WO2003080608A2 - Quinoline and aza-indole derivatives and their use as 5-ht6 ligands - Google Patents
Quinoline and aza-indole derivatives and their use as 5-ht6 ligands Download PDFInfo
- Publication number
- WO2003080608A2 WO2003080608A2 PCT/EP2003/003195 EP0303195W WO03080608A2 WO 2003080608 A2 WO2003080608 A2 WO 2003080608A2 EP 0303195 W EP0303195 W EP 0303195W WO 03080608 A2 WO03080608 A2 WO 03080608A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- formula
- independently represent
- piperazin
- Prior art date
Links
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract description 10
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 title abstract description 3
- 239000003446 ligand Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 115
- 150000001875 compounds Chemical class 0.000 claims description 79
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000026139 Memory disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 230000001149 cognitive effect Effects 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000005533 aryl carboxamido group Chemical group 0.000 claims description 2
- 125000005421 aryl sulfonamido group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 23
- 239000000203 mixture Substances 0.000 abstract description 15
- 238000002360 preparation method Methods 0.000 abstract description 7
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 134
- 239000002904 solvent Substances 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 238000001819 mass spectrum Methods 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 13
- -1 fluoromethanesulfonyloxy Chemical group 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 239000012425 OXONE® Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- BJGYVCYBPNAQIE-UHFFFAOYSA-N 1-[4-(2-aminophenyl)piperazin-1-yl]-2,2,2-trifluoroethanone Chemical compound NC1=CC=CC=C1N1CCN(C(=O)C(F)(F)F)CC1 BJGYVCYBPNAQIE-UHFFFAOYSA-N 0.000 description 4
- UQBHTZMAMCECSI-UHFFFAOYSA-N 1-[4-(4-chloro-2-methylquinolin-8-yl)piperazin-1-yl]-2,2,2-trifluoroethanone Chemical compound C12=NC(C)=CC(Cl)=C2C=CC=C1N1CCN(C(=O)C(F)(F)F)CC1 UQBHTZMAMCECSI-UHFFFAOYSA-N 0.000 description 4
- LMQYQXMVGVUZCW-UHFFFAOYSA-N 1-[4-[4-(benzenesulfonyl)-2-methylquinolin-8-yl]piperazin-1-yl]-2,2,2-trifluoroethanone Chemical compound C12=NC(C)=CC(S(=O)(=O)C=3C=CC=CC=3)=C2C=CC=C1N1CCN(C(=O)C(F)(F)F)CC1 LMQYQXMVGVUZCW-UHFFFAOYSA-N 0.000 description 4
- SSRLRVMFEGGGMQ-UHFFFAOYSA-N 1-methyl-4-(2-nitrophenyl)piperazine Chemical compound C1CN(C)CCN1C1=CC=CC=C1[N+]([O-])=O SSRLRVMFEGGGMQ-UHFFFAOYSA-N 0.000 description 4
- WIHZWTRUHHFGKQ-UHFFFAOYSA-N 2,2,2-trifluoro-1-[4-(2-nitrophenyl)piperazin-1-yl]ethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1N1CCN(C(=O)C(F)(F)F)CC1 WIHZWTRUHHFGKQ-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- JWXRRUUTSBZHCR-UHFFFAOYSA-N 4-(benzenesulfonyl)-2-methyl-8-piperazin-1-ylquinoline Chemical compound C12=NC(C)=CC(S(=O)(=O)C=3C=CC=CC=3)=C2C=CC=C1N1CCNCC1 JWXRRUUTSBZHCR-UHFFFAOYSA-N 0.000 description 4
- JMOQRBVYCJSVKO-UHFFFAOYSA-N 4-(benzenesulfonyl)-8-piperazin-1-ylquinoline Chemical compound C=1C=NC2=C(N3CCNCC3)C=CC=C2C=1S(=O)(=O)C1=CC=CC=C1 JMOQRBVYCJSVKO-UHFFFAOYSA-N 0.000 description 4
- LLBYZZCOVUGZSS-UHFFFAOYSA-N 4-chloro-7-iodo-2-methylquinoline Chemical compound C1=CC(I)=CC2=NC(C)=CC(Cl)=C21 LLBYZZCOVUGZSS-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 235000019502 Orange oil Nutrition 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 239000010502 orange oil Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- VIGCKDDNUOSXAG-UHFFFAOYSA-N 7-iodo-2-methylquinoline Chemical compound C1=CC(I)=CC2=NC(C)=CC=C21 VIGCKDDNUOSXAG-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000006242 amine protecting group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 3
- FDNAFGFBUMBUCN-UHFFFAOYSA-N 3-(2-fluorophenyl)sulfonyl-7-piperazin-1-yl-1h-pyrrolo[2,3-c]pyridine;hydrochloride Chemical compound Cl.FC1=CC=CC=C1S(=O)(=O)C1=CNC2=C(N3CCNCC3)N=CC=C12 FDNAFGFBUMBUCN-UHFFFAOYSA-N 0.000 description 2
- ZYGOWWXWDMXGAK-UHFFFAOYSA-N 3-(3-fluorophenyl)sulfonyl-7-piperazin-1-yl-1h-pyrrolo[2,3-c]pyridine;hydrochloride Chemical compound Cl.FC1=CC=CC(S(=O)(=O)C=2C3=CC=NC(=C3NC=2)N2CCNCC2)=C1 ZYGOWWXWDMXGAK-UHFFFAOYSA-N 0.000 description 2
- SXTGWTWMDRKBIO-UHFFFAOYSA-N 3-(benzenesulfonyl)-1-methyl-7-piperazin-1-ylpyrrolo[3,2-b]pyridine Chemical compound C=12N(C)C=C(S(=O)(=O)C=3C=CC=CC=3)C2=NC=CC=1N1CCNCC1 SXTGWTWMDRKBIO-UHFFFAOYSA-N 0.000 description 2
- LAPFNWXUBADSMA-UHFFFAOYSA-N 3-(benzenesulfonyl)-4-methyl-7-piperazin-1-ylpyrrolo[3,2-b]pyridine Chemical compound C=12N=CC(S(=O)(=O)C=3C=CC=CC=3)=C2N(C)C=CC=1N1CCNCC1 LAPFNWXUBADSMA-UHFFFAOYSA-N 0.000 description 2
- ZDYUBLYSCSBHRG-UHFFFAOYSA-N 3-(benzenesulfonyl)-7-piperazin-1-yl-1h-pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=1C=CC=CC=1S(=O)(=O)C(C1=NC=C2)=CNC1=C2N1CCNCC1 ZDYUBLYSCSBHRG-UHFFFAOYSA-N 0.000 description 2
- JGVKBLDKUVPTJV-UHFFFAOYSA-N 4-(benzenesulfonyl)-2-methyl-8-piperazin-1-ylquinoline;hydrochloride Chemical compound Cl.C12=NC(C)=CC(S(=O)(=O)C=3C=CC=CC=3)=C2C=CC=C1N1CCNCC1 JGVKBLDKUVPTJV-UHFFFAOYSA-N 0.000 description 2
- RFTUWRQVCRJTPU-UHFFFAOYSA-N 4-(benzenesulfonyl)-8-iodoquinoline Chemical compound C1=CN=C2C(I)=CC=CC2=C1S(=O)(=O)C1=CC=CC=C1 RFTUWRQVCRJTPU-UHFFFAOYSA-N 0.000 description 2
- YROWEOANZNUIJB-UHFFFAOYSA-N 4-(benzenesulfonyl)-8-piperazin-1-ylquinoline;hydrochloride Chemical compound Cl.C=1C=NC2=C(N3CCNCC3)C=CC=C2C=1S(=O)(=O)C1=CC=CC=C1 YROWEOANZNUIJB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000002619 bicyclic group Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 238000006900 dealkylation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- CHLCPTJLUJHDBO-UHFFFAOYSA-M sodium;benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=CC=C1 CHLCPTJLUJHDBO-UHFFFAOYSA-M 0.000 description 2
- AMLUYVFRRGHCKO-UHFFFAOYSA-N tert-butyl 4-[4-(benzenesulfonyl)quinolin-8-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C(S(=O)(=O)C=3C=CC=CC=3)C=CN=C12 AMLUYVFRRGHCKO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- FFCSRWGYGMRBGD-UHFFFAOYSA-N 3-iodoaniline Chemical compound NC1=CC=CC(I)=C1 FFCSRWGYGMRBGD-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
- NTPIFVWREJZWBD-UHFFFAOYSA-N 4-bromo-8-iodoquinoline Chemical compound C1=CC=C2C(Br)=CC=NC2=C1I NTPIFVWREJZWBD-UHFFFAOYSA-N 0.000 description 1
- JOTRPRKONYTVBV-UHFFFAOYSA-N 4-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CN=CC=C1Cl JOTRPRKONYTVBV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010033664 Panic attack Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Chemical group 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000007000 age related cognitive decline Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000011230 binding agent Substances 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
- 210000004556 brain Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- NHARUBKBOVJXQN-UHFFFAOYSA-N ethyl 3-[2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]anilino]but-2-enoate Chemical compound CCOC(=O)C=C(C)NC1=CC=CC=C1N1CCN(C(=O)C(F)(F)F)CC1 NHARUBKBOVJXQN-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 229940093858 ethyl acetoacetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 208000003906 hydrocephalus Diseases 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007514 neuronal growth Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/22—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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
Definitions
- This invention relates to novel quinoline and aza indole compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
- WO 98/27081 discloses a series of aryl sulphonamide compounds that are said to be 5- HT 6 receptor antagonists and which are claimed to be useful in the treatment of various CNS disorders.
- GB-2341549, WO 99/47516 and WO 99/65906 all disclose a series of indole derivatives that are claimed to have 5-HT 6 receptor affinity.
- JP 02262627 Japan Synthetic Rubber Co
- JP 02262627 describes a series of substituted quinoline derivatives useful as wavelength converting elements.
- WO 01/83456 (Yamanouchi Pharmaceutical Co. Ltd) describes a series of bicyclic or thcyclic fused heteroaryl compounds with phosphatidylinositol 3-kinase activity.
- WO 00/42026 (Novo Nordisk) describes a series of quinoline and quinoxaline compounds for use as GLP-1 agonists.
- JP 08003144 (Chugai Pharmaceutical Co. Ltd.) describes a series of quinazoline and quinoline derivatives as potassium channel openers.
- WO 97/03069 (Glaxo Group Limited) and WO 96/09294 (The Wellcome Foundation Limited) both describe a series of substituted quinolines and quinazolines as protein tyrosine kinase inhibitors.
- a structurally novel class of compounds has now been found which also possess affinity for the 5-HT 6 receptor.
- the present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
- R 1 and R 2 independently represent hydrogen or C ⁇ _ 6 alkyl or R 1 is linked to R 2 to form a group (CH 2 ) 2 , (CH 2 ) 3 or (CH 2 ) 4 ; p represents 1 or 2; m represents an integer from 1 to 4, when m is an integer greater than 1 , two R 2 groups may instead be linked to form a group CH 2 , (CH 2 ) 2 or (CH 2 ) 3 ;
- Q represents a group of formula (i), (ii), (iii) or (iv):
- R 3 and R 4 independently represent hydrogen, halogen, cyano, -CF 3 , -OCF 3 , C ⁇ - 6 alkyl, C 1 - 6 alkoxy, C 1-6 alkanoyl or a group -CONR 6 R 7 ;
- R .3a and R independently represent hydrogen or C ⁇ alkyl
- R 6 and R 7 independently represent hydrogen or d-e alkyl or together may be fused to form a 5- to 7- membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom
- n and q independently represent 1 or 2
- r and s independently represent an integer from 1 to 3
- A represents a group -Ar 1 or -
- Ar 1 , Ar 2 and Ar 3 independently represent an aryl group or a heteroaryl group, both of which may be optionally substituted by one or more (eg. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, t fluoromethanesulfonyloxy, pentafluoroethyl, C 1-6 alkoxy, arylC ⁇ . 6 alkoxy, C ⁇ . 6 alkylthio, C ⁇ -6 alkoxyC ⁇ -6 alkyl, C 3-7 cycloalkylC ⁇ .
- R 8 and R 9 independently represent hydrogen or C 1-6 alkyl or together may be fused to form a 5- to 7- membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom; or solvates thereof.
- Alkyl groups may be straight chain or branched and the groups alkoxy and alkanoyl shall be interpreted similarly.
- Alkyl moieties are more preferably alkyl, eg. methyl or ethyl.
- the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
- aryl includes phenyl and naphthyl.
- heteroaryl is intended to mean a 5-7 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur.
- monocyclic aromatic rings include thienyl, furyl, pyrrolyl, thazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.
- fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
- benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzo
- Heteroaryl groups as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where otherwise indicated above. It will be appreciated that wherein the above mentioned aryl or heteroaryl groups have more than one substituent, said substituents may be linked to form a ring, for example a carboxyl and amine group may be linked to form an amide group.
- R 1 represents hydrogen or methyl, more preferably hydrogen.
- R 2 represents hydrogen or methyl.
- R 3 represents hydrogen, methyl or halogen, more preferably hydrogen.
- R 3a and R 5 independently represent hydrogen or methyl.
- n, p each represent 1.
- Ar 1 preferably represents optionally substituted phenyl or pyridyl, more preferably phenyl optionally substituted with halogen, cyano, t fluoromethyl or thfluoromethoxy.
- Particularly preferred Ar 1 is phenyl optionally substituted with halogen (such as 2-fluohne).
- Ar 2 and Ar 3 preferably both independently represent phenyl or monocyclic heteroaryl group as defined above.
- A represents a group -Ar 1 .
- R 1 represents hydrogen or methyl, more preferably hydrogen.
- R 2 represents hydrogen
- R 3 represents hydrogen, methyl or halogen, more preferably hydrogen.
- Y represents -N(R 5 )-.
- R 3a and R 5 independently represent hydrogen or methyl, more preferably hydrogen.
- n, p each represent 1.
- Ar 1 preferably represents optionally substituted phenyl or pyridyl, more preferably phenyl optionally substituted with halogen, cyano, trifluoromethyl or trifluoromethoxy.
- Particularly preferred Ar 1 is phenyl optionally substituted with halogen (such as 2-fluorine and 3-fluorine).
- Ar 2 and Ar 3 preferably both independently represent phenyl or monocyclic heteroaryl group as defined above.
- A represents a group -Ar 1 .
- R 1 represents hydrogen or methyl, more preferably hydrogen.
- R 2 represents hydrogen.
- R 3 represents hydrogen, methyl or halogen, more preferably hydrogen or methyl.
- R 4 represents hydrogen or halogen, more preferably hydrogen.
- m, n, p and s each represent 1.
- Ar 1 preferably represents optionally substituted phenyl or pyridyl, more preferably phenyl optionally substituted with halogen, cyano, t fluoromethyl or t fluoromethoxy. Particularly preferred Ar 1 is unsubstituted phenyl.
- Ar 2 and Ar 3 preferably both independently represent phenyl or monocyclic heteroaryl group as defined above; Preferably A represents a group -Ar 1 .
- R 1 represents hydrogen or methyl, more preferably hydrogen.
- R 2 represents hydrogen
- R 3 represents hydrogen or a halogen atom.
- R 4 represents hydrogen or methyl (particularly 2-methyl).
- m, p, q and r all represent 1.
- Ar 3 is preferably linked to Ar 2 via a carbon atom of Ar 3 , and preferably Ar 2 and Ar 3 independently represent phenyl or a monocyclic heteroaryl group as defined above.
- A represents -Ar 1 .
- -Ar 1 is phenyl or pyridyl optionally substituted by one or more halogen atoms or cyano, thfluoromethoxy or thfluoromethyl groups, more preferably unsubstituted phenyl, 2-fluorophenyl, 3-fluorophenyl or 3-chlorophenyl.
- Preferred compounds according to the invention include examples E1-E16 as shown below, or a pharmaceutically acceptable salt thereof.
- the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfu c, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartahc, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
- the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
- the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate.
- This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water).
- Certain compounds of formula (I) are capable of existing in stereoisome c forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
- the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
- the invention also extends to any tautomeric forms and mixtures thereof.
- the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
- R 1a is as defined for R 1 or an ⁇ /-protecting group and Q, R 2 , m, p and A are as defined above, and thereafter as necessary removing an R 1a /V-protecting group; or
- A is as defined above and L represents a leaving group, such as a halogen atom, with a compound of formula (V)
- R 1a is as defined for R 1 or an /V-protecting group such as terf-butyloxycarbonyl (t-Boc), R 2 , m and p are as defined above, followed by subsequent deprotection as necessary; or
- the /V-protecting group used may be any conventional group e.g. f-butyloxycarbonyl (Boc) or benzyloxycarbonyl.
- Process (a) typically comprises the use of an oxidant such as a peracid (e.g. 3- chloroperbenzoic acid or peracetic acid) or potassium monopersulfate, in a suitable solvent such as dichloromethane or aqueous methanol.
- an oxidant such as a peracid (e.g. 3- chloroperbenzoic acid or peracetic acid) or potassium monopersulfate
- a suitable solvent such as dichloromethane or aqueous methanol.
- Process (b) wherein a compound of formula (III) is reacted with a compound of formula A-SO 2 H typically comprises use of basic conditions and may be most conveniently carried out by using a suitable salt of the compound A-SO 2 H (e.g. the sodium salt) in an appropriate solvent such as ⁇ /, ⁇ /-dimethylformamide, in the presence of a transition metal salt such as copper (I) iodide.
- Process (b) wherein a compound of formula (III) is reacted with a compound of formula A-SH typically comprises use of basic conditions e.g. by using a suitable salt of the compound A-SH (e.g.
- the sodium salt in an appropriate solvent such as N,N- dimethylformamide, in the presence of a suitable metal salt such as copper (I) iodide, followed by use of a suitable oxidant such as 3-chloroperbenzoic acid, peracetic acid or potassium monopersulfate.
- a suitable metal salt such as copper (I) iodide
- a suitable oxidant such as 3-chloroperbenzoic acid, peracetic acid or potassium monopersulfate.
- Process (c) typically comprises the use of a palladium catalyst, eg. palladium acetate in the presence of a suitable ligand, eg. BINAP and a suitable base, eg. caesium carbonate in a suitable solvent, eg. dioxane.
- a palladium catalyst eg. palladium acetate
- a suitable ligand eg. BINAP
- a suitable base eg. caesium carbonate
- a suitable solvent eg. dioxane.
- Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g.
- Suitable amine protecting groups include t fluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Mer field resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
- a further amine protecting group includes methyl which may be removed using standard methods for N-dealkylation (e.g. 1-chloroethyl chloroformate under basic conditions followed by treatment with methanol).
- Process (e) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
- interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
- ⁇ /-dealkylation of a compound of formula (I) wherein R 1 represents an alkyl group to give a compound of formula (I) wherein R 1 represents hydrogen.
- interconversion may be interconversion of protected derivatives of formula (I) which may subsequently be deprotected following interconversion.
- Step (i) typically comprises the use of a base such as triethylamine or an excess of the compound of formula (V) and an inert solvent such as dichloromethane.
- Step (ii) typically comprises the use of an inert solvent such as tetrahydrofuran at a suitable temperature (e.g. -40 °C).
- a suitable temperature e.g. -40 °C.
- R 1a is as defined above for R 1 or an /V-protecting group
- R 2 , m and p are as defined above
- Q represents a group of formula (iii) or (iv)
- L 1 represents a suitable leaving group, such as iodo or trifluoromethylsulfonyloxy
- L 5 represents a suitable leaving group, such as chlorine.
- Step (i) typically comprises reacting a compound of formula (X) with a suitable oxidant such as a peracid (e.g. 3-chloroperbenzoic acid or peracetic acid) in an inert solvent such as dichloromethane in order to generate the quinoline- ⁇ /-oxide, followed by a combination of Lewis acid and nucleophile; for example this latter step may be advantageously carried out using phosphorus oxychloride.
- a suitable oxidant such as a peracid (e.g. 3-chloroperbenzoic acid or peracetic acid)
- an inert solvent such as dichloromethane
- Step (ii) typically comprises heating a mixture of compounds of formula (XI) and (V) in a suitable solvent such as ethanol, optionally in the presence of additional base (e.g. triethylamine or an excess of the compound of formula (V)).
- a suitable solvent such as ethanol
- additional base e.g. triethylamine or an excess of the compound of formula (V)
- R 3 , R 4 , r, q, A and L 2 are as defined above and L 6 represents a suitable leaving group, such as halogen atom.
- Step (i) is typically carried out under basic conditions, for example using the sodium salt of the sulfinic acid compound in the presence of a suitable solvent, eg. dimethylformamide.
- a suitable solvent eg. dimethylformamide.
- this transformation may be carried out using a compound of formula A-SH and subsequent oxidation in a manner similar to that described above for process (b).
- L 7 represents a suitable leaving group, eg. an alkoxy group and P 1 represents a suitable protecting group, eg. trifluoroacetyl.
- Step (i) typically comprises an initial condensation reaction under acidic conditions, followed by a thermal cyclisation of the resulting enamine in the presence of a suitably high boiling solvent, eg. diphenyl ether.
- a suitably high boiling solvent eg. diphenyl ether.
- Step (ii) typically comprises the use of a suitable phosphorus halide or phosphoryl halide at an elevated temperature.
- compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
- Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for the 5-HT 6 receptor and are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, cognitive memory disorders (e.g. Alzheimers disease, age related cognitive decline and mild cognitive impairment), Parkinsons Disease, ADHD (Attention Deficit Disorder/Hyperactivity Syndrome), sleep disorders (including disturbances of Circadian rhythm), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia (in particular cognitive deficits of schizophrenia), stroke and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- Compounds of the invention are also expected to be of use in the treatment of certain Gl (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome).
- Compounds of the invention are also expected to be of use in the treatment of obesity.
- the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
- the invention provides for a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of depression, anxiety, obesity and cognitive memory disorders
- the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prophylaxis of the above disorders.
- 5-HT 6 antagonists have the potential to be capable of increasing basal and learning- induced polysialylated neuron cell frequency in brain regions such as the rat medial temporal lobe and associated hippocampus, as described in International Patent Application No. PCT/EP03/00462.
- a method of promoting neuronal growth within the central nervous system of a mammal which comprises the step of administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
- Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
- fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
- the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
- suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 200 mg, for example 20 to 40 mg; and such unit doses will preferably be administered once a day, although administration more than once a day may be required; and such therapy may extend for a number of weeks or months.
- reaction mixture cooled to room temperature and diluted with dichloromethane (50 ml), washed with water (2 x 50 ml) and the combined aqueous layers re-extracted with dichloromethane (2 x 50 ml). The combined organic layers were dried (Na 2 SO 4 ) and the solvents evaporated in vacuo. Purification by flash chromatography (EtOAc / dichloromethane 2:98 - 20:80) gave the product as a white solid (D10) (55 mg)
- Crotonaldehyde (4.96 ml, 60.0 mmol) was added dropwise over 1 h, via syringe pump, to a solution of 3-iodoaniline (12.5 g, 57.0 mmol) in bM HCI (30 ml) at 90 °C.
- the reaction mixture was then heated at 100 °C for 3 h, before being cooled to room temperature and washed with Et 2 O.
- To the aqueous solution was then added approx. 1 eq. of zinc (II) chloride, with vigorous stirring.
- the solution was then cooled to 0 °C and stirred for 45 min.
- the solid material was filtered off and washed (x 2) with cold 5M HCI.
- Examples E6-E16 exhibited pKi values > 7.5 and Examples E9-E16 exhibited pKi values
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60309852T DE60309852T2 (en) | 2002-03-27 | 2003-03-25 | CHINOLINE AND AZA INDOLE DERIVATIVES AND THEIR USE AS 5-HT6 LIGANDS |
EP03744860A EP1497291B1 (en) | 2002-03-27 | 2003-03-25 | Quinoline and aza-indole derivatives and their use as 5-ht6 ligands |
US10/509,077 US20050124626A1 (en) | 2002-03-27 | 2003-03-25 | Novel compounds |
JP2003578362A JP2005527542A (en) | 2002-03-27 | 2003-03-25 | Quinoline and azaindole derivatives and their use as 5-HT6 ligands |
AU2003226724A AU2003226724A1 (en) | 2002-03-27 | 2003-03-25 | Quinoline and aza-indole derivatives and their use as 5-ht6 ligands |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0207282A GB0207282D0 (en) | 2002-03-27 | 2002-03-27 | Novel compounds |
GB0207282.5 | 2002-03-27 | ||
GB0207278.3 | 2002-03-27 | ||
GB0207278A GB0207278D0 (en) | 2002-03-27 | 2002-03-27 | Novel compounds |
GB0207275.9 | 2002-03-27 | ||
GB0207275A GB0207275D0 (en) | 2002-03-27 | 2002-03-27 | Novel compounds |
GB0207281A GB0207281D0 (en) | 2002-03-27 | 2002-03-27 | Novel compounds |
GB0207281.7 | 2002-03-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003080608A2 true WO2003080608A2 (en) | 2003-10-02 |
WO2003080608A3 WO2003080608A3 (en) | 2004-02-05 |
Family
ID=28457826
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/003195 WO2003080608A2 (en) | 2002-03-27 | 2003-03-25 | Quinoline and aza-indole derivatives and their use as 5-ht6 ligands |
Country Status (8)
Country | Link |
---|---|
US (1) | US20050124626A1 (en) |
EP (1) | EP1497291B1 (en) |
JP (1) | JP2005527542A (en) |
AT (1) | ATE346068T1 (en) |
AU (1) | AU2003226724A1 (en) |
DE (1) | DE60309852T2 (en) |
ES (1) | ES2277098T3 (en) |
WO (1) | WO2003080608A2 (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004074286A1 (en) * | 2003-02-14 | 2004-09-02 | Wyeth | Heterocyclyl-3-sulfonylazaindole or -azaindazole derivatives as 5-hydroxytryptamine-6 ligands |
US6825212B2 (en) | 2002-06-04 | 2004-11-30 | Wyeth | 1-(aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands |
WO2005021530A1 (en) * | 2003-08-29 | 2005-03-10 | Glaxo Group Limited | 8- (1-piperazinyl)- quinoline derivatives and their use in the treatment of cns disorders |
WO2005061498A1 (en) * | 2003-12-11 | 2005-07-07 | Aventis Pharmaceuticals Inc. | Substituted 1h-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase i epsilon |
WO2005095346A1 (en) * | 2004-03-29 | 2005-10-13 | Glaxo Group Limited | 3-((hetero)arylsulfonyl)-8-` (aminoalkyl)oxy!quinolines as 5-ht6 receptor antagonists for the treatment of cns disorders |
WO2006053785A1 (en) * | 2004-11-19 | 2006-05-26 | Glaxo Group Limited | Radiolabelled quinoline-based ligands for the 5-ht6 receptor functionality |
US7238696B2 (en) | 2003-02-14 | 2007-07-03 | Wyeth | Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands |
WO2007025798A3 (en) * | 2005-07-27 | 2007-07-26 | Hoffmann La Roche | 4-aryloxy quinoline derivatives as 5-ht6 modulators |
US7452888B2 (en) | 2002-03-27 | 2008-11-18 | Glaxo Group Limited | Quinoline derivatives and their use as 5-ht6 ligands |
US7482461B2 (en) | 2006-04-05 | 2009-01-27 | Wyeth | Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands |
US7589206B2 (en) | 2004-06-09 | 2009-09-15 | Glaxo Group Limited | Pyrrolopyridine derivatives |
US9745270B2 (en) | 2008-10-28 | 2017-08-29 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US9775829B2 (en) | 2003-07-22 | 2017-10-03 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US9808455B2 (en) | 2007-12-12 | 2017-11-07 | Axovant Sciences Gmbh | Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline |
US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US10059691B2 (en) | 2008-04-02 | 2018-08-28 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
WO2021096335A1 (en) * | 2019-11-11 | 2021-05-20 | 엠비디 주식회사 | Novel quinoline compound and use thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2334580T3 (en) * | 2005-12-15 | 2010-03-12 | F. Hoffmann-La Roche Ag | PIRROLO DERIVATIVES (2,3-C) PIRIDINE. |
RU2369600C1 (en) * | 2008-01-24 | 2009-10-10 | Андрей Александрович Иващенко | SUBSTITUTED 4-SULPHONYL-PYRAZOLES AND 3-SULPHONYL-PYRAZOLO[1,5-a]PYRIMIDINES-ANTAGONISTS OF SEROTONIN 5-HT6 RECEPTORS, ACTIVE COMPONENT, PHARMACEUTICAL COMPOSITION, MEDICINAL AGENT AND METHOD OF OBTAINING THEM |
CN104725295B (en) | 2013-12-20 | 2019-05-24 | 广东东阳光药业有限公司 | Aromatic heterocyclic derivatives and its application on drug |
CN105541693B (en) | 2014-07-08 | 2018-10-16 | 广东东阳光药业有限公司 | Aromatic heterocyclic derivatives and its application on drug |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999065906A1 (en) * | 1998-06-15 | 1999-12-23 | Allelix Biopharmaceuticals Inc. | Bicyclic piperidine and piperazine compounds having 5-ht6 receptor affinity |
WO2001012629A1 (en) * | 1999-08-12 | 2001-02-22 | Nps Allelix Corp. | Azaindoles having serotonin receptor affinity |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7943639B2 (en) * | 2002-06-20 | 2011-05-17 | Proximagen Limited | Compounds |
EP1592690A1 (en) * | 2003-02-14 | 2005-11-09 | Wyeth | Heterocyclyl-3-sulfonylazaindole or -azaindazole derivatives as 5-hydroxytryptamine-6 ligands |
-
2003
- 2003-03-25 JP JP2003578362A patent/JP2005527542A/en active Pending
- 2003-03-25 AT AT03744860T patent/ATE346068T1/en not_active IP Right Cessation
- 2003-03-25 WO PCT/EP2003/003195 patent/WO2003080608A2/en active IP Right Grant
- 2003-03-25 DE DE60309852T patent/DE60309852T2/en not_active Expired - Fee Related
- 2003-03-25 US US10/509,077 patent/US20050124626A1/en not_active Abandoned
- 2003-03-25 ES ES03744860T patent/ES2277098T3/en not_active Expired - Lifetime
- 2003-03-25 AU AU2003226724A patent/AU2003226724A1/en not_active Abandoned
- 2003-03-25 EP EP03744860A patent/EP1497291B1/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999065906A1 (en) * | 1998-06-15 | 1999-12-23 | Allelix Biopharmaceuticals Inc. | Bicyclic piperidine and piperazine compounds having 5-ht6 receptor affinity |
WO2001012629A1 (en) * | 1999-08-12 | 2001-02-22 | Nps Allelix Corp. | Azaindoles having serotonin receptor affinity |
Cited By (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7799774B2 (en) | 2002-03-27 | 2010-09-21 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US7452888B2 (en) | 2002-03-27 | 2008-11-18 | Glaxo Group Limited | Quinoline derivatives and their use as 5-ht6 ligands |
US8236947B2 (en) | 2002-03-27 | 2012-08-07 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US7977337B2 (en) | 2002-03-27 | 2011-07-12 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US7601837B2 (en) | 2002-03-27 | 2009-10-13 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US6825212B2 (en) | 2002-06-04 | 2004-11-30 | Wyeth | 1-(aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands |
US7585873B2 (en) | 2002-06-04 | 2009-09-08 | Wyeth | 1-(aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands |
US7074792B2 (en) | 2002-06-04 | 2006-07-11 | Wyeth | 1-(aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands |
US7238696B2 (en) | 2003-02-14 | 2007-07-03 | Wyeth | Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands |
US7560470B2 (en) | 2003-02-14 | 2009-07-14 | Wyeth | Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands |
WO2004074286A1 (en) * | 2003-02-14 | 2004-09-02 | Wyeth | Heterocyclyl-3-sulfonylazaindole or -azaindazole derivatives as 5-hydroxytryptamine-6 ligands |
JP2006517966A (en) * | 2003-02-14 | 2006-08-03 | ワイス | Heterocyclyl-3-sulfonylazaindole or -azaindazole derivatives as 5-hydroxytryptamine-6 ligands |
US7576087B2 (en) | 2003-02-14 | 2009-08-18 | Wyeth | Heterocyclyl-3-sulfonylazaindole or -azaindazole derivatives as 5-hydroxytryptamine-6 ligands |
US9775829B2 (en) | 2003-07-22 | 2017-10-03 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
WO2005021530A1 (en) * | 2003-08-29 | 2005-03-10 | Glaxo Group Limited | 8- (1-piperazinyl)- quinoline derivatives and their use in the treatment of cns disorders |
JP2007513950A (en) * | 2003-12-11 | 2007-05-31 | アベンティス・ファーマスーティカルズ・インコーポレイテツド | Substituted 1H-pyrrolo [3,2-b, 3,2-c, and 2,3-c] pyridine-2-carboxamides and related analogs as inhibitors of casein kinase Iε |
US7626027B2 (en) | 2003-12-11 | 2009-12-01 | Aventis Pharmaceuticals Inc | Substituted 1H-pyrrolo[2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase Iε |
WO2005061498A1 (en) * | 2003-12-11 | 2005-07-07 | Aventis Pharmaceuticals Inc. | Substituted 1h-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase i epsilon |
CN100439367C (en) * | 2003-12-11 | 2008-12-03 | 安万特药物公司 | Substituted 1H-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase lepsilon |
US7402672B2 (en) | 2003-12-11 | 2008-07-22 | Aventis Pharmaceuticals Inc. | Substituted 1H-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase lepsilon |
WO2005095346A1 (en) * | 2004-03-29 | 2005-10-13 | Glaxo Group Limited | 3-((hetero)arylsulfonyl)-8-` (aminoalkyl)oxy!quinolines as 5-ht6 receptor antagonists for the treatment of cns disorders |
US7589206B2 (en) | 2004-06-09 | 2009-09-15 | Glaxo Group Limited | Pyrrolopyridine derivatives |
WO2006053785A1 (en) * | 2004-11-19 | 2006-05-26 | Glaxo Group Limited | Radiolabelled quinoline-based ligands for the 5-ht6 receptor functionality |
WO2007025798A3 (en) * | 2005-07-27 | 2007-07-26 | Hoffmann La Roche | 4-aryloxy quinoline derivatives as 5-ht6 modulators |
JP2009502853A (en) * | 2005-07-27 | 2009-01-29 | エフ.ホフマン−ラ ロシュ アーゲー | Aryloxyquinolines and their use as 5-HT6 modulators |
US7307089B2 (en) | 2005-07-27 | 2007-12-11 | Roche Palo Alto Llc | Aryloxy quinolines and uses thereof |
US7482461B2 (en) | 2006-04-05 | 2009-01-27 | Wyeth | Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands |
US9808455B2 (en) | 2007-12-12 | 2017-11-07 | Axovant Sciences Gmbh | Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline |
US10059691B2 (en) | 2008-04-02 | 2018-08-28 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
US10787437B2 (en) | 2008-04-02 | 2020-09-29 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
US9745270B2 (en) | 2008-10-28 | 2017-08-29 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US11304932B2 (en) | 2015-07-15 | 2022-04-19 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
WO2021096335A1 (en) * | 2019-11-11 | 2021-05-20 | 엠비디 주식회사 | Novel quinoline compound and use thereof |
Also Published As
Publication number | Publication date |
---|---|
EP1497291A2 (en) | 2005-01-19 |
AU2003226724A8 (en) | 2003-10-08 |
EP1497291B1 (en) | 2006-11-22 |
DE60309852T2 (en) | 2007-06-06 |
DE60309852D1 (en) | 2007-01-04 |
ATE346068T1 (en) | 2006-12-15 |
US20050124626A1 (en) | 2005-06-09 |
AU2003226724A1 (en) | 2003-10-08 |
ES2277098T3 (en) | 2007-07-01 |
WO2003080608A3 (en) | 2004-02-05 |
JP2005527542A (en) | 2005-09-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1497291B1 (en) | Quinoline and aza-indole derivatives and their use as 5-ht6 ligands | |
US7799774B2 (en) | Quinoline derivatives and their use as 5-HT6 ligands | |
US7538121B2 (en) | Vanilloid receptor modulators | |
EP1228066A2 (en) | Sulfonamide derivatives | |
US20080214571A1 (en) | Novel compounds | |
EP1730112B1 (en) | 3-((hetero)arylsulfonyl)-8'[ (aminoalkyl)oxy]quinolines as 5-ht6 receptor antagonists for the treatment of cns disorders | |
EP1414442A1 (en) | 3-arylsulfonyl-7-piperazinyl- indoles, -benzofurans and -benzothiophenes with 5-ht6 receptor affinity for treating cns disorders | |
US7439244B2 (en) | Quinoline compounds and pharmeceutical compositions containing them | |
US20050090485A1 (en) | 7-Arylsulfonamido-2,3,4,5-tetrahydro-1h-benzo'diazepine derivatives with 5ht6 receptor affinity for the reatment of cns disorders | |
EP1660483B1 (en) | 8-(1-piperazinyl)-quinoline derivatives and their use in the treatment of cns disorders | |
Ahmed et al. | Quinoline derivatives and their use as 5-HT6 ligands |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2003744860 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10509077 Country of ref document: US Ref document number: 2003578362 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2003744860 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 2003744860 Country of ref document: EP |