JP2008513405A - メチレンジピペリジン誘導体 - Google Patents
メチレンジピペリジン誘導体 Download PDFInfo
- Publication number
- JP2008513405A JP2008513405A JP2007531711A JP2007531711A JP2008513405A JP 2008513405 A JP2008513405 A JP 2008513405A JP 2007531711 A JP2007531711 A JP 2007531711A JP 2007531711 A JP2007531711 A JP 2007531711A JP 2008513405 A JP2008513405 A JP 2008513405A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- heteroaryl
- aryl
- methyl
- piperidinyl
- 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.)
- Withdrawn
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- LRKYLKBLUJXTFL-UHFFFAOYSA-N 1-(piperidin-1-ylmethyl)piperidine Chemical class C1CCCCN1CN1CCCCC1 LRKYLKBLUJXTFL-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 35
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 111
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- 229910005965 SO 2 Inorganic materials 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- OBOLYNQLHKRMQA-UHFFFAOYSA-N C1=CC=C(C=C1)ON(C(=O)C2=CC=CC=C2OS(=O)(=O)C3=CC=CC=C3)NS(=O)(=O)C4=CC=CC=C4 Chemical compound C1=CC=C(C=C1)ON(C(=O)C2=CC=CC=C2OS(=O)(=O)C3=CC=CC=C3)NS(=O)(=O)C4=CC=CC=C4 OBOLYNQLHKRMQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 26
- 238000002360 preparation method Methods 0.000 abstract description 11
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 208000020016 psychiatric disease Diseases 0.000 abstract description 3
- 210000000653 nervous system Anatomy 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 97
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- -1 benzooxazol-2-yl Chemical group 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000007787 solid Substances 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 229960001340 histamine Drugs 0.000 description 21
- 150000002500 ions Chemical class 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000005557 antagonist Substances 0.000 description 14
- HRTRWQNFWISBIG-UHFFFAOYSA-N 4-(piperidin-4-ylmethyl)-1-propan-2-ylpiperidine Chemical compound C1CN(C(C)C)CCC1CC1CCNCC1 HRTRWQNFWISBIG-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- WCXBRTFDFRZNLD-UHFFFAOYSA-N 1-cyclobutyl-4-(piperidin-4-ylmethyl)piperidine Chemical compound C1CN(C2CCC2)CCC1CC1CCNCC1 WCXBRTFDFRZNLD-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- CFAFAIASRGBKNN-UHFFFAOYSA-N 5-[4-[(1-cyclobutylpiperidin-4-yl)methyl]piperidin-1-yl]-n-propan-2-ylpyrazine-2-carboxamide Chemical compound C1=NC(C(=O)NC(C)C)=CN=C1N1CCC(CC2CCN(CC2)C2CCC2)CC1 CFAFAIASRGBKNN-UHFFFAOYSA-N 0.000 description 8
- 102000004384 Histamine H3 receptors Human genes 0.000 description 8
- 108090000981 Histamine H3 receptors Proteins 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 8
- 230000008485 antagonism Effects 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 230000003595 spectral effect Effects 0.000 description 8
- JFKOSNRSLHVFMJ-UHFFFAOYSA-N tert-butyl 4-(piperidin-4-ylmethyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CC1CCNCC1 JFKOSNRSLHVFMJ-UHFFFAOYSA-N 0.000 description 8
- OQYUXZCXKPMJDN-UHFFFAOYSA-N 1-methyl-4-(piperidin-4-ylmethyl)piperidine Chemical compound C1CN(C)CCC1CC1CCNCC1 OQYUXZCXKPMJDN-UHFFFAOYSA-N 0.000 description 7
- PFMNQJRTADLGGT-UHFFFAOYSA-N 3-methyl-5-[5-[4-[(1-propan-2-ylpiperidin-4-yl)methyl]piperidin-1-yl]pyridin-2-yl]-1,2,4-oxadiazole Chemical compound C1CN(C(C)C)CCC1CC1CCN(C=2C=NC(=CC=2)C=2ON=C(C)N=2)CC1 PFMNQJRTADLGGT-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- MNNQIBXLAHVDDL-UHFFFAOYSA-N 5-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)C=N1 MNNQIBXLAHVDDL-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- QGWNDRXFNXRZMB-UUOKFMHZSA-K GDP(3-) Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-K 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 5
- SDAQHVUVINMOSR-UHFFFAOYSA-N 1-(cyclopropylmethyl)-4-(piperidin-4-ylmethyl)piperidine Chemical compound C1CN(CC2CC2)CCC1CC1CCNCC1 SDAQHVUVINMOSR-UHFFFAOYSA-N 0.000 description 5
- XESYQFVZWPXMEF-UHFFFAOYSA-N 1-[5-[4-[(1-propan-2-ylpiperidin-4-yl)methyl]piperidin-1-yl]pyridin-2-yl]ethanone Chemical compound C1CN(C(C)C)CCC1CC1CCN(C=2C=NC(=CC=2)C(C)=O)CC1 XESYQFVZWPXMEF-UHFFFAOYSA-N 0.000 description 5
- AVXXUFMZRHQRTK-UHFFFAOYSA-N 5-(4-bromophenyl)-3-methyl-1,2,4-oxadiazole Chemical compound CC1=NOC(C=2C=CC(Br)=CC=2)=N1 AVXXUFMZRHQRTK-UHFFFAOYSA-N 0.000 description 5
- CTNBHHKFCAFNSS-UHFFFAOYSA-N 5-(5-bromopyridin-2-yl)-3-methyl-1,2,4-oxadiazole Chemical compound CC1=NOC(C=2N=CC(Br)=CC=2)=N1 CTNBHHKFCAFNSS-UHFFFAOYSA-N 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 208000010877 cognitive disease Diseases 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- YNUMGPGJIZSXSX-UHFFFAOYSA-N 1-[5-[4-[(1-cyclobutylpiperidin-4-yl)methyl]piperidin-1-yl]pyridin-2-yl]ethanone Chemical compound C1=NC(C(=O)C)=CC=C1N1CCC(CC2CCN(CC2)C2CCC2)CC1 YNUMGPGJIZSXSX-UHFFFAOYSA-N 0.000 description 4
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- UNVRCIYSLCUMOB-UHFFFAOYSA-N 3-methyl-5-[4-[4-[(1-propan-2-ylpiperidin-4-yl)methyl]piperidin-1-yl]phenyl]-1,2,4-oxadiazole Chemical compound C1CN(C(C)C)CCC1CC1CCN(C=2C=CC(=CC=2)C=2ON=C(C)N=2)CC1 UNVRCIYSLCUMOB-UHFFFAOYSA-N 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- UEEAPQSHLNOYBM-UHFFFAOYSA-N 5-(4-bromo-3-fluorophenyl)-3-methyl-1,2,4-oxadiazole Chemical compound CC1=NOC(C=2C=C(F)C(Br)=CC=2)=N1 UEEAPQSHLNOYBM-UHFFFAOYSA-N 0.000 description 4
- GIDQEHZBYYQURN-UHFFFAOYSA-N 5-[4-[(1-propan-2-ylpiperidin-4-yl)methyl]piperidin-1-yl]pyridine-2-carbonitrile Chemical compound C1CN(C(C)C)CCC1CC1CCN(C=2C=NC(=CC=2)C#N)CC1 GIDQEHZBYYQURN-UHFFFAOYSA-N 0.000 description 4
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 4
- 208000028698 Cognitive impairment Diseases 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
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- ZAZJSJFQRJUTAM-UHFFFAOYSA-N methyl 5-[4-[(1-cyclobutylpiperidin-4-yl)methyl]piperidin-1-yl]pyrazine-2-carboxylate Chemical compound C1=NC(C(=O)OC)=CN=C1N1CCC(CC2CCN(CC2)C2CCC2)CC1 ZAZJSJFQRJUTAM-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 4
- 229960003081 probenecid Drugs 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000002821 scintillation proximity assay Methods 0.000 description 4
- ZJRKDFNEAJFWMG-UHFFFAOYSA-N tert-butyl 4-(pyridin-4-ylmethyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CC1=CC=NC=C1 ZJRKDFNEAJFWMG-UHFFFAOYSA-N 0.000 description 4
- WVNSMDASXXXKQL-UHFFFAOYSA-N tert-butyl 5-[4-[(1-propan-2-ylpiperidin-4-yl)methyl]piperidin-1-yl]pyridine-2-carboxylate Chemical compound C1CN(C(C)C)CCC1CC1CCN(C=2C=NC(=CC=2)C(=O)OC(C)(C)C)CC1 WVNSMDASXXXKQL-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- FBZVZUSVGKOWHG-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethylethanamine Chemical compound COC(C)(OC)N(C)C FBZVZUSVGKOWHG-UHFFFAOYSA-N 0.000 description 3
- JXDITEKFBWFLLS-UHFFFAOYSA-N 1-[4-[4-[(1-cyclobutylpiperidin-4-yl)methyl]piperidin-1-yl]phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N1CCC(CC2CCN(CC2)C2CCC2)CC1 JXDITEKFBWFLLS-UHFFFAOYSA-N 0.000 description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- A61P25/28—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Indole Compounds (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
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|---|---|---|---|
| GB0420831A GB0420831D0 (en) | 2004-09-17 | 2004-09-17 | Novel compounds |
| PCT/EP2005/010169 WO2006029906A1 (en) | 2004-09-17 | 2005-09-16 | Methylene dipiperidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2008513405A true JP2008513405A (ja) | 2008-05-01 |
| JP2008513405A5 JP2008513405A5 (US06653308-20031125-C00057.png) | 2008-10-16 |
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| JP2007531711A Withdrawn JP2008513405A (ja) | 2004-09-17 | 2005-09-16 | メチレンジピペリジン誘導体 |
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| EP2049472B1 (en) | 2006-06-23 | 2015-01-21 | AbbVie Bahamas Ltd. | Cyclopropyl amine derivatives as histamin h3 receptor modulators |
| US9108948B2 (en) | 2006-06-23 | 2015-08-18 | Abbvie Inc. | Cyclopropyl amine derivatives |
| US8653262B2 (en) | 2007-05-31 | 2014-02-18 | Boehringer Ingelheim International Gmbh | CCR2 receptor antagonists and uses thereof |
| PL2379525T3 (pl) | 2008-12-19 | 2016-01-29 | Centrexion Therapeutics Corp | Cykliczne pirymidyno-4-karboksamidy jako antagoniści receptora CCR2 do leczenia stanów zapalnych, astmy oraz COPD |
| US9186353B2 (en) * | 2009-04-27 | 2015-11-17 | Abbvie Inc. | Treatment of osteoarthritis pain |
| EP2477981A1 (en) * | 2009-09-14 | 2012-07-25 | Recordati Ireland Limited | Heterocyclic mglu5 antagonists |
| JP5632014B2 (ja) | 2009-12-17 | 2014-11-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ｃｃｒ２受容体アンタゴニスト及びこれらの使用 |
| CA2788721A1 (en) * | 2010-02-04 | 2011-08-11 | Timothy J. Laros | Method for treating tailings |
| EP2569295B1 (en) | 2010-05-12 | 2014-11-19 | Boehringer Ingelheim International GmbH | New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
| EP2569298B1 (en) | 2010-05-12 | 2015-11-25 | Boehringer Ingelheim International GmbH | Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
| JP5647339B2 (ja) | 2010-05-17 | 2014-12-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ｃｃｒ２アンタゴニスト及びこれらの使用 |
| EP2576542B1 (en) | 2010-05-25 | 2015-04-22 | Boehringer Ingelheim International GmbH | Cyclic amide derivatives of pyridazine-3-carboxylic acids and their use in the treatment of pulmonary, pain, immune related and cardiovascular diseases |
| US8962656B2 (en) | 2010-06-01 | 2015-02-24 | Boehringer Ingelheim International Gmbh | CCR2 antagonists |
| US8853390B2 (en) | 2010-09-16 | 2014-10-07 | Abbvie Inc. | Processes for preparing 1,2-substituted cyclopropyl derivatives |
| EP2731941B1 (en) | 2011-07-15 | 2019-05-08 | Boehringer Ingelheim International GmbH | Novel and selective ccr2 antagonists |
| WO2013151982A1 (en) | 2012-04-03 | 2013-10-10 | Arena Pharmaceuticals, Inc. | Methods and compounds useful in treating pruritus, and methods for identifying such compounds |
| EP2647377A1 (en) | 2012-04-06 | 2013-10-09 | Sanofi | Use of an h3 receptor antagonist for the treatment of alzheimer's disease |
| WO2017004537A1 (en) | 2015-07-02 | 2017-01-05 | Centrexion Therapeutics Corporation | (4-((3r,4r)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2r,6s)-6-(p-tolyl)tetrahydro-2h-pyran-2-yl)methylamino)pyrimidin-4yl)methanone citrate |
| EP3383853B1 (en) * | 2015-12-01 | 2020-11-04 | Merck Sharp & Dohme Corp. | Homobispiperidinyl derivatives as liver x receptor (lxr) beta agonists for treating e.g. alzheimer's disease |
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| JPH0418071A (ja) | 1990-05-11 | 1992-01-22 | Sumitomo Pharmaceut Co Ltd | ビスピペリジン誘導体 |
| ATE346050T1 (de) | 1998-01-27 | 2006-12-15 | Aventis Pharma Inc | Substituierte oxoazaheterocyclyl faktor xa hemmer |
| MXPA01009871A (es) | 1999-04-01 | 2002-04-24 | Pfizer Prod Inc | Aminopiridinas como inhibidores de la sorbitol deshidrogenasa. |
| MXPA02000888A (es) | 1999-07-28 | 2002-07-30 | Aventis Pharm Prod Inc | Compuestos de oxoazaheterociclilos substituidos. |
| PE20020507A1 (es) * | 2000-10-17 | 2002-06-25 | Schering Corp | Compuestos no-imidazoles como antagonistas del receptor histamina h3 |
| EP1337271B1 (en) | 2000-11-30 | 2004-11-03 | Pfizer Products Inc. | Combination of gaba agonists and sorbitol dehydrogenase inhibitors |
| AU2002253929A1 (en) * | 2001-02-08 | 2002-09-24 | Schering Corporation | Use of dual h3/m2 antagonists with a bipiperidinic structure in the treatment of cognition deficit disorders |
| US6660858B2 (en) | 2001-03-28 | 2003-12-09 | Lion Bioscience Ag | 2-aminobenzoxazole derivatives and combinatorial libraries thereof |
| US6956040B2 (en) | 2001-07-16 | 2005-10-18 | Ranbaxy Laboratories Limited | Oxazolidinone piperazinyl derivatives as potential antimicrobials |
| WO2003031432A1 (en) * | 2001-10-12 | 2003-04-17 | Novo Nordisk A/S | Substituted piperidines and their use for the treatment of diseases related to the histamine h3 receptor |
-
2004
- 2004-09-17 GB GB0420831A patent/GB0420831D0/en not_active Ceased
-
2005
- 2005-09-16 JP JP2007531711A patent/JP2008513405A/ja not_active Withdrawn
- 2005-09-16 ES ES05789636T patent/ES2326182T3/es active Active
- 2005-09-16 DE DE602005015002T patent/DE602005015002D1/de active Active
- 2005-09-16 AT AT05789636T patent/ATE433966T1/de not_active IP Right Cessation
- 2005-09-16 EP EP05789636A patent/EP1789410B1/en active Active
- 2005-09-16 WO PCT/EP2005/010169 patent/WO2006029906A1/en active Application Filing
- 2005-09-16 US US11/575,311 patent/US7638631B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1789410B1 (en) | 2009-06-17 |
| WO2006029906A1 (en) | 2006-03-23 |
| ATE433966T1 (de) | 2009-07-15 |
| US7638631B2 (en) | 2009-12-29 |
| EP1789410A1 (en) | 2007-05-30 |
| DE602005015002D1 (de) | 2009-07-30 |
| ES2326182T3 (es) | 2009-10-02 |
| GB0420831D0 (en) | 2004-10-20 |
| US20080108624A1 (en) | 2008-05-08 |
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