JP4348422B2 - アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 - Google Patents
アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 Download PDFInfo
- Publication number
- JP4348422B2 JP4348422B2 JP2004533455A JP2004533455A JP4348422B2 JP 4348422 B2 JP4348422 B2 JP 4348422B2 JP 2004533455 A JP2004533455 A JP 2004533455A JP 2004533455 A JP2004533455 A JP 2004533455A JP 4348422 B2 JP4348422 B2 JP 4348422B2
- Authority
- JP
- Japan
- Prior art keywords
- aza
- yloxy
- octane
- bicyclo
- pyridin
- 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 - Lifetime
Links
- 239000000556 agonist Substances 0.000 title abstract description 6
- 150000002170 ethers Chemical class 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical group 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 239000012458 free base Substances 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- -1 cyano, methylenedioxy Chemical group 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
- NPDLTEZXGWRMLQ-IBGZPJMESA-N (3r)-3-[6-(4-methylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound C1=CC(C)=CC=C1C(N=C1)=CC=C1O[C@@H]1C(CC2)CCN2C1 NPDLTEZXGWRMLQ-IBGZPJMESA-N 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 2
- UOXAHMAZBMSBFV-SFHVURJKSA-N (3r)-3-(6-phenylpyridin-3-yl)oxy-1-azabicyclo[2.2.2]octane Chemical compound O([C@@H]1C2CCN(C1)CC2)C(C=N1)=CC=C1C1=CC=CC=C1 UOXAHMAZBMSBFV-SFHVURJKSA-N 0.000 claims 3
- PLYXOZYCJHNCBB-FQEVSTJZSA-N (3r)-3-[6-(3,4-dimethylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound C1=C(C)C(C)=CC=C1C(N=C1)=CC=C1O[C@@H]1C(CC2)CCN2C1 PLYXOZYCJHNCBB-FQEVSTJZSA-N 0.000 claims 3
- LGEUYNJFMHYSQP-FQEVSTJZSA-N (3r)-3-[6-(4-ethylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound C1=CC(CC)=CC=C1C(N=C1)=CC=C1O[C@@H]1C(CC2)CCN2C1 LGEUYNJFMHYSQP-FQEVSTJZSA-N 0.000 claims 3
- GQYDUHGUESRXHN-KRWDZBQOSA-N (3r)-3-(5-phenylpyridin-2-yl)oxy-1-azabicyclo[2.2.2]octane Chemical compound O([C@@H]1C2CCN(C1)CC2)C(N=C1)=CC=C1C1=CC=CC=C1 GQYDUHGUESRXHN-KRWDZBQOSA-N 0.000 claims 1
- BLTQDRSIHMDRPW-FQEVSTJZSA-N (3r)-3-[6-(2,3-dimethylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound CC1=CC=CC(C=2N=CC(O[C@@H]3C4CCN(CC4)C3)=CC=2)=C1C BLTQDRSIHMDRPW-FQEVSTJZSA-N 0.000 claims 1
- WSCIJSCYGIMIAZ-IBGZPJMESA-N (3r)-3-[6-(2-chloro-4-methylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound ClC1=CC(C)=CC=C1C(N=C1)=CC=C1O[C@@H]1C(CC2)CCN2C1 WSCIJSCYGIMIAZ-IBGZPJMESA-N 0.000 claims 1
- PXWMKYPBANXDTE-SFHVURJKSA-N (3r)-3-[6-(2-chlorophenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound ClC1=CC=CC=C1C(N=C1)=CC=C1O[C@@H]1C(CC2)CCN2C1 PXWMKYPBANXDTE-SFHVURJKSA-N 0.000 claims 1
- NHGFYZRLKYOZQH-IBGZPJMESA-N (3r)-3-[6-(2-methylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound CC1=CC=CC=C1C(N=C1)=CC=C1O[C@@H]1C(CC2)CCN2C1 NHGFYZRLKYOZQH-IBGZPJMESA-N 0.000 claims 1
- ONAYMGNZDQFCPD-IBGZPJMESA-N (3r)-3-[6-(3-methylphenyl)pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound CC1=CC=CC(C=2N=CC(O[C@@H]3C4CCN(CC4)C3)=CC=2)=C1 ONAYMGNZDQFCPD-IBGZPJMESA-N 0.000 claims 1
- KBHFNIASBJVKAQ-SFHVURJKSA-N (3r)-3-[6-[3-(trifluoromethyl)phenyl]pyridin-3-yl]oxy-1-azabicyclo[2.2.2]octane Chemical compound FC(F)(F)C1=CC=CC(C=2N=CC(O[C@@H]3C4CCN(CC4)C3)=CC=2)=C1 KBHFNIASBJVKAQ-SFHVURJKSA-N 0.000 claims 1
- GQYDUHGUESRXHN-UHFFFAOYSA-N 3-(5-phenylpyridin-2-yl)oxy-1-azabicyclo[2.2.2]octane Chemical compound C1CN(C2)CCC1C2OC(N=C1)=CC=C1C1=CC=CC=C1 GQYDUHGUESRXHN-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 39
- 238000000034 method Methods 0.000 abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 6
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 abstract description 2
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 abstract description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 abstract 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- 239000000203 mixture Substances 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 5
- 125000001624 naphthyl group Chemical group 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002825 functional assay Methods 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000003098 Ganglion Cysts Diseases 0.000 description 3
- 102100030643 Hydroxycarboxylic acid receptor 2 Human genes 0.000 description 3
- 101710125793 Hydroxycarboxylic acid receptor 2 Proteins 0.000 description 3
- 208000005400 Synovial Cyst Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IVLICPVPXWEGCA-ZETCQYMHSA-N (3r)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@@H](O)CN1CC2 IVLICPVPXWEGCA-ZETCQYMHSA-N 0.000 description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 2
- BZUUVQCSPHPUQA-UHFFFAOYSA-N 2-bromo-5-chloropyridine Chemical compound ClC1=CC=C(Br)N=C1 BZUUVQCSPHPUQA-UHFFFAOYSA-N 0.000 description 2
- JJNIWMPNOFGQEA-UHFFFAOYSA-N 2-chloro-5-phenylpyrimidine Chemical compound C1=NC(Cl)=NC=C1C1=CC=CC=C1 JJNIWMPNOFGQEA-UHFFFAOYSA-N 0.000 description 2
- IVLICPVPXWEGCA-UHFFFAOYSA-N 3-quinuclidinol Chemical compound C1C[C@@H]2C(O)C[N@]1CC2 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 2
- WJKQDBJZUXOSBB-UHFFFAOYSA-N 5-chloro-2-(4-methylphenyl)pyridine Chemical compound C1=CC(C)=CC=C1C1=CC=C(Cl)C=N1 WJKQDBJZUXOSBB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 102000015296 acetylcholine-gated cation-selective channel activity proteins Human genes 0.000 description 2
- 108040006409 acetylcholine-gated cation-selective channel activity proteins Proteins 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 239000003643 water by type Substances 0.000 description 2
- LIXXGOMAGHXIMP-UHFFFAOYSA-N (2-fluoro-4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C(F)=C1 LIXXGOMAGHXIMP-UHFFFAOYSA-N 0.000 description 1
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 1
- 0 **ON1C(CC2)C*N2C1 Chemical compound **ON1C(CC2)C*N2C1 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- BOOUVSNRSCUOIL-UHFFFAOYSA-N 3-(5-phenylpyrimidin-2-yl)oxy-1-azabicyclo[2.2.2]octane Chemical compound C1CN(C2)CCC1C2OC(N=C1)=NC=C1C1=CC=CC=C1 BOOUVSNRSCUOIL-UHFFFAOYSA-N 0.000 description 1
- WZEKOPJYIHWNCT-UHFFFAOYSA-N 3-chloro-6-(2-fluoro-4-methylphenyl)pyridazine Chemical compound FC1=CC(C)=CC=C1C1=CC=C(Cl)N=N1 WZEKOPJYIHWNCT-UHFFFAOYSA-N 0.000 description 1
- LYFFDJDAWPESSH-UHFFFAOYSA-N 3-chloro-6-(4-fluorophenyl)pyridazine Chemical compound C1=CC(F)=CC=C1C1=CC=C(Cl)N=N1 LYFFDJDAWPESSH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- METGWBDPLLMREH-NTISSMGPSA-N 5-bromo-2-chloropyrimidine (3R)-3-(5-phenylpyrimidin-2-yl)oxy-1-azabicyclo[2.2.2]octane Chemical compound BrC=1C=NC(=NC1)Cl.C1(=CC=CC=C1)C=1C=NC(=NC1)O[C@H]1CN2CCC1CC2 METGWBDPLLMREH-NTISSMGPSA-N 0.000 description 1
- 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 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- RQSPQZWRGJYWNE-UHFFFAOYSA-N B(OC(C)C)(OC(C)C)OC(C)C.FC1=C(C=CC(=C1)C)B(O)O Chemical compound B(OC(C)C)(OC(C)C)OC(C)C.FC1=C(C=CC(=C1)C)B(O)O RQSPQZWRGJYWNE-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- TVQUTOOAHUKLKB-UHFFFAOYSA-N ClC=1N=NC(=CC1)Cl.ClC=1N=NC(=CC1)C1=C(C=C(C=C1)C)F Chemical compound ClC=1N=NC(=CC1)Cl.ClC=1N=NC(=CC1)C1=C(C=C(C=C1)C)F TVQUTOOAHUKLKB-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 208000026097 Factitious disease Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- DMMHIXYXGIUDKX-KNAFFEALSA-N N12C[C@@H](C(CC1)CC2)O.FC2=C(C=CC(=C2)C)C2=CC=C(N=N2)O[C@H]2CN1CCC2CC1 Chemical compound N12C[C@@H](C(CC1)CC2)O.FC2=C(C=CC(=C2)C)C2=CC=C(N=N2)O[C@H]2CN1CCC2CC1 DMMHIXYXGIUDKX-KNAFFEALSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010052276 Pseudodementia Diseases 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- KAQWKMQZEYHCPZ-FYZYNONXSA-N [Br].C1(=CC=C(C=C1)C1=CC=C(C=N1)O[C@H]1CN2CCC1CC2)C Chemical compound [Br].C1(=CC=C(C=C1)C1=CC=C(C=N1)O[C@H]1CN2CCC1CC2)C KAQWKMQZEYHCPZ-FYZYNONXSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 201000003723 learning disability Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007074 memory dysfunction Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- PQSOLLURQXDZSZ-UHFFFAOYSA-N n,n-diethylethanamine;ethyl acetate;methanol Chemical compound OC.CCOC(C)=O.CCN(CC)CC PQSOLLURQXDZSZ-UHFFFAOYSA-N 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- DBSMLQTUDJVICQ-CJODITQLSA-N onametostat Chemical compound NC1=C2C=CN([C@@H]3C[C@H](CCC4=CC=C5C=C(Br)C(N)=NC5=C4)[C@@H](O)[C@H]3O)C2=NC=N1 DBSMLQTUDJVICQ-CJODITQLSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant 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
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000009151 sensory gating Effects 0.000 description 1
- 230000009155 sensory pathway Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Tropical Medicine & Parasitology (AREA)
- Psychology (AREA)
- Physical Education & Sports Medicine (AREA)
- Virology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Addiction (AREA)
- Vascular Medicine (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- AIDS & HIV (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
XはCH2または結合であり;
Yは式:
Rは置換もしくは非置換のC5〜C10アリールまたは置換もしくは非置換のヘテロ−C5〜C10アリール、N(R1)(R4)またはN(R2)(CHR3R4)であり;ここにR1、R2およびR3の各々は独立にH、C1〜C4アルキルまたはCF3であり;
R4は置換もしくは非置換のC5〜C10アリールまたは置換もしくは非置換のヘテロ−C5〜C10アリールである]
で示される化合物を遊離塩基または酸付加塩の形で提供する。
(a)XがCH2であり;
(b)Yが式:
(c)Yが式:
(d)Rが1−イソベンゾフラニルまたは非置換または、たとえば2、3または4位に塩素またはフッ素、2または3位にCF3、2位にメトキシ;3位にトリフルオロメトキシ;ベンゾ[1.3]−ジオキソール;2,3−ジヒドロベンゾ[1.4]ジオキシン;シアノ;でモノ置換され;またはたとえば2位および5位、3位および5位にフッ素;または2位に塩素および6位にフッ素でジ置換された置換フェニルである。
XはCH2または一重結合であり;
Yは式:
Rはフェニル、ナフチル、テトラヒドロナフチル、インダニル、チエニル、ベンゾチエニル、フラニル、ベンゾフラニルおよびイソベンゾフラニルであるが、いずれの場合も非置換であるか、次の各基でモノ−、ジ−もしくはトリ置換されていることができる:
ハロゲン、シアノ、ホルミル、アセチル、C1〜C3アルコキシカルボニル、N,N−ジ(C1〜C3アルキル)カルバモイル、フェニル、フェノキシ、メチレンジオキシ、エチレンジオキシ;または
C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニルまたはC1〜C4アルコキシ、但し、この残基自体も非置換であるかまたはハロゲンでモノ−、ジ−もしくはトリ置換されていることができる。
XはCH2または一重結合であり;
Yは式:
Rが
(a)非置換のフェニルであるかまたは
ハロゲン、シアノ、メチレンジオキシ、
非置換であるかまたはハロゲンでモノ−、ジ−もしくはトリ置換されたC1〜C4アルキル、または
非置換であるかまたはハロゲンでモノ−、ジ−もしくはトリ置換されたC1〜C4アルコキシ、
でモノ−、ジ−もしくはトリ置換されたフェニルであるか;
(b)ナフチル、インダニル、テトラリニルであるか;または
(c)フラニル、ベンゾフラニル、イソベンゾフラニル、ベンゾチエニルまたはチエニルであり;
化合物の遊離塩基または酸付加塩形である。
XがCH2または一重結合であり;
Yが式:
Rが
(a)非置換フェニルまたはハロゲン、シアノ、メチレンジオキシ、
非置換またはハロゲンでモノ−、ジ−もしくはトリ置換されたC1〜C4アルキル、または
非置換またはハロゲンでモノ−、ジ−もしくはトリ置換されたC1〜C4アルコキシ、
でモノ−、ジ−もしくはトリ置換されたフェニルであるか;
(b)ナフチルであるか;または
(c)フラニル、ベンゾフラニル、イソベンゾフラニルまたはチエニルであり;
化合物の遊離塩基または酸付加塩形である。
で示される化合物と式III:
で示される化合物とを反応させる工程、および得られる遊離塩基または酸付加塩形にある式Iで示される化合物を回収する工程を含む。
XおよびRは前記と同意義であり、および
Y’は
で示される化合物は
式IV:
で示される化合物と式V:
で示される化合物とを反応させ、生成する式I’で示される化合物の遊離塩基または酸付加塩形を回収する工程を含む製法によって製造できる。
Y’は
で示される化合物とを反応させて製造できる。
式Vで示される化合物(たとえば非置換のまたは置換されたフェニルボロン酸)は公知であるかまたは対応する公知化合物から製造できる。たとえば、式VI:
で示される化合物とボロン酸トリアルキルとをベンゼン、トルエン、テトラヒドロフランまたはその混液のような不活性溶媒中、ブチルリチウムを添加して、約−78℃〜−25℃、たとえば約−40℃の温度で、約1〜6時間にわたって反応させて式Vで示される化合物を得る。
AcOEt=酢酸エチル
aq.=水性
DEAD=アゾジカルボン酸ジエチルエステル
DMF=ジメチルホルムアミド
EtOH=エタノール
FC=フラッシュクロマトグラフィー
h=時間
HV=高真空
MeOH=メタノール
RP−HPLC=逆相高速液体クロマトグラフィー
rt=室温
rac.=ラセミ体
soln.=溶液
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
(rac.)−3−[6−(4−フルオロフェニル)ピリダジン−3−イルオキシ]−1−アザビシクロ[2,2,2]オクタンの製造
(rac.)−3−キヌクリジノール(0.007モル)のTHF乾燥溶液を窒素気流下に水素化ナトリウム(鉱油中60%、1.1当量)で処理する。室温で1時間後、3−クロロ−6−(4−フルオロフェニル)ピリダジン(1.0当量)のTHF(30mL)溶液を加え、反応混合物を6時間加熱還流する。室温に冷却後、THFを蒸発し、残渣を酢酸エチル(100mL)に溶解し、水(3×20mL)、続いて塩化ナトリウム溶液(20mL)で洗浄する。酢酸エチル層を無水硫酸マグネシウムで乾燥し、濾過し、蒸発乾固し、残留する油をシリカゲルカラムクロマトグラフィー(溶離液:酢酸エチル−メタノール−トリエチルアミン(50:10:2))で精製して(rac.)−3−[6−(4−フルオロフェニル)ピリダジン−3−イルオキシ]−1−アザビシクロ[2,2,2]オクタンを無色固体として得る。
1H-NMR (400MHz, CDCl3):δ= 8.00 (m, 2H), 7.75 (d, 1H), 7.17 (m, 2H), 7.1 (d, 1H), 5.35 (m, 1H), 3.5 (m, 1H), 2.99-2.83 (m, 5H), 2.32 (m, 1H), 1.98 (m, 1H), 1.76-1.68 (m, 2H), 1.46 (m, 1H)。
(rac.)−3−(5−フェニルピリミジン−2−イルオキシ)−1−アザビシクロ[2.2.2]オクタンの製造
5−ブロモ−2−ヒドロキシピリミジン(400mg、2.29ミリモル)、(rac.)−3−キヌクリジノール(432mg、3.36ミリモル)およびトリフェニルホスフィン(890mg、3.40ミリモル)をTHF(25mL)に溶解する。−10℃で10分間攪拌後、DEAD(522μL、3.36ミリモル)のTHF(20mL)溶液を滴下する。反応混合物室温まで温め、室温で16時間攪拌する。反応混合物を蒸発して橙色半固体(2.50g)を得、これをAcOEtとかき混ぜ、濾過して(rac.)−3−(5−ブロモピリミジン−2−イルオキシ)−1−アザビシクロ[2.2.2]オクタンを白色固体として得る。濾液をFC(シリカゲル、溶離液:AcOEt/MeOH9:1、次にAcOEt/MeOH/NEt3=70:27:3)で精製する。(rac.)−3−(5−ブロモピリミジン−2−イルオキシ)−1−アザビシクロ[2.2.2]オクタン(150mg、0.53ミリモル)、フェニルボロン酸(66mg、0.54ミリモル)とテトラキス(トリフェニルホスフィン)パラジウムとをトルエン:EtOH=9:1(15mL)に溶解する。Na2CO3(225mg、2.12ミリモル)を水(1.5mL)に溶解して反応混合物に加え、混合物を90℃に20時間加熱する。室温に冷却後、セライトで濾過し、トルエン層を分離して食塩水で洗浄する。水層はAcOEtで再抽出し、有機抽出物を集めてMgSO4で乾燥し、濾過する。濾液を蒸発して明黄色ゴム状物(195mg)とし、これをFC(シリカゲル、溶離液、AcOEt/MeOH=9:1、次にAcOEt/MeOH/NEt3=70:27:3)で精製して、未だに出発物質を含有する白色固体を得る。第二の精製はRP−HPLC(Phenomenex RP 18カラム、勾配0.08%HCOOH水/CH3CN95:5→CH3CN、20’)によって行い、(rac)−3−(5−フェニルピリミジン−2−イルオキシ)−1−アザビシクロ[2.2.2]オクタンをギ酸塩として得る。
HPLC rt (分): 5.4。mp ℃:108〜114。 M+H+: 282.2。
(R)−3−(5−フェニルピリミジン−2−イルオキシ)−1−アザビシクロ[2.2.2]オクタンの製造
5−ブロモ−2−クロロピリミジン(400mg、2.03ミリモル)、フェニルボロン酸(253mg、2.07ミリモル)およびテトラキス(トリフェニルホスフィン)パラジウム(118mg、0.102ミリモル)をトルエン/EtOH=9:1(50mL)に溶解する。Na2CO3(861mg、8.12ミリモル)を水(4mL)に溶解し、反応混合物に加える。混合物を90℃で19時間攪拌し、室温まで冷却し、セライトで濾過する。トルエン層を分離し、食塩水で洗浄する。水層をAcOEtで再抽出し、有機抽出物を集め、MgSO4で乾燥し、濾過する。濾液を蒸発して黄色固体(503mg)を得、これをFC(シリカゲル、溶離液:シクロヘキサン−AcOEt/シクロヘキサン=1:9)で精製して2−クロロ−5−フェニルピリミジンを得る。(R)−3−キヌクリジノール(478mg、3.76ミリモル)をNaH(164mg、60%鉱油分散液、4.09ミリモル)のDMF(10mL)懸濁液に加える。混合物を室温で1時間攪拌する。2−クロロ−5−フェニルピリミジン(177mg、0.93ミリモル)を加え、混合物を3.5時間90℃に加熱する。反応混合物をトルエンで希釈し、1M−NaOH水溶液および食塩水で洗浄する。水層はトルエン(3×)で再抽出する。有機抽出物を集め、MgSO4で乾燥し、濾過する。濾液を蒸発して黄色固体(310mg)を得、これをFC(シリカゲル、溶離液:AcOEt次にAcOEt/MeOH/NEt3=80:18:2)で精製する。第二の精製はRP−HPLC(Phenomenex RP18 カラム, 勾配0.08%ギ酸水→0.08%HCOOH水/CH3CN=80:20、10'→CH3CN、15')で行い、(R)−3−(5−フェニルピリミジン−2−イルオキシ)−1−アザビシクロ[2.2.2]オクタンをそのギ酸塩として得る。
HPLC rt (分): 5.4。mp ℃: 108-110。 [α]D rt +8.6 (1.03, MeOH)。 M+H+: 282.2。
(R)−3−(6−p−トルイルピリジン−3−イルオキシ)−1−アザビシクロ[2.2.2]オクタンの製造
臭素(18.0mL、353.7ミリモル)を2−アミノ−5−クロロピリジン(15.0g、116.7ミリモル)の47%HBr水(75.0mL)溶液に−10℃で徐々に加える。これにNaNO2(28.1g、407.3ミリモル)の水溶液を徐々に加える。混合物を−10〜−5℃で1時間、次に5℃で1時間攪拌する。温度を25℃以下に維持しながら混合物を5M−NaOH水溶液で中和する。沈殿を濾取、ペンタンから再結晶して2−ブロモ−5−クロロピリジンを得る。2−ブロモ−5−クロロピリジン(5.0g、26.0ミリモル)、p−トルイルボロン酸(4.0g、29.4ミリモル)およびテトラキス(トリフェニルホスフィン)パラジウム(1.44g、1.2ミリモル)をトルエン:EtOH=9:1(1375mL)に溶解する。2M−Na2CO3水溶液(62.5mL)を反応混合物に加える。混合物を90℃で24時間攪拌し、室温まで冷却し、セライトで濾過する。トルエン層を分離し、食塩水で洗浄する。水層をAcOEtで抽出する。有機抽出物を集め、MgSO4で乾燥して濾過する。濾液を蒸発して褐色の固体を得、これをFC(シリカゲル、溶離液:トルエン)で精製して5−クロロ−2−p−トルイルピリジンを得る。(R)−3−キヌクリジノール(2.97g、23.4ミリモル)をNaH(0.96g、鉱油中60%分散液、22.8ミリモル)のDMF(90mL)懸濁液に加える。混合物を室温で1時間攪拌する。5−クロロ−2−p−トルイルピリジン(4.00g、19.6ミリモル)を混合物に加え、135℃に135時間加熱する。反応混合物をトルエンで希釈し、1M−NaOH水と食塩水で洗浄する。水層をトルエンで再抽出(3×)する。有機抽出物を集め、MgSO4で乾燥し、濾過する。濾液を蒸発して褐色油状物を得、これをFC(シリカゲル、溶離液AcOEt、次にAcOEt/MeOH/NEt3=87:10:3)で精製し、CH3CNから再結晶して(R)−3−(6−p−トルイルピリジン−3−イルオキシ)−1−アザビシクロ[2.2.2]オクタンを得る。
mp ℃: 110-112。[α]D rt = +21.2°(0.50, MeOH)。 M+H+: 295.2。
実施例1〜21、27〜29、32、33、35〜38、41〜46、48〜53用:
カラム:Phenomenex LunaまたはKingsorb C18, 30×4.6mm, 3μM。勾配:(A=H2O+0.08%HCOOH。B=CH3CN。):0〜5分/A:B=100:0〜80:20。5〜10分/A:B=80:20〜0:100。流速3.0mL/分。
実施例22〜26用:
カラム:Waters Xterra MS C18, 50×2.1mm, 2.5μM。勾配:(A=H2O+0.02%TFA。B=CH3CN+0.02%TFA。):0〜2分/A:B=90:10〜5:95。2〜4分/A:B=5:95。4〜5.5分/A:B=5:95〜10:90。5.5〜6分/A:B=10:90〜90:10。6〜7分/A:B=90:10。流速0.35mL/分。
カラム:Waters Xterra MS C18, 150×2.1 mm, 3.5μM。
勾配:(A=H2O+0.02%TFA。B=CH3CN+0.02%TFA。):0〜3分/A:B=90:10〜10:90。3〜8分/A:B=10:90。8〜9分/A:B=10:90〜90:10。9〜15分/A:B=90:10。流速0.35mL/分。
R−3−(6−(2−フルオロ−4−メチルフェニル)ピリダジン−3−イルオキシ)−1−アザビシクロ[2.2.2]オクタンの製造
(R)−(−)−3−キヌクリジノール(0.742g、5.84ミリモル)の乾燥DMF(5mL)溶液を水素化ナトリウム(60%鉱油分散液、0.234g、5.84ミリモル)のDMF(5mL)懸濁液に徐々に加え、50℃で2時間攪拌する。反応混合物を室温まで冷却し、3−クロロ−6−(2−フルオロ−4−メチルフェニル)ピリダジン(1.05g、4.49ミリモル)のDMF(10mL)溶液を加える。得られる反応混合物を24時間攪拌し、H2Oを加えて反応を停止させ、高真空で蒸発させて橙色残渣を得る。この残渣にH2O(100mL)を加え、EtOAc(3×50mL)で抽出する。有機抽出物を集め、H2O(100mL)で洗い、MgSO4(無水)で乾燥し、減圧濃縮して黄色固体を得、これをクロマトグラフィーで精製して標記生成物を得る。
HPLC rt (分):4.7。mp ℃:128〜130。[α]D rt=+37°(0.1%、MeOH)。
トルエン(160mL)とTHF(40mL)との混合物にホウ酸トリイソプロピル(13.56mL、58.42ミリモル)と3−フルオロ−4−ブロモトルエン(10.0g、48.69ミリモル)とを加える。この混合物を−40℃に冷却し、n−ブチルリチウム(2.5M−ヘキサン中)(23.4mL、58.42ミリモル)を1時間にわたって徐々に加え、温度を−40℃に保ちながら混合物をさらに1時間攪拌する。アセトン/ドライアイス浴を去り、反応混合物を−20℃まで温めた後、2.5M−HCl溶液(20mL)を加える。混合物が室温に達した時、水層をEtOAc(3×50mL)で抽出し、有機抽出物を集めMgSO4(無水)で乾燥し、減圧濃縮して黄色固体を得、これをアセトニトリルから再結晶して標記生成物を得る。
3,6−ジクロロピリダジン(2.0g、13.42ミリモル)の1,4−ジオキサン(20mL)溶液にPD2(dba)3(0.21g、0.2ミリモル)、P(tBu)3(0.122g、0.6ミリモル)の1,4−ジオキサン(1mL)溶液、KF(2.57g、44.3ミリモル)および2−フルオロ−4−メチルベンゼンボロン酸(工程31.1、2.68g、17.45ミリモル)を加える。得られる混合物を120℃に48時間加熱する。反応混合物をセライトで濾過し、濾床をEtOAcで洗浄する。濾液をH2Oで洗い、MgSO4(無水)で乾燥し、減圧濃縮して褐色固体を得、これをクロマトグラフィーで精製して標記生成物を得る。
ソフトカプセル
活性成分として前記実施例に記載の式Iで示される化合物0.05gを含むソフトゼラチンカプセル5000個を次のようにして製造する:
組成物
活性成分 250g
ラウログリコール 2リットル
製造法:粉砕した活性成分をラウログリコール(登録商標)(プロピレングリコール・ラウレート、Gattefosse S.A., Saint Priest, France)に懸濁し、湿式粉砕機で摩砕して粒径を約1〜3μmとする。この混合物0.419gを各ソフトゼラチンカプセルにカプセル充填機で注入する。
Claims (9)
- (R)−3−(6−p−トルイル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(ラセミ体)−3−(5−フェニル−ピリジン−2−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(5−フェニル−ピリジン−2−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−フェニル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(3−トリフルオロメチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(2−クロロ−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−o−トルイル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−m−トルイル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(2,3−ジメチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(4−エチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(3,4−ジメチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(2−クロロ−4−メチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、および
(R)−3−(6−(2−クロロ−5−メチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン
から選択される、遊離塩基または酸付加塩形態の請求項1に記載の式Iのアザ−ビシクロアルキル誘導体。 - (R)−3−(6−p−トルイル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−フェニル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、
(R)−3−(6−(4−エチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン、および
(R)−3−(6−(3,4−ジメチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタン
から選択される、遊離塩基または酸付加塩形態の請求項1に記載の式Iのアザ−ビシクロアルキル誘導体。 - (R)−3−(6−p−トルイル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタンである、遊離塩基または酸付加塩形態の請求項1に記載の式Iのアザ−ビシクロアルキル誘導体。
- (R)−3−(6−フェニル−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタンである、遊離塩基または酸付加塩形態の請求項1に記載の式Iのアザ−ビシクロアルキル誘導体。
- (R)−3−(6−(4−エチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタンである、遊離塩基または酸付加塩形態の請求項1に記載の式Iのアザ−ビシクロアルキル誘導体。
- (R)−3−(6−(3,4−ジメチル−フェニル)−ピリジン−3−イルオキシ)−1−アザ−ビシクロ[2.2.2]オクタンである、遊離塩基または酸付加塩形態の請求項1に記載の式Iのアザ−ビシクロアルキル誘導体。
- 医薬として使用するための、遊離塩基または薬学的に許容される酸付加塩形態の請求項1から7のいずれかに記載のアザ−ビシクロアルキル誘導体。
- 精神疾患または神経変性疾患の予防または処置において使用するための、遊離塩基または薬学的に許容される酸付加塩形態の請求項1から7のいずれかに記載のアザ−ビシクロアルキル誘導体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0220581A GB0220581D0 (en) | 2002-09-04 | 2002-09-04 | Organic Compound |
PCT/EP2003/009772 WO2004022556A1 (en) | 2002-09-04 | 2003-09-03 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonist |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009036918A Division JP5124714B2 (ja) | 2002-09-04 | 2009-02-19 | アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2005539057A JP2005539057A (ja) | 2005-12-22 |
JP4348422B2 true JP4348422B2 (ja) | 2009-10-21 |
Family
ID=9943515
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2004533455A Expired - Lifetime JP4348422B2 (ja) | 2002-09-04 | 2003-09-03 | アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 |
JP2009036918A Expired - Fee Related JP5124714B2 (ja) | 2002-09-04 | 2009-02-19 | アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009036918A Expired - Fee Related JP5124714B2 (ja) | 2002-09-04 | 2009-02-19 | アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 |
Country Status (26)
Country | Link |
---|---|
US (8) | US20060167002A1 (ja) |
EP (3) | EP1537104B1 (ja) |
JP (2) | JP4348422B2 (ja) |
KR (2) | KR20070058027A (ja) |
CN (1) | CN1325493C (ja) |
AT (1) | ATE448225T1 (ja) |
AU (1) | AU2003260486C1 (ja) |
BR (2) | BR122014026685B1 (ja) |
CA (1) | CA2495685C (ja) |
CY (1) | CY1109765T1 (ja) |
DE (1) | DE60330015D1 (ja) |
DK (1) | DK1537104T3 (ja) |
EC (1) | ECSP055621A (ja) |
ES (1) | ES2336099T3 (ja) |
GB (1) | GB0220581D0 (ja) |
HK (2) | HK1077822A1 (ja) |
IL (2) | IL166918A (ja) |
MX (1) | MXPA05002546A (ja) |
NO (1) | NO331556B1 (ja) |
NZ (1) | NZ538534A (ja) |
PL (1) | PL209425B1 (ja) |
PT (1) | PT1537104E (ja) |
RU (1) | RU2352569C2 (ja) |
SI (1) | SI1537104T1 (ja) |
WO (1) | WO2004022556A1 (ja) |
ZA (1) | ZA200500816B (ja) |
Families Citing this family (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6262265A (ja) * | 1985-09-13 | 1987-03-18 | Hitachi Ltd | 復水器自動検査補修システム |
DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
GB0220581D0 (en) | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
DE602004031124D1 (de) | 2003-08-13 | 2011-03-03 | Neurosearch As | Neue chinuklidinderivative und deren pharmazeutische verwendung |
US20050137217A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | Spirocyclic quinuclidinic ether derivatives |
US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137398A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-Quinuclidinyl heteroatom bridged biaryl derivatives |
US20050245531A1 (en) * | 2003-12-22 | 2005-11-03 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137203A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-quinuclidinyl amino-substituted biaryl derivatives |
EP1824848A1 (en) * | 2004-12-10 | 2007-08-29 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7160876B2 (en) | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7241773B2 (en) | 2003-12-22 | 2007-07-10 | Abbott Laboratories | 3-quinuclidinyl heteroatom bridged biaryl derivatives |
US7309699B2 (en) | 2003-12-22 | 2007-12-18 | Abbott Laboratories | 3-Quinuclidinyl amino-substituted biaryl derivatives |
AR049401A1 (es) | 2004-06-18 | 2006-07-26 | Novartis Ag | Aza-biciclononanos |
GB0415746D0 (en) | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
JP5149009B2 (ja) * | 2004-09-20 | 2013-02-20 | 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 | ヒトステアロイル−CoAデサチュラーゼを阻害するためのピリダジン誘導体 |
EP1804799B1 (en) | 2004-09-20 | 2013-08-21 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
MX2007003332A (es) | 2004-09-20 | 2007-06-05 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de estearoil-coa-desaturasa. |
GB0424564D0 (en) | 2004-11-05 | 2004-12-08 | Novartis Ag | Organic compounds |
MX2007015216A (es) | 2005-06-03 | 2008-02-22 | Xenon Pharmaceuticals Inc | Derivados de aminotiazol y sus usos como agentes terapeuticos. |
GB0521508D0 (en) * | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
GB0525672D0 (en) * | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
GB0525673D0 (en) * | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
WO2007093601A1 (en) | 2006-02-14 | 2007-08-23 | Neurosearch A/S | 3, 9-diazabicyclo(3.3.1)non-3-yl-aryl methanone derivatives as nicotinic acetylcholine receptor agonists |
EP1987029B1 (en) * | 2006-02-16 | 2010-01-13 | Neurosearch A/S | Enantiopure quinuclidinyloxy pyridazines and their use as nicotinic acetylcholine receptor ligands |
MX2009001875A (es) | 2006-08-21 | 2009-03-02 | Genentech Inc | Compuestos de aza-benzotiofenilo y metodos de uso de los mismos. |
RU2476220C2 (ru) * | 2007-08-02 | 2013-02-27 | Таргасепт, Инк. | (2s,3r)-n-(2-((3-пиридинил)метил)-1-азабицикло[2.2.2]окт-3-ил)бензофуран-2-карбоксамид, новые солевые формы и способы их применения |
US8383657B2 (en) | 2007-12-21 | 2013-02-26 | Abbott Laboratories | Thiazolylidine urea and amide derivatives and methods of use thereof |
BRPI0910175A2 (pt) | 2008-07-01 | 2017-03-21 | Genentech Inc | composto de fórmula i e ii, composição farmacêutica, método de inibição do crescimento de células anormais ou de tratamento de um distúrbio hiperproliferativo em um mamífero e método de tratamento de uma doença inflamatória em um mamífero |
MX2010014565A (es) | 2008-07-01 | 2011-03-04 | Genentech Inc | Isoindolona y metodos de uso. |
KR20180011888A (ko) | 2008-11-19 | 2018-02-02 | 포럼 파마슈티칼즈 인크. | (r)-7-클로로-n-(퀴누클리딘-3-일)벤조[b]티오펜-2-카르복사미드 및 그 약학적으로 허용가능한 염을 이용한 인지 장애의 치료 |
BRPI1014793A2 (pt) * | 2009-05-11 | 2016-04-05 | Envivo Pharmaceuticals Inc | tratamento de distúrbios de cognição com determinados receptores de ácido alfa-7-nicotínico em combinação com inibidores de acetil-colinesterase |
EP2959902A1 (en) * | 2009-07-23 | 2015-12-30 | Novartis AG | Use of azabicycloalkyl derivatives for the treatment or prevention of ataxia |
JO3250B1 (ar) | 2009-09-22 | 2018-09-16 | Novartis Ag | إستعمال منشطات مستقبل نيكوتينيك أسيتيل كولين ألفا 7 |
US8841289B2 (en) | 2009-10-13 | 2014-09-23 | Merck Sharp & Dohme B.V. | Heterocyclic derivatives |
RS54742B1 (sr) | 2010-05-17 | 2016-10-31 | Forum Pharmaceuticals Inc | Kristalni oblik (r)-7-hlor-n-(hinuklidin-3-il)benzo[b]tiofen-2-karboksamid hidrohlorid monohidrata |
CN103442701A (zh) * | 2011-01-27 | 2013-12-11 | 诺瓦提斯公司 | 烟碱乙酰胆碱受体α7激活剂的用途 |
EP2685977A1 (en) * | 2011-03-18 | 2014-01-22 | Novartis AG | COMBINATIONS OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATORS AND mGluR5 ANTAGONISTS FOR USE IN DOPAMINE INDUCED DYSKINESIA IN PARKINSON'S DISEASE |
WO2013010679A1 (en) | 2011-07-15 | 2013-01-24 | Novartis Ag | Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors |
CA3083244C (en) * | 2011-10-20 | 2023-01-03 | Novartis Ag | Biomarkers predictive of responsiveness to alpha 7 nicotinic acetylcholine receptor activator treatment |
WO2013169646A1 (en) | 2012-05-08 | 2013-11-14 | Envivo Pharmaceuticals, Inc. | Methods of maintaining, treating or improving cognitive function |
AU2013356914B2 (en) | 2012-12-11 | 2017-01-05 | Novartis Ag | Biomarker predictive of responsiveness to alpha 7 nicotinic acetylcholine receptor activator treatment |
EP3251673A1 (en) * | 2012-12-13 | 2017-12-06 | IP Gesellschaft für Management mbH | Combination therapy comprising a cdk4/6 inhibitor and a pi3k inhibitor for use in the treatment of cancer |
BR112015016994A8 (pt) * | 2013-01-15 | 2018-01-23 | Novartis Ag | uso de agonistas do receptor alfa 7 nicotínico de acetilcolina |
US20150313884A1 (en) | 2013-01-15 | 2015-11-05 | Novartis Ag | Use of alpha 7 nicotinic acetylcholine receptor agonists |
KR101879920B1 (ko) * | 2013-01-15 | 2018-07-18 | 노파르티스 아게 | 알파 7 니코틴성 아세틸콜린 수용체 작용물질의 용도 |
CA2898045C (en) * | 2013-01-15 | 2018-08-28 | Novartis Ag | Use of alpha 7 nicotinic acetylcholine receptor agonists |
GB201301626D0 (en) | 2013-01-30 | 2013-03-13 | Dignity Sciences Ltd | Composition comprising 15-OHEPA and methods of using the same |
US20210315851A1 (en) | 2020-04-03 | 2021-10-14 | Afimmune Limited | Compositions comprising 15-hepe and methods of treating or preventing hematologic disorders, and/or related diseases |
WO2022115526A1 (en) | 2020-11-25 | 2022-06-02 | Vanda Pharmaceuticals Inc. | Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist |
WO2023213740A1 (en) * | 2022-05-05 | 2023-11-09 | Philip Morris Products S.A. | Nicotinic acetylcholine receptor ligands |
Family Cites Families (96)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB809574A (en) | 1956-01-26 | 1959-02-25 | Gasaccumulator Svenska Ab | Improvements in or relating to electrical signal light systems |
US3539573A (en) | 1967-03-22 | 1970-11-10 | Jean Schmutz | 11-basic substituted dibenzodiazepines and dibenzothiazepines |
BE759371A (fr) | 1969-11-24 | 1971-05-24 | Bristol Myers Co | Azaspirodecanediones heterocycliques et procedes pour leur preparation |
DE2139107A1 (de) | 1971-08-04 | 1973-02-15 | Merck Patent Gmbh | Heterocyclisch substituierte adenosinverbindungen |
ZA848275B (en) | 1983-12-28 | 1985-08-28 | Degussa | New piridine-2-ethers or pyridine-2-thioethers having a nitrogen-containing cycloaliphatic ring |
US4605652A (en) | 1985-02-04 | 1986-08-12 | A. H. Robins Company, Inc. | Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes |
DE3687980T2 (de) | 1986-01-07 | 1993-06-17 | Beecham Group Plc | Indolderivate mit einer azabicyclischen seitenkette, verfahren zu ihrer herstellung, zwischenprodukte und pharmazeutische zusammensetzungen. |
KR880007433A (ko) | 1986-12-22 | 1988-08-27 | 메리 앤 터커 | 3-아릴옥시-3-치환된 프로판아민 |
AU614513B2 (en) | 1987-04-15 | 1991-09-05 | Beecham Group Plc | 1-azabicyclic 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 |
US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
DE3839385A1 (de) | 1988-11-22 | 1990-05-23 | Boehringer Ingelheim Kg | Neue quinuclidine, ihre herstellung als arzneimittel und verfahren zu ihrer herstellung |
GB8829079D0 (en) | 1988-12-13 | 1989-01-25 | Beecham Group Plc | Novel compounds |
CA2002182C (en) | 1989-11-03 | 2000-06-13 | Richard J. Wurtman | Compositions for treating the premenstrual or late luteal phase syndrome and methods for their use |
DE4116582A1 (de) | 1990-05-19 | 1991-11-21 | Boehringer Ingelheim Kg | Bicyclische 1-aza-cycloalkane |
YU84791A (sh) | 1990-05-19 | 1994-06-10 | Boehringer Ingelheim Kg. | Biciklicni 1-aza-cikloalkalni |
CA2090027A1 (en) | 1990-08-31 | 1992-03-01 | Shoichi Chokai | Pyrimidine derivatives and drugs |
JP3087763B2 (ja) | 1990-11-30 | 2000-09-11 | 三井化学株式会社 | 新規な複素環式化合物およびそれを含有する医薬組成物 |
US5260303A (en) | 1991-03-07 | 1993-11-09 | G. D. Searle & Co. | Imidazopyridines as serotonergic 5-HT3 antagonists |
US5385912A (en) | 1991-03-08 | 1995-01-31 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Multicyclic tertiary amine polyaromatic squalene synthase inhibitors |
WO1992015579A1 (en) | 1991-03-08 | 1992-09-17 | Rhone-Poulenc Rorer International (Holdings) Inc. | Multicyclic tertiary amine polyaromatic squalene synthetase inhibitors |
JPH05310732A (ja) | 1992-03-12 | 1993-11-22 | Mitsubishi Kasei Corp | シンノリン−3−カルボン酸誘導体 |
JPH06508377A (ja) | 1992-04-10 | 1994-09-22 | ゼネカ リミテッド | ヘテロ環式化合物 |
IL107184A (en) | 1992-10-09 | 1997-08-14 | Abbott Lab | Heterocyclic ether compounds that enhance cognitive function |
WO1995031458A1 (en) | 1992-10-13 | 1995-11-23 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | 3-hydroxyquinuclidin-3-ylphenylquinolines as squalene synthase inhibitors |
AU6010594A (en) | 1993-02-12 | 1994-08-29 | Sankyo Company Limited | Isoxazoleoxy derivative |
JPH06293768A (ja) | 1993-02-12 | 1994-10-21 | Sankyo Co Ltd | イソオキサゾールオキシ誘導体 |
JP4208267B2 (ja) | 1993-07-30 | 2009-01-14 | キヤノン株式会社 | 制御装置 |
JP3235913B2 (ja) | 1993-07-30 | 2001-12-04 | エーザイ株式会社 | アミノ安息香酸誘導体 |
US5998404A (en) | 1994-10-24 | 1999-12-07 | Eli Lilly And Company | Heterocyclic compounds and their use |
EP0853621A1 (en) | 1995-09-22 | 1998-07-22 | Novo Nordisk A/S | Novel substituted azacyclic or azabicyclic compounds |
SE9600683D0 (sv) | 1996-02-23 | 1996-02-23 | Astra Ab | Azabicyclic esters of carbamic acids useful in therapy |
NZ500643A (en) | 1997-05-30 | 2001-12-21 | Neurosearch As | Spiro-quinuclidine derivatives and their use in treating conditions responsive to nicotinic ACh receptor modulators |
AR013184A1 (es) | 1997-07-18 | 2000-12-13 | Astrazeneca Ab | Aminas heterociclicas espiroazobiciclicas, composicion farmaceutica, uso de dichas aminas para preparar medicamentos y metodo de tratamiento o profilaxis |
US6432975B1 (en) | 1998-12-11 | 2002-08-13 | Targacept, Inc. | Pharmaceutical compositions and methods for use |
US6953855B2 (en) | 1998-12-11 | 2005-10-11 | Targacept, Inc. | 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof |
SE9900100D0 (sv) | 1999-01-15 | 1999-01-15 | Astra Ab | New compounds |
WO2001008684A1 (en) | 1999-07-28 | 2001-02-08 | The Board Of Trustees Of The Leland Stanford Junior University | Nicotine in therapeutic angiogenesis and vasculogenesis |
SE9903760D0 (sv) | 1999-10-18 | 1999-10-18 | Astra Ab | New compounds |
SE9904176D0 (sv) | 1999-11-18 | 1999-11-18 | Astra Ab | New use |
SE0000540D0 (sv) * | 2000-02-18 | 2000-02-18 | Astrazeneca Ab | New compounds |
AU2001241056A1 (en) | 2000-03-09 | 2001-09-17 | Mitsubishi Pharma Corporation | Spiro compounds, process for preparing the same and use thereof as drugs |
GB0010955D0 (en) | 2000-05-05 | 2000-06-28 | Novartis Ag | Organic compounds |
JP4616971B2 (ja) | 2000-07-18 | 2011-01-19 | 田辺三菱製薬株式会社 | 1−アザビシクロアルカン化合物およびその医薬用途 |
JP2004506735A (ja) | 2000-08-18 | 2004-03-04 | ファルマシア・アンド・アップジョン・カンパニー | 疾患治療用キヌクリジン置換アリール化合物 |
WO2002015662A2 (en) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic acetylcholine receptor antagonists |
GB0021885D0 (en) | 2000-09-06 | 2000-10-18 | Fujisawa Pharmaceutical Co | New use |
PE20021019A1 (es) | 2001-04-19 | 2002-11-13 | Upjohn Co | Grupos azabiciclicos sustituidos |
AR036040A1 (es) | 2001-06-12 | 2004-08-04 | Upjohn Co | Compuestos de heteroarilo multiciclicos sustituidos con quinuclidinas y composiciones farmaceuticas que los contienen |
JP2005511574A (ja) | 2001-10-26 | 2005-04-28 | ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー | Nachrアゴニストとしてのn−アザビシクロ−置換ヘテロ二環式カルボキサミド |
DE10156719A1 (de) | 2001-11-19 | 2003-05-28 | Bayer Ag | Heteroarylcarbonsäureamide |
DE10162375A1 (de) | 2001-12-19 | 2003-07-10 | Bayer Ag | Bicyclische N-Aryl-amide |
EP1478646A1 (en) | 2002-02-20 | 2004-11-24 | PHARMACIA & UPJOHN COMPANY | Azabicyclic compounds with alfa7 nicotinic acetylcholine receptor activity |
DE10211415A1 (de) | 2002-03-15 | 2003-09-25 | Bayer Ag | Bicyclische N-Biarylamide |
DE10211416A1 (de) | 2002-03-15 | 2003-09-25 | Bayer Ag | Essig- und Propionsäureamide |
DE10234424A1 (de) | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
CA2493245A1 (en) | 2002-08-14 | 2004-02-26 | Neurosearch A/S | Novel quinuclidine derivatives and their use |
GB0220581D0 (en) * | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
CA2499128C (en) | 2002-09-25 | 2012-07-31 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof |
WO2004039321A2 (en) | 2002-10-29 | 2004-05-13 | Miicro, Inc. | Combinative nicotinic/d1 agonism therapy for the treatment of alzheimer’s disease |
WO2004039815A2 (en) | 2002-11-01 | 2004-05-13 | Pharmacia & Upjohn Company Llc | Compounds having both alpha7 nachr agonist and 5ht antagonist activity for treatment of cns diseases |
AU2003269413A1 (en) | 2002-11-01 | 2004-05-25 | Pharmacia & Upjohn Company Llc | Nicotinic acetylcholine agonists in the treatment of glaucoma and retinal neuropathy |
DE60309740T2 (de) | 2002-11-11 | 2007-03-29 | Neurosearch A/S | 1,4-dizabicyclo(3,2,2)nonane derivative, verfahren zu ihrer herstellung und therapeutical verwendung |
KR20050085535A (ko) | 2002-12-11 | 2005-08-29 | 파마시아 앤드 업존 캄파니 엘엘씨 | 알파 7 니코틴성 아세틸콜린 수용체 아고니스트와 다른화합물의 조합물을 사용한 질환의 치료 방법 |
PL378026A1 (pl) | 2003-01-22 | 2006-02-20 | Pharmacia & Upjohn Company Llc | Leczenie chorób z zastosowaniem pełnych agonistów receptora Ó-7 nACh |
WO2005013910A2 (en) | 2003-08-07 | 2005-02-17 | University Of South Florida | Cholinergic modulation of microglial activation via alpha-7 nicotinic receptors |
JP4226981B2 (ja) | 2003-09-24 | 2009-02-18 | 三井金属鉱業株式会社 | プリント配線板の製造方法及びその製造方法で得られたプリント配線板 |
US7241773B2 (en) | 2003-12-22 | 2007-07-10 | Abbott Laboratories | 3-quinuclidinyl heteroatom bridged biaryl derivatives |
US20050245531A1 (en) | 2003-12-22 | 2005-11-03 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137398A1 (en) | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-Quinuclidinyl heteroatom bridged biaryl derivatives |
US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
EP1824848A1 (en) | 2004-12-10 | 2007-08-29 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137203A1 (en) | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-quinuclidinyl amino-substituted biaryl derivatives |
US20050137204A1 (en) | 2003-12-22 | 2005-06-23 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20070060588A1 (en) | 2003-12-22 | 2007-03-15 | Jianguo Ji | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7160876B2 (en) | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
CA2549638A1 (en) | 2003-12-23 | 2005-07-14 | Pfizer Products Inc. | Therapeutic combination for cognition enhancement and psychotic disorders |
US7875624B2 (en) | 2004-02-20 | 2011-01-25 | Novartis Vaccines And Diagnostics, Inc. | Modulating and measuring cellular adhesion |
KR20070030196A (ko) | 2004-04-13 | 2007-03-15 | 이카겐, 인코포레이티드 | 칼륨 이온 채널 조절제로서의 폴리시클릭 피리딘 |
WO2005111033A2 (en) | 2004-05-19 | 2005-11-24 | Neurosearch A/S | Novel azabicyclic aryl derivatives |
AR049401A1 (es) | 2004-06-18 | 2006-07-26 | Novartis Ag | Aza-biciclononanos |
GB0415746D0 (en) | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
AU2005293510A1 (en) | 2004-10-15 | 2006-04-20 | Neurosearch A/S | Novel azabicyclic aryl derivatives and their medical use |
GB0424564D0 (en) | 2004-11-05 | 2004-12-08 | Novartis Ag | Organic compounds |
WO2006087305A1 (en) | 2005-02-16 | 2006-08-24 | Neurosearch A/S | Novel diazabicyclic aryl derivatives and their medical use |
US20060211686A1 (en) | 2005-03-18 | 2006-09-21 | Abbott Laboratories | Alpha7 Neuronal nicotinic receptor ligand and antipsychotic compositions |
JP2008536932A (ja) | 2005-04-18 | 2008-09-11 | サイード・アール・カーン | チューブリン重合阻害剤:ボンゾイルフェニル尿素(bpu)硫黄類似体の設計及び合成 |
FR2884822B1 (fr) | 2005-04-22 | 2007-06-29 | Aventis Pharma Sa | Derives de triazines, leur preparation et leur application en therapeutique |
GB0508314D0 (en) | 2005-04-25 | 2005-06-01 | Novartis Ag | Organic compounds |
KR20080029965A (ko) | 2005-06-14 | 2008-04-03 | 쉐링 코포레이션 | 아스파르틸 프로테아제 억제제 |
GB0521508D0 (en) | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
GB0525673D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
GB0525672D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
TW200813067A (en) | 2006-05-17 | 2008-03-16 | Astrazeneca Ab | Nicotinic acetylcholine receptor ligands |
US20110218128A1 (en) | 2008-10-17 | 2011-09-08 | Nok Kluber Co., Ltd. | Lubricating grease composition and method for producing the same |
-
2002
- 2002-09-04 GB GB0220581A patent/GB0220581D0/en not_active Ceased
-
2003
- 2003-09-03 PT PT03793791T patent/PT1537104E/pt unknown
- 2003-09-03 CN CNB038207303A patent/CN1325493C/zh not_active Expired - Lifetime
- 2003-09-03 PL PL374013A patent/PL209425B1/pl unknown
- 2003-09-03 AU AU2003260486A patent/AU2003260486C1/en not_active Expired
- 2003-09-03 WO PCT/EP2003/009772 patent/WO2004022556A1/en active IP Right Grant
- 2003-09-03 EP EP20030793791 patent/EP1537104B1/en not_active Expired - Lifetime
- 2003-09-03 BR BR122014026685-5A patent/BR122014026685B1/pt not_active IP Right Cessation
- 2003-09-03 CA CA 2495685 patent/CA2495685C/en not_active Expired - Lifetime
- 2003-09-03 BR BRPI0314325A patent/BRPI0314325B8/pt active IP Right Grant
- 2003-09-03 SI SI200331746T patent/SI1537104T1/sl unknown
- 2003-09-03 MX MXPA05002546A patent/MXPA05002546A/es active IP Right Grant
- 2003-09-03 EP EP20090164576 patent/EP2100893A1/en not_active Withdrawn
- 2003-09-03 JP JP2004533455A patent/JP4348422B2/ja not_active Expired - Lifetime
- 2003-09-03 EP EP20100184187 patent/EP2308876A1/en not_active Withdrawn
- 2003-09-03 KR KR1020077011698A patent/KR20070058027A/ko not_active Application Discontinuation
- 2003-09-03 DK DK03793791T patent/DK1537104T3/da active
- 2003-09-03 NZ NZ538534A patent/NZ538534A/en not_active IP Right Cessation
- 2003-09-03 AT AT03793791T patent/ATE448225T1/de active
- 2003-09-03 US US10/526,759 patent/US20060167002A1/en not_active Abandoned
- 2003-09-03 ES ES03793791T patent/ES2336099T3/es not_active Expired - Lifetime
- 2003-09-03 DE DE60330015T patent/DE60330015D1/de not_active Expired - Lifetime
- 2003-09-03 RU RU2005109913A patent/RU2352569C2/ru active
- 2003-09-03 KR KR20057003665A patent/KR100808324B1/ko active IP Right Review Request
-
2005
- 2005-01-27 ZA ZA200500816A patent/ZA200500816B/xx unknown
- 2005-02-15 IL IL16691805A patent/IL166918A/en active IP Right Grant
- 2005-02-22 EC ECSP055621 patent/ECSP055621A/es unknown
- 2005-04-01 NO NO20051626A patent/NO331556B1/no not_active IP Right Cessation
- 2005-11-07 HK HK05109896A patent/HK1077822A1/xx not_active IP Right Cessation
- 2005-11-30 HK HK05110918A patent/HK1078868A1/xx not_active IP Right Cessation
-
2007
- 2007-06-26 US US11/823,312 patent/US7579362B2/en not_active Expired - Lifetime
-
2008
- 2008-10-31 US US12/262,896 patent/US8236803B2/en not_active Expired - Fee Related
-
2009
- 2009-02-19 JP JP2009036918A patent/JP5124714B2/ja not_active Expired - Fee Related
-
2010
- 2010-02-10 CY CY101100129T patent/CY1109765T1/el unknown
-
2012
- 2012-05-02 US US13/462,187 patent/US9012451B2/en not_active Expired - Lifetime
-
2013
- 2013-02-28 IL IL225002A patent/IL225002A/en active IP Right Grant
-
2015
- 2015-03-10 US US14/643,275 patent/US9567343B2/en not_active Expired - Lifetime
-
2017
- 2017-01-04 US US15/398,427 patent/US9849117B2/en not_active Expired - Lifetime
- 2017-11-21 US US15/819,535 patent/US20180078536A1/en not_active Abandoned
-
2018
- 2018-11-15 US US16/191,693 patent/US20190083474A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4348422B2 (ja) | アザビシクロアルキルエーテルおよびそのα7−NACHRアゴニストとしての使用 | |
EP0632809B1 (en) | Quinuclidine derivatives as substance p antagonists | |
EP0665843B1 (en) | Substituted quinuclidines as substance p antagonists | |
EP0665844B1 (en) | Substituted benzylaminoquinuclidines as substance p antagonists | |
JP4898062B2 (ja) | アザ二環式カルバメートおよびアルファ−7ニコチン性アセチルコリンレセプターアゴニストとしてのその使用 | |
AU2001262257A1 (en) | Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists | |
IE83327B1 (en) | Substituted 3-aminoquinuclidines | |
JP2006507241A (ja) | ニコチン性アセチルコリン作用剤としてのビアリールジアザビシクロアルカンアミド | |
IE921662A1 (en) | Substituted 3-aminoquinuclidines | |
US5604241A (en) | Substituted benzylaminoquinuclidines as substance P antagonists | |
ES2352231T3 (es) | Compuestos furilo. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080819 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20081110 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20081117 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20081210 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20081217 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20090116 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090123 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090219 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20090220 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090616 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090622 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120731 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4348422 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120731 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130731 Year of fee payment: 4 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
EXPY | Cancellation because of completion of term |