JP2002523413A - ニコチン性アセチルコリン受容体のリガンドとしてのピリジルエーテルおよびチオエーテル、ならびにその治療的用途 - Google Patents
ニコチン性アセチルコリン受容体のリガンドとしてのピリジルエーテルおよびチオエーテル、ならびにその治療的用途Info
- Publication number
- JP2002523413A JP2002523413A JP2000566270A JP2000566270A JP2002523413A JP 2002523413 A JP2002523413 A JP 2002523413A JP 2000566270 A JP2000566270 A JP 2000566270A JP 2000566270 A JP2000566270 A JP 2000566270A JP 2002523413 A JP2002523413 A JP 2002523413A
- Authority
- JP
- Japan
- Prior art keywords
- group
- alkyl
- phenyl
- substituted
- ring
- 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.)
- Pending
Links
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 title claims abstract description 19
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 title claims abstract description 19
- -1 Pyridyl ethers Chemical class 0.000 title claims description 115
- 230000001225 therapeutic effect Effects 0.000 title description 12
- 239000003446 ligand Substances 0.000 title description 4
- 150000003568 thioethers Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 18
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 18
- 208000002193 Pain Diseases 0.000 claims abstract description 8
- 206010012289 Dementia Diseases 0.000 claims abstract description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- 208000000044 Amnesia Diseases 0.000 claims abstract description 5
- 208000026139 Memory disease Diseases 0.000 claims abstract description 5
- 230000006984 memory degeneration Effects 0.000 claims abstract description 5
- 208000023060 memory loss Diseases 0.000 claims abstract description 5
- 230000007659 motor function Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000004432 carbon atom Chemical group C* 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 229910052799 carbon Inorganic materials 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 150000001340 alkali metals Chemical class 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-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
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 4
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-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
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000000129 anionic group Chemical group 0.000 claims description 4
- 239000005557 antagonist Substances 0.000 claims description 4
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 4
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 4
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 4
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 claims description 4
- HKIOYBQGHSTUDB-UHFFFAOYSA-N folpet Chemical group C1=CC=C2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2=C1 HKIOYBQGHSTUDB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 239000004576 sand Substances 0.000 claims description 4
- 125000000213 sulfino group Chemical group [H]OS(*)=O 0.000 claims description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- 125000000565 sulfonamide group Chemical group 0.000 claims description 4
- 125000004354 sulfur functional group Chemical group 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 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 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 claims 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 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 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
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 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
- 229940050411 fumarate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 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
- 229940095064 tartrate Drugs 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 201000010099 disease Diseases 0.000 claims 8
- 229910052738 indium Inorganic materials 0.000 claims 3
- 208000000094 Chronic Pain Diseases 0.000 claims 2
- 230000001154 acute effect Effects 0.000 claims 2
- 208000005298 acute pain Diseases 0.000 claims 2
- 239000000556 agonist Substances 0.000 claims 2
- 230000036592 analgesia Effects 0.000 claims 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-M 1,1-dioxo-1,2-benzothiazol-3-olate Chemical compound C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-M 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 102000034337 acetylcholine receptors Human genes 0.000 claims 1
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- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
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- 238000011282 treatment Methods 0.000 abstract description 4
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- 239000000243 solution Substances 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 19
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- 238000004519 manufacturing process Methods 0.000 description 8
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- 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
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- 238000002360 preparation method Methods 0.000 description 5
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 5
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- 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 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- 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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- 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]
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (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 | |
| US60/097,853 | 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 |
|---|---|
| JP2002523413A true JP2002523413A (ja) | 2002-07-30 |
| JP2002523413A5 JP2002523413A5 (https=) | 2006-10-12 |
Family
ID=22265449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000566270A Pending JP2002523413A (ja) | 1998-08-25 | 1999-08-25 | ニコチン性アセチルコリン受容体のリガンドとしてのピリジルエーテルおよびチオエーテル、ならびにその治療的用途 |
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=) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005007644A1 (ja) * | 2003-06-27 | 2005-01-27 | Banyu Pharmaceutical Co., Ltd | ヘテロアリールオキシ含窒素飽和へテロ環誘導体 |
| JP2007533635A (ja) * | 2003-09-30 | 2007-11-22 | アムジエン・インコーポレーテツド | バニロイド受容体リガンドおよび治療おけるこれらの使用 |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE247104T1 (de) * | 1997-11-05 | 2003-08-15 | Neurosearch As | Azaring-ether-derivate und ihre verwendung als nicotinic-ach-rezeptormodulatoren |
| JP2003529547A (ja) * | 1999-09-14 | 2003-10-07 | アボット・ラボラトリーズ | 化学シナプス伝達のコントロールに有効な３−ピロリジニルオキシ−３’−ピリジルエーテル化合物 |
| JP2001302643A (ja) * | 2000-04-21 | 2001-10-31 | Suntory Ltd | 環状アミジン化合物 |
| 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 |
| US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
| 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 |
| BR0313255A (pt) * | 2002-08-08 | 2005-07-12 | Amgen Inc | Composto, composição farmacêutica, uso de um composto e métodos de fabricar um medicamento e de preparar um composto |
| EP1638939A2 (en) * | 2003-06-24 | 2006-03-29 | Neurosearch A/S | Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
| EP1780211A3 (en) * | 2003-09-30 | 2007-06-06 | 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 |
| JP2007522233A (ja) * | 2004-02-11 | 2007-08-09 | アムジエン・インコーポレーテツド | バニロイド受容体リガンド及び治療におけるそれらの使用 |
| JP5254616B2 (ja) | 2004-09-13 | 2013-08-07 | クロノ セラピューティクス、インコーポレイテッド | 生物学的同調性（ｂｉｏｓｙｎｃｈｒｏｎｏｕｓ）経皮的薬物送達 |
| US7829712B2 (en) * | 2004-09-20 | 2010-11-09 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase |
| AU2005286648A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| JP5080256B2 (ja) * | 2004-09-20 | 2012-11-21 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | 二環式複素環誘導体およびステアロイル−ＣｏＡデサチュラーゼ（ＳＣＤ）のインヒビターとしてのそれらの使用 |
| CA2580857A1 (en) * | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| US20060183763A1 (en) * | 2004-12-31 | 2006-08-17 | Pfizer Inc | Novel pyrrolidyl derivatives of heteroaromatic compounds |
| WO2006089311A1 (en) * | 2005-02-15 | 2006-08-24 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| US20060235036A1 (en) * | 2005-04-15 | 2006-10-19 | Doherty Elizabeth M | Vanilloid receptor ligands and their use in treatments |
| AU2006343359A1 (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 |
| EP2322168A1 (en) | 2007-04-02 | 2011-05-18 | Parkinson's Institute | Methods and Compositions for Reduction of Side Effects of Therapeutic Treatments |
| AR081402A1 (es) | 2010-05-17 | 2012-08-29 | Envivo Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin-3-il) benzo(b)tiofeno-2-carboxamida monohidrato |
| WO2013071097A1 (en) * | 2011-11-11 | 2013-05-16 | Georgetown University | 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof |
| CA2872005A1 (en) | 2012-05-08 | 2013-11-14 | Forum Pharmaceuticals, Inc. | Methods of maintaining, treating or improving cognitive function |
| EP2983666B1 (en) | 2013-03-27 | 2019-10-09 | Georgetown University | 2-halo-5-alkynyl-pyridyl nicotinic ligands |
| JP2018511355A (ja) | 2015-01-28 | 2018-04-26 | クロノ セラピューティクス インコーポレイテッドＣｈｒｏｎｏ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． | 薬剤送達方法及びシステム |
| EP3565617A1 (en) | 2017-01-06 | 2019-11-13 | Chrono Therapeutics Inc. | Transdermal drug delivery devices and methods |
| EP3801732A4 (en) | 2018-05-29 | 2022-04-27 | Morningside Venture Investments Limited | METHODS AND SYSTEMS FOR DRUG DELIVERY |
| US12397141B2 (en) | 2018-11-16 | 2025-08-26 | Morningside Venture Investments Limited | Thermally regulated transdermal drug delivery system |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5993047A (ja) * | 1982-09-30 | 1984-05-29 | エイ・エツチ・ロビンス・カンパニ−・インコ−ポレ−テツド | 融合芳香族オキサゼピノン類およびそれらのイオウ類似体類 |
| US4667031A (en) * | 1985-10-15 | 1987-05-19 | Ethyl Corporation | Process for preparing oxazepinones |
| WO1999024422A1 (en) * | 1997-11-05 | 1999-05-20 | Neurosearch A/S | Azaring-ether derivatives and their use as nicotinic ach receptor modulators |
| JP2002515038A (ja) * | 1996-06-06 | 2002-05-21 | アボツト・ラボラトリーズ | 化学シナプス伝達を制御するのに有用な３―ピリジルオキシメチル複素環式エーテル化合物 |
Family Cites Families (2)
| 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. |
| JP2003529547A (ja) | 1999-09-14 | 2003-10-07 | アボット・ラボラトリーズ | 化学シナプス伝達のコントロールに有効な３−ピロリジニルオキシ−３’−ピリジルエーテル化合物 |
-
1999
- 1999-08-25 WO PCT/US1999/018954 patent/WO2000010997A1/en not_active Ceased
- 1999-08-25 ES ES99942347T patent/ES2226427T3/es not_active Expired - Lifetime
- 1999-08-25 DK DK99942347T patent/DK1107965T3/da active
- 1999-08-25 AT AT99942347T patent/ATE273298T1/de not_active IP Right Cessation
- 1999-08-25 DE DE69919361T patent/DE69919361T2/de not_active Expired - Fee Related
- 1999-08-25 US US09/383,142 patent/US6562847B1/en not_active Expired - Lifetime
- 1999-08-25 CA CA002341989A patent/CA2341989A1/en not_active Abandoned
- 1999-08-25 AU AU55747/99A patent/AU5574799A/en not_active Abandoned
- 1999-08-25 JP JP2000566270A patent/JP2002523413A/ja active Pending
- 1999-08-25 PT PT99942347T patent/PT1107965E/pt unknown
- 1999-08-25 EP EP99942347A patent/EP1107965B1/en not_active Expired - Lifetime
-
2003
- 2003-04-02 US US10/405,250 patent/US6888001B2/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5993047A (ja) * | 1982-09-30 | 1984-05-29 | エイ・エツチ・ロビンス・カンパニ−・インコ−ポレ−テツド | 融合芳香族オキサゼピノン類およびそれらのイオウ類似体類 |
| US4667031A (en) * | 1985-10-15 | 1987-05-19 | Ethyl Corporation | Process for preparing oxazepinones |
| JP2002515038A (ja) * | 1996-06-06 | 2002-05-21 | アボツト・ラボラトリーズ | 化学シナプス伝達を制御するのに有用な３―ピリジルオキシメチル複素環式エーテル化合物 |
| WO1999024422A1 (en) * | 1997-11-05 | 1999-05-20 | Neurosearch A/S | Azaring-ether derivatives and their use as nicotinic ach receptor modulators |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005007644A1 (ja) * | 2003-06-27 | 2005-01-27 | Banyu Pharmaceutical Co., Ltd | ヘテロアリールオキシ含窒素飽和へテロ環誘導体 |
| JPWO2005007644A1 (ja) * | 2003-06-27 | 2006-08-31 | 萬有製薬株式会社 | ヘテロアリールオキシ含窒素飽和ヘテロ環誘導体 |
| JP4735261B2 (ja) * | 2003-06-27 | 2011-07-27 | Ｍｓｄ株式会社 | ヘテロアリールオキシ含窒素飽和ヘテロ環誘導体 |
| JP2007533635A (ja) * | 2003-09-30 | 2007-11-22 | アムジエン・インコーポレーテツド | バニロイド受容体リガンドおよび治療おけるこれらの使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2226427T3 (es) | 2005-03-16 |
| DE69919361T2 (de) | 2005-09-08 |
| WO2000010997A1 (en) | 2000-03-02 |
| US6562847B1 (en) | 2003-05-13 |
| CA2341989A1 (en) | 2000-03-02 |
| EP1107965B1 (en) | 2004-08-11 |
| DK1107965T3 (da) | 2004-11-29 |
| EP1107965A1 (en) | 2001-06-20 |
| AU5574799A (en) | 2000-03-14 |
| PT1107965E (pt) | 2004-10-29 |
| US6888001B2 (en) | 2005-05-03 |
| DE69919361D1 (de) | 2004-09-16 |
| US20030207858A1 (en) | 2003-11-06 |
| ATE273298T1 (de) | 2004-08-15 |
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