DE69919361T2 - Pyridyl-ether und -thioether als nikotin-acetylcholin-rezeptorliganden und ihre therapeutische anwendung - Google Patents
Pyridyl-ether und -thioether als nikotin-acetylcholin-rezeptorliganden und ihre therapeutische anwendung Download PDFInfo
- Publication number
- DE69919361T2 DE69919361T2 DE69919361T DE69919361T DE69919361T2 DE 69919361 T2 DE69919361 T2 DE 69919361T2 DE 69919361 T DE69919361 T DE 69919361T DE 69919361 T DE69919361 T DE 69919361T DE 69919361 T2 DE69919361 T2 DE 69919361T2
- Authority
- DE
- Germany
- Prior art keywords
- group
- alkyl
- compound
- butyl
- phenyl
- 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.)
- Expired - Fee Related
Links
- 230000001225 therapeutic effect Effects 0.000 title description 12
- 239000003446 ligand Substances 0.000 title description 4
- JMTMWFZXOIWTLX-UHFFFAOYSA-N 2-pyridin-2-yloxypyridine Chemical compound C=1C=CC=NC=1OC1=CC=CC=N1 JMTMWFZXOIWTLX-UHFFFAOYSA-N 0.000 title description 2
- 150000003568 thioethers Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims abstract description 17
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 208000002193 Pain Diseases 0.000 claims abstract description 6
- 206010012289 Dementia Diseases 0.000 claims abstract description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 4
- 208000000044 Amnesia Diseases 0.000 claims abstract description 4
- 208000026139 Memory disease Diseases 0.000 claims abstract description 4
- 230000006984 memory degeneration Effects 0.000 claims abstract description 4
- 208000023060 memory loss Diseases 0.000 claims abstract description 4
- 230000007659 motor function Effects 0.000 claims abstract description 4
- -1 carbomethoxy, acetoxy Chemical group 0.000 claims description 116
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 150000003254 radicals Chemical class 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 5
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 3
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 2
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 claims description 2
- 235000011437 Amygdalus communis Nutrition 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 claims description 2
- 239000000556 agonist Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 235000020224 almond Nutrition 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 claims 1
- 208000000094 Chronic Pain Diseases 0.000 claims 1
- 241000220304 Prunus dulcis Species 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 208000005298 acute pain Diseases 0.000 claims 1
- 230000036592 analgesia Effects 0.000 claims 1
- 239000005557 antagonist Substances 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims 1
- 230000008506 pathogenesis Effects 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000009739 binding Methods 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 230000027455 binding Effects 0.000 description 11
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 8
- 239000007995 HEPES buffer Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 102000015296 acetylcholine-gated cation-selective channel activity proteins Human genes 0.000 description 6
- 108040006409 acetylcholine-gated cation-selective channel activity proteins Proteins 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000009871 nonspecific binding Effects 0.000 description 5
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 5
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 229940027564 cytisine Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 230000001537 neural effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- FLVFPAIGVBQGET-UHFFFAOYSA-N 1-methylpyrrolidin-3-ol Chemical compound CN1CCC(O)C1 FLVFPAIGVBQGET-UHFFFAOYSA-N 0.000 description 3
- SSZZSICQMXUHQC-ZCFIWIBFSA-N 3-bromo-2-chloro-5-[(3r)-pyrrolidin-3-yl]oxypyridine Chemical compound C1=C(Br)C(Cl)=NC=C1O[C@H]1CNCC1 SSZZSICQMXUHQC-ZCFIWIBFSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 102000009660 Cholinergic Receptors Human genes 0.000 description 3
- 108010009685 Cholinergic Receptors Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- MKTAGSRKQIGEBH-SSDOTTSWSA-N tebanicline Chemical compound C1=NC(Cl)=CC=C1OC[C@@H]1NCC1 MKTAGSRKQIGEBH-SSDOTTSWSA-N 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- VFUDNJMUDPUINO-SECBINFHSA-N tert-butyl (3r)-3-(5-bromo-6-chloropyridin-3-yl)oxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@H]1OC1=CN=C(Cl)C(Br)=C1 VFUDNJMUDPUINO-SECBINFHSA-N 0.000 description 3
- JHHZLHWJQPUNKB-BYPYZUCNSA-N (3s)-pyrrolidin-3-ol Chemical compound O[C@H]1CCNC1 JHHZLHWJQPUNKB-BYPYZUCNSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- MXKYFUQSGMVSEQ-MRVPVSSYSA-N 2-chloro-5-[(3r)-pyrrolidin-3-yl]oxypyridine Chemical compound C1=NC(Cl)=CC=C1O[C@H]1CNCC1 MXKYFUQSGMVSEQ-MRVPVSSYSA-N 0.000 description 2
- NGSIOFODGXAYEH-UHFFFAOYSA-N 3-(1-ethylpyrrolidin-3-yl)oxypyridine Chemical compound C1N(CC)CCC1OC1=CC=CN=C1 NGSIOFODGXAYEH-UHFFFAOYSA-N 0.000 description 2
- QAHVCSGRTAMUOX-UHFFFAOYSA-N 3-(1-propan-2-ylpyrrolidin-3-yl)oxypyridine Chemical compound C1N(C(C)C)CCC1OC1=CC=CN=C1 QAHVCSGRTAMUOX-UHFFFAOYSA-N 0.000 description 2
- QTFWLMMAUAFUMN-UHFFFAOYSA-N 3-(azetidin-3-yloxy)pyridine Chemical compound C1NCC1OC1=CC=CN=C1 QTFWLMMAUAFUMN-UHFFFAOYSA-N 0.000 description 2
- DCWKRPJLVIHGCZ-SECBINFHSA-N 3-[(3r)-pyrrolidin-3-yl]oxypyridine Chemical compound C1NCC[C@H]1OC1=CC=CN=C1 DCWKRPJLVIHGCZ-SECBINFHSA-N 0.000 description 2
- GHJPZQCAVQYABA-JTQLQIEISA-N 3-[(3s)-piperidin-3-yl]oxypyridine Chemical compound C1CCNC[C@H]1OC1=CC=CN=C1 GHJPZQCAVQYABA-JTQLQIEISA-N 0.000 description 2
- DCWKRPJLVIHGCZ-VIFPVBQESA-N 3-[(3s)-pyrrolidin-3-yl]oxypyridine Chemical compound C1NCC[C@@H]1OC1=CC=CN=C1 DCWKRPJLVIHGCZ-VIFPVBQESA-N 0.000 description 2
- GHJPZQCAVQYABA-UHFFFAOYSA-N 3-piperidin-3-yloxypyridine Chemical compound C1CCNCC1OC1=CC=CN=C1 GHJPZQCAVQYABA-UHFFFAOYSA-N 0.000 description 2
- DCWKRPJLVIHGCZ-UHFFFAOYSA-N 3-pyrrolidin-3-yloxypyridine Chemical compound C1NCCC1OC1=CC=CN=C1 DCWKRPJLVIHGCZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 210000002182 synaptic membrane Anatomy 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XRRXRQJQQKMFBC-UHFFFAOYSA-N tert-butyl 3-hydroxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)C1 XRRXRQJQQKMFBC-UHFFFAOYSA-N 0.000 description 2
- UIJXHKXIOCDSEB-UHFFFAOYSA-N tert-butyl 3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(O)C1 UIJXHKXIOCDSEB-UHFFFAOYSA-N 0.000 description 2
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 2
- QESASQYUJWIMBE-UHFFFAOYSA-N tert-butyl 3-pyridin-3-yloxyazetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1OC1=CC=CN=C1 QESASQYUJWIMBE-UHFFFAOYSA-N 0.000 description 2
- DVIUPRYKCFLHPK-UHFFFAOYSA-N tert-butyl 3-pyridin-3-yloxypiperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1OC1=CC=CN=C1 DVIUPRYKCFLHPK-UHFFFAOYSA-N 0.000 description 2
- HZFUHDXSZJTWKB-UHFFFAOYSA-N tert-butyl 3-pyridin-3-yloxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1OC1=CC=CN=C1 HZFUHDXSZJTWKB-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NLPRAJRHRHZCQQ-UTLUCORTSA-N (1r,3s,4s)-3-(6-chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane Chemical compound C1=NC(Cl)=CC=C1[C@H]1[C@@H](N2)CC[C@@H]2C1 NLPRAJRHRHZCQQ-UTLUCORTSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BIWOSRSKDCZIFM-RXMQYKEDSA-N (3r)-piperidin-3-ol Chemical compound O[C@@H]1CCCNC1 BIWOSRSKDCZIFM-RXMQYKEDSA-N 0.000 description 1
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 1
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical class CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 description 1
- IDBNECMSCRAUNU-UHFFFAOYSA-N 1-ethylpyrrolidin-3-ol Chemical compound CCN1CCC(O)C1 IDBNECMSCRAUNU-UHFFFAOYSA-N 0.000 description 1
- MYFPIRLHESHOGR-UHFFFAOYSA-N 1-propan-2-ylpyrrolidin-3-ol Chemical compound CC(C)N1CCC(O)C1 MYFPIRLHESHOGR-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IQCQHGQPQPBWLI-UHFFFAOYSA-N 3-(1-methylpyrrolidin-3-yl)oxypyridine Chemical compound C1N(C)CCC1OC1=CC=CN=C1 IQCQHGQPQPBWLI-UHFFFAOYSA-N 0.000 description 1
- IQCQHGQPQPBWLI-SNVBAGLBSA-N 3-[(3r)-1-methylpyrrolidin-3-yl]oxypyridine Chemical compound C1N(C)CC[C@H]1OC1=CC=CN=C1 IQCQHGQPQPBWLI-SNVBAGLBSA-N 0.000 description 1
- XUROMMQAFZTGAW-UHFFFAOYSA-N 5-bromo-6-chloropyridin-3-ol Chemical compound OC1=CN=C(Cl)C(Br)=C1 XUROMMQAFZTGAW-UHFFFAOYSA-N 0.000 description 1
- KVCOOWROABTXDJ-UHFFFAOYSA-N 6-chloropyridin-3-ol Chemical compound OC1=CC=C(Cl)N=C1 KVCOOWROABTXDJ-UHFFFAOYSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- QEHPFSYDPGOMJI-UHFFFAOYSA-N N#Cc(cc1)ccc1-c(cc(cn1)OC2CNCC2)c1Cl Chemical compound N#Cc(cc1)ccc1-c(cc(cn1)OC2CNCC2)c1Cl QEHPFSYDPGOMJI-UHFFFAOYSA-N 0.000 description 1
- 229940123859 Nicotinic receptor antagonist Drugs 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 0.000 description 1
- QKDLQFSLLCQTOH-UHFFFAOYSA-N Trichodonin Natural products C1C(O)C2C3(COC(=O)C)C(C=O)C(C)(C)CCC3OC(=O)C22C(=O)C(=C)C1C2 QKDLQFSLLCQTOH-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 230000008856 allosteric binding Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960002130 benzoin Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001962 neuropharmacologic effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000000631 nonopiate Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008008 oral excipient Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9785398P | 1998-08-25 | 1998-08-25 | |
| US97853P | 1998-08-25 | ||
| PCT/US1999/018954 WO2000010997A1 (en) | 1998-08-25 | 1999-08-25 | Pyridyl ethers and thioethers as ligands for nicotinic acetylcholine receptor and its therapeutic application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69919361D1 DE69919361D1 (de) | 2004-09-16 |
| DE69919361T2 true DE69919361T2 (de) | 2005-09-08 |
Family
ID=22265449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69919361T Expired - Fee Related DE69919361T2 (de) | 1998-08-25 | 1999-08-25 | Pyridyl-ether und -thioether als nikotin-acetylcholin-rezeptorliganden und ihre therapeutische anwendung |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6562847B1 (https=) |
| EP (1) | EP1107965B1 (https=) |
| JP (1) | JP2002523413A (https=) |
| AT (1) | ATE273298T1 (https=) |
| AU (1) | AU5574799A (https=) |
| CA (1) | CA2341989A1 (https=) |
| DE (1) | DE69919361T2 (https=) |
| DK (1) | DK1107965T3 (https=) |
| ES (1) | ES2226427T3 (https=) |
| PT (1) | PT1107965E (https=) |
| WO (1) | WO2000010997A1 (https=) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024422A1 (en) * | 1997-11-05 | 1999-05-20 | Neurosearch A/S | Azaring-ether derivatives and their use as nicotinic ach receptor modulators |
| MXPA02002115A (es) * | 1999-09-14 | 2002-10-31 | Abbott Lab | Compuestos de eter 3-pirrolidiniloxi-3'-piridilico, utiles para controlar la transmision sinaptica quimica. . |
| JP2001302643A (ja) * | 2000-04-21 | 2001-10-31 | Suntory Ltd | 環状アミジン化合物 |
| US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
| JP2005516927A (ja) * | 2001-12-13 | 2005-06-09 | アボット・ラボラトリーズ | 癌治療用のキナーゼ阻害剤としての３−（フェニル−アルコキシ）−５−（フェニル）−ピリジン誘導体および関連化合物 |
| US20050119251A1 (en) * | 2001-12-21 | 2005-06-02 | Jian-Min Fu | Nicotinamide derivatives and their use as therapeutic agents |
| DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| AR041191A1 (es) * | 2002-08-08 | 2005-05-04 | Amgen Inc | Ligandos del receptor vanilloide y su uso en tratamientos |
| WO2004113297A2 (en) * | 2003-06-24 | 2004-12-29 | Neurosearch A/S | Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
| AU2004257025B9 (en) * | 2003-06-27 | 2010-05-27 | Msd K.K. | Heteroaryloxy nitrogenous saturated heterocyclic derivative |
| EP1670794A2 (en) | 2003-09-30 | 2006-06-21 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| EP1775295A1 (en) * | 2003-09-30 | 2007-04-18 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| MY139645A (en) * | 2004-02-11 | 2009-10-30 | Amgen Inc | Vanilloid receptor ligands and their use in treatments |
| AU2005212438A1 (en) * | 2004-02-11 | 2005-08-25 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| AU2005284908B2 (en) | 2004-09-13 | 2011-12-08 | Morningside Venture Investments Limited | Biosynchronous transdermal drug delivery |
| AU2005286790A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-CoA-desaturase (SCD) |
| BRPI0515500A (pt) * | 2004-09-20 | 2008-07-29 | Xenon Pharmaceuticals Inc | derivados piridazina para inibição de estearoil-coa-desaturase |
| MX2007003332A (es) * | 2004-09-20 | 2007-06-05 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de estearoil-coa-desaturasa. |
| BRPI0515482A (pt) * | 2004-09-20 | 2008-07-22 | Xenon Pharmaceuticals Inc | derivados heterocìclicos e seus usos como agentes terapêuticos |
| US20060183763A1 (en) * | 2004-12-31 | 2006-08-17 | Pfizer Inc | Novel pyrrolidyl derivatives of heteroaromatic compounds |
| US7301022B2 (en) * | 2005-02-15 | 2007-11-27 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| WO2006113769A1 (en) * | 2005-04-15 | 2006-10-26 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| CA2618646A1 (en) * | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
| US7879913B2 (en) * | 2005-06-28 | 2011-02-01 | Catholic Healthcare West | Iptakalim hydrochloride for decreasing nicotine use |
| CN103977003A (zh) | 2007-04-02 | 2014-08-13 | 帕金森氏病研究院 | 用于降低治疗的副作用的方法和组合物 |
| PE20170923A1 (es) | 2010-05-17 | 2017-07-12 | Forum Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin-3-il)benzo[b]tiofeno-2-carboxamida monohidratado |
| WO2013071097A1 (en) | 2011-11-11 | 2013-05-16 | Georgetown University | 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof |
| EP3461481A1 (en) | 2012-05-08 | 2019-04-03 | Forum Pharmaceuticals Inc. | Methods of maintaining, treating or improving cognitive function |
| CA2944179A1 (en) * | 2013-03-27 | 2014-10-02 | Georgetown University | 2-halo-5-alkynyl-pyridyl nicotinic ligands |
| AU2016211330A1 (en) | 2015-01-28 | 2017-08-03 | Chrono Therapeutics Inc. | Drug delivery methods and systems |
| CA3049529A1 (en) | 2017-01-06 | 2018-07-12 | Chrono Therapeutics Inc. | Transdermal drug delivery devices and methods |
| US11596779B2 (en) | 2018-05-29 | 2023-03-07 | Morningside Venture Investments Limited | Drug delivery methods and systems |
| US12397141B2 (en) | 2018-11-16 | 2025-08-26 | Morningside Venture Investments Limited | Thermally regulated transdermal drug delivery system |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3382028D1 (de) * | 1982-09-30 | 1991-01-10 | Robins Co Inc A H | Kondensierte aromatische oxazepinone und sulphuranaloge, ihrer herstellung und verwendung als histamin-antagonist. |
| ZA836994B (en) * | 1982-09-30 | 1984-05-30 | Robins Co Inc A H | Fused aromatic oxazepinones and sulfur analogs thereof |
| US4667031A (en) | 1985-10-15 | 1987-05-19 | Ethyl Corporation | Process for preparing oxazepinones |
| US5629325A (en) * | 1996-06-06 | 1997-05-13 | Abbott Laboratories | 3-pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission |
| WO1999024422A1 (en) | 1997-11-05 | 1999-05-20 | Neurosearch A/S | Azaring-ether derivatives and their use as nicotinic ach receptor modulators |
| MXPA02002115A (es) | 1999-09-14 | 2002-10-31 | Abbott Lab | Compuestos de eter 3-pirrolidiniloxi-3'-piridilico, utiles para controlar la transmision sinaptica quimica. . |
-
1999
- 1999-08-25 AU AU55747/99A patent/AU5574799A/en not_active Abandoned
- 1999-08-25 DE DE69919361T patent/DE69919361T2/de not_active Expired - Fee Related
- 1999-08-25 WO PCT/US1999/018954 patent/WO2000010997A1/en not_active Ceased
- 1999-08-25 DK DK99942347T patent/DK1107965T3/da active
- 1999-08-25 EP EP99942347A patent/EP1107965B1/en not_active Expired - Lifetime
- 1999-08-25 JP JP2000566270A patent/JP2002523413A/ja active Pending
- 1999-08-25 US US09/383,142 patent/US6562847B1/en not_active Expired - Lifetime
- 1999-08-25 AT AT99942347T patent/ATE273298T1/de not_active IP Right Cessation
- 1999-08-25 CA CA002341989A patent/CA2341989A1/en not_active Abandoned
- 1999-08-25 PT PT99942347T patent/PT1107965E/pt unknown
- 1999-08-25 ES ES99942347T patent/ES2226427T3/es not_active Expired - Lifetime
-
2003
- 2003-04-02 US US10/405,250 patent/US6888001B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2226427T3 (es) | 2005-03-16 |
| WO2000010997A1 (en) | 2000-03-02 |
| EP1107965B1 (en) | 2004-08-11 |
| DE69919361D1 (de) | 2004-09-16 |
| US6562847B1 (en) | 2003-05-13 |
| ATE273298T1 (de) | 2004-08-15 |
| PT1107965E (pt) | 2004-10-29 |
| US6888001B2 (en) | 2005-05-03 |
| AU5574799A (en) | 2000-03-14 |
| EP1107965A1 (en) | 2001-06-20 |
| DK1107965T3 (da) | 2004-11-29 |
| JP2002523413A (ja) | 2002-07-30 |
| CA2341989A1 (en) | 2000-03-02 |
| US20030207858A1 (en) | 2003-11-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69919361T2 (de) | Pyridyl-ether und -thioether als nikotin-acetylcholin-rezeptorliganden und ihre therapeutische anwendung | |
| DE60309598T2 (de) | Als histamin-h3-antagonisten geeignete indolderivate | |
| DE60018037T2 (de) | Substituierte 2-aryl-3-(heteroaryl)-imidazo[1,2-alpha]pyrimidine und ihren verwandten arzneimittel und verfahren | |
| DE69628556T2 (de) | Tricyclische verbindungen als inhibitoren von farnesyl protein transferase | |
| DE60222409T2 (de) | Trizyklische verbindungen, nützlich als angiotensin ii agonisten | |
| AT396933B (de) | Tetrahydrocarbazolonderivate | |
| EP2231645B1 (de) | 5-Halogen-substitutierte Oxindol-Derivate und ihre Verwendung zur Herstellung eines Medikaments zur Behandlung von Vasopressin-abhängigen Erkrankungen | |
| EP2231643B1 (de) | Amidomethyl-substitutierte Oxindol-Derivate und ihre Verwendung zur Herstellung eines Medikaments zur Behandlung von Vasopressin-abhängigen Erkrankungen | |
| EP2231644A2 (de) | 5,6-disubstituierte oxindol-derivate und ihre verwendung zur behandlung von vasopressin-abhängigen erkrankungen | |
| DE69819903T2 (de) | Bicyclische verbindungen als liganden der 5-ht1 rezeptoren | |
| DE69533284T2 (de) | Neue cyclische und acyclische amide zur erhöhung der neurotransmitter ausschüttung | |
| EP1866304A2 (de) | Substituierte oxindol-derivate, diese enthaltende arzneimittel und deren verwendung | |
| EP1861392A2 (de) | Substituierte oxindol-derivate, diese enthaltende arzneimittel und deren verwendung | |
| EP1831197A2 (de) | Substituierte oxindol-derivate, diese enthaltende arzneimittel und deren verwendung | |
| EP2066657A1 (de) | Subtituierte oxindol-derivate und deren verwendung als vasopressin-und/oder oxytocin-rezeptor liganden | |
| EP2227463A1 (de) | Substituierte oxindol-derivate und ihre verwendung zur behandlung von vasopressin-abhängigen erkrankungen | |
| DE102005014936A1 (de) | Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung | |
| DE69825608T2 (de) | Benzo[5,6]cycloheptapyridin derivate anwendbar als farnesyl protein transferase inhibitoren | |
| DE69218795T2 (de) | Verbindungen,die neurotransmitter freisetzen,um die lernfähigkeit zu erhöhen | |
| DE69920516T2 (de) | Substituierte oxime und hydrazone als neurokinin antagonisten | |
| WO2009071691A2 (de) | Oxindol-derivate und ihre verwendung als medikament | |
| DE60133014T2 (de) | Substituierte imidazole als duale histamin h1 und h3 agonisten oder antagonisten | |
| DE69827614T2 (de) | Chinoxalindionen | |
| DE4320432A1 (de) | Substituierte Mono- und Bipyridylmethylderivate | |
| DE69817826T2 (de) | Benzo[5,6]cyclohepta[1,2b]pyridine derivate anwendbar als farnesyl protein transferase inhibitoren |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8328 | Change in the person/name/address of the agent |
Representative=s name: BOEHMERT & BOEHMERT, 28209 BREMEN |
|
| 8339 | Ceased/non-payment of the annual fee |