]nonanes |
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US8609662B2 (en) | 2004-07-14 | 2013-12-17 | Novartis Ag | 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases |
US9657010B2 (en) | 2004-07-14 | 2017-05-23 | Novartis Ag | Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators |
US8173667B2 (en) | 2005-10-21 | 2012-05-08 | Novartis Ag | 1-aza-bicycloalkyl derivatives |
US8637517B2 (en) | 2005-12-16 | 2014-01-28 | Novartis Ag | Organic compounds |
US8759346B2 (en) | 2005-12-16 | 2014-06-24 | Novartis Ag | Organic compounds |
US8048885B2 (en) | 2005-12-16 | 2011-11-01 | Novartis Ag | Organic compounds |
US9206181B2 (en) | 2005-12-16 | 2015-12-08 | Novartis Ag | 1-aza-bicyclo[3.3.1] non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders |
Also Published As
Publication number | Publication date |
---|---|
IE911688A1 (en) | 1991-11-20 |
FI912409A (en) | 1991-11-20 |
NO911934D0 (en) | 1991-05-16 |
AU648789B2 (en) | 1994-05-05 |
PT97703A (en) | 1992-02-28 |
CS144891A3 (en) | 1992-05-13 |
KR910020009A (en) | 1991-12-19 |
NO911934L (en) | 1991-11-20 |
JPH04226981A (en) | 1992-08-17 |
HUT58091A (en) | 1992-01-28 |
HU911663D0 (en) | 1991-11-28 |
IL98176A0 (en) | 1992-06-21 |
CZ281837B6 (en) | 1997-02-12 |
EP0458214A1 (en) | 1991-11-27 |
JP2853837B2 (en) | 1999-02-03 |
YU84791A (en) | 1994-06-10 |
AU7713091A (en) | 1991-11-21 |
FI912409A0 (en) | 1991-05-17 |
SK279168B6 (en) | 1998-07-08 |
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