JP2009501745A - ヒスタミンh3受容体アンタゴニストおよび/または逆アゴニストとして有用なピペラジノン誘導体 - Google Patents
ヒスタミンh3受容体アンタゴニストおよび/または逆アゴニストとして有用なピペラジノン誘導体 Download PDFInfo
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- JP2009501745A JP2009501745A JP2008521869A JP2008521869A JP2009501745A JP 2009501745 A JP2009501745 A JP 2009501745A JP 2008521869 A JP2008521869 A JP 2008521869A JP 2008521869 A JP2008521869 A JP 2008521869A JP 2009501745 A JP2009501745 A JP 2009501745A
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- 239000003395 histamine H3 receptor antagonist Substances 0.000 title description 5
- 229940115480 Histamine H3 receptor antagonist Drugs 0.000 title 1
- 229940122931 Histamine H3 receptor inverse agonist Drugs 0.000 title 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 150000003839 salts Chemical class 0.000 claims abstract description 69
- 239000000203 mixture Substances 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 208000010668 atopic eczema Diseases 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 230000000172 allergic effect Effects 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 239000000938 histamine H1 antagonist Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 239000004335 litholrubine BK Substances 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- LAQGPQNMQRFDIM-UHFFFAOYSA-N 4-(2,4-difluorobenzoyl)-1-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]piperazin-2-one Chemical compound CC1CCCN1CCCOC1=CC=C(N2C(CN(CC2)C(=O)C=2C(=CC(F)=CC=2)F)=O)C=C1 LAQGPQNMQRFDIM-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 206010039083 rhinitis Diseases 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- -1 azocanyl Chemical group 0.000 description 57
- 239000000243 solution Substances 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 229960001340 histamine Drugs 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 229910021529 ammonia Inorganic materials 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- JZUHHDAETNVMRM-UHFFFAOYSA-N tert-butyl 4-[4-(3-chloropropoxy)phenyl]-3-oxopiperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(OCCCCl)C=C1 JZUHHDAETNVMRM-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 102000004384 Histamine H3 receptors Human genes 0.000 description 12
- 108090000981 Histamine H3 receptors Proteins 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 235000019253 formic acid Nutrition 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000000048 adrenergic agonist Substances 0.000 description 8
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 8
- JZJSDNNVKIOJTL-UHFFFAOYSA-N benzyl 3-oxo-4-(4-piperidin-4-yloxyphenyl)piperazine-1-carboxylate Chemical compound C1CN(C=2C=CC(OC3CCNCC3)=CC=2)C(=O)CN1C(=O)OCC1=CC=CC=C1 JZJSDNNVKIOJTL-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 7
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 239000000812 cholinergic antagonist Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 6
- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- GTYRZGSKTZTHMF-UHFFFAOYSA-N tert-butyl 4-(4-hydroxyphenyl)-3-oxopiperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(O)C=C1 GTYRZGSKTZTHMF-UHFFFAOYSA-N 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
- 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 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
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- 229940044551 receptor antagonist Drugs 0.000 description 5
- 239000002464 receptor antagonist Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- PTEHWBIWKFLJPG-UHFFFAOYSA-N tert-butyl 3-oxo-4-(4-phenylmethoxyphenyl)piperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC=C1 PTEHWBIWKFLJPG-UHFFFAOYSA-N 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- RSEVXQZGASWIBI-UHFFFAOYSA-N 1-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.O=C1CNCCN1C(C=C1)=CC=C1OCCCN1CCCCC1 RSEVXQZGASWIBI-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 206010028735 Nasal congestion Diseases 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910005965 SO 2 Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical class C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
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- 125000002393 azetidinyl group Chemical group 0.000 description 4
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 4
- XAOOIHDKTRQTDN-UHFFFAOYSA-N benzyl 4-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-3-oxopiperazine-1-carboxylate Chemical compound C1CN(C=2C=CC(OC3CCN(CC3)C3CCC3)=CC=2)C(=O)CN1C(=O)OCC1=CC=CC=C1 XAOOIHDKTRQTDN-UHFFFAOYSA-N 0.000 description 4
- QVXXPPMVOROFJZ-UHFFFAOYSA-N benzyl 4-[4-(1-cyclopentylpiperidin-4-yl)oxyphenyl]-3-oxopiperazine-1-carboxylate Chemical compound C1CN(C=2C=CC(OC3CCN(CC3)C3CCCC3)=CC=2)C(=O)CN1C(=O)OCC1=CC=CC=C1 QVXXPPMVOROFJZ-UHFFFAOYSA-N 0.000 description 4
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- 238000001816 cooling Methods 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
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- 239000007788 liquid Substances 0.000 description 4
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- YUPJYYHTOTVBEP-UHFFFAOYSA-N methyl 4-(2-methoxyethylcarbamoyl)benzoate Chemical compound COCCNC(=O)C1=CC=C(C(=O)OC)C=C1 YUPJYYHTOTVBEP-UHFFFAOYSA-N 0.000 description 4
- PUXOBYVATJHYLR-UHFFFAOYSA-N methyl 4-(azetidine-1-carbonyl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C(=O)N1CCC1 PUXOBYVATJHYLR-UHFFFAOYSA-N 0.000 description 4
- WPECEEMTRHDRSU-UHFFFAOYSA-N methyl 4-[2-methoxyethyl(methyl)carbamoyl]benzoate Chemical compound COCCN(C)C(=O)C1=CC=C(C(=O)OC)C=C1 WPECEEMTRHDRSU-UHFFFAOYSA-N 0.000 description 4
- 125000002757 morpholinyl group Chemical group 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 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
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
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- 230000006920 protein precipitation Effects 0.000 description 4
- 230000002889 sympathetic effect Effects 0.000 description 4
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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/18—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0514812.7A GB0514812D0 (en) | 2005-07-19 | 2005-07-19 | Compounds |
| PCT/EP2006/007036 WO2007009741A1 (en) | 2005-07-19 | 2006-07-17 | Piperazinone derivatives useful as histamine h3 receptor antagonists and/or inverse agonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2009501745A true JP2009501745A (ja) | 2009-01-22 |
| JP2009501745A5 JP2009501745A5 (enExample) | 2009-09-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| JP2008521869A Pending JP2009501745A (ja) | 2005-07-19 | 2006-07-17 | ヒスタミンh3受容体アンタゴニストおよび/または逆アゴニストとして有用なピペラジノン誘導体 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20080275027A1 (enExample) |
| EP (1) | EP1906964A1 (enExample) |
| JP (1) | JP2009501745A (enExample) |
| GB (1) | GB0514812D0 (enExample) |
| WO (1) | WO2007009741A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009501744A (ja) * | 2005-07-19 | 2009-01-22 | グラクソ グループ リミテッド | 化合物 |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5698887B2 (ja) | 2007-05-03 | 2015-04-08 | セファロン、インク. | (r)−2−メチルピロリジンおよび(s)−2−メチルピロリジンならびにその酒石酸塩を調製するための方法 |
| CN101855211B (zh) | 2007-11-13 | 2013-06-12 | 大正制药株式会社 | 苯基吡唑衍生物 |
| US20090131417A1 (en) * | 2007-11-20 | 2009-05-21 | Letavic Michael A | Substituted pyridyl amide compounds as modulators of the histamine h3 receptor |
| CA2706328C (en) * | 2007-11-20 | 2016-04-19 | Janssen Pharmaceutica N.V. | Cycloalkyloxy- and heterocycloalkyloxypyridine compounds as modulators of the histamine h3 receptor |
| JP5791500B2 (ja) | 2008-05-23 | 2015-10-07 | パンミラ ファーマシューティカルズ,エルエルシー. | 5−リポキシゲナーゼ活性化タンパク質阻害剤 |
| JP5740838B2 (ja) * | 2009-05-12 | 2015-07-01 | 大正製薬株式会社 | フェニルピラゾール誘導体 |
| WO2013151982A1 (en) | 2012-04-03 | 2013-10-10 | Arena Pharmaceuticals, Inc. | Methods and compounds useful in treating pruritus, and methods for identifying such compounds |
| US20170100385A1 (en) | 2014-05-12 | 2017-04-13 | Glaxosmithkline Intellectual Property (No. 2) Limited | Pharmaceutical compositions comprising danirixin for treating infectious diseases |
| JP6633618B2 (ja) | 2014-08-21 | 2020-01-22 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 強力なrock阻害剤としてのタイドバックのベンズアミド誘導体 |
| US10821106B2 (en) | 2015-08-21 | 2020-11-03 | Srx Cardio, Llc | Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity |
| HK1260897A1 (zh) | 2015-08-21 | 2019-12-27 | Portola Pharmaceuticals, Inc. | 使用四氢异喹啉小分子来结合并调节pcsk9的蛋白活性的组合物和方法 |
| US10568882B2 (en) | 2015-08-21 | 2020-02-25 | Srx Cardio, Llc | Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use |
| WO2017147328A1 (en) | 2016-02-23 | 2017-08-31 | Portola Pharmaceuticals, Inc. | Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9) |
| CN108486155A (zh) * | 2018-04-27 | 2018-09-04 | 中国医学科学院输血研究所 | 构建Doxycycline/Mifepristone诱导过表达的带有荧光蛋白标记基因的双诱导表达载体 |
| WO2021191875A1 (en) | 2020-03-26 | 2021-09-30 | Glaxosmithkline Intellectual Property Development Limited | Cathepsin inhibitors for preventing or treating viral infections |
| US12115154B2 (en) | 2020-12-16 | 2024-10-15 | Srx Cardio, Llc | Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006223A1 (en) * | 2000-07-13 | 2002-01-24 | Abbott Laboratories | 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications |
| GB0224084D0 (en) * | 2002-10-16 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
| WO2004037800A1 (en) * | 2002-10-22 | 2004-05-06 | Glaxo Group Limited | Aryloxyalkylamine derivates as h3 receptor ligands |
| GB0308333D0 (en) * | 2003-04-10 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
-
2005
- 2005-07-19 GB GBGB0514812.7A patent/GB0514812D0/en not_active Ceased
-
2006
- 2006-07-17 WO PCT/EP2006/007036 patent/WO2007009741A1/en not_active Ceased
- 2006-07-17 EP EP06762670A patent/EP1906964A1/en not_active Withdrawn
- 2006-07-17 JP JP2008521869A patent/JP2009501745A/ja active Pending
- 2006-07-17 US US11/995,929 patent/US20080275027A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009501744A (ja) * | 2005-07-19 | 2009-01-22 | グラクソ グループ リミテッド | 化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1906964A1 (en) | 2008-04-09 |
| US20080275027A1 (en) | 2008-11-06 |
| GB0514812D0 (en) | 2005-08-24 |
| WO2007009741A1 (en) | 2007-01-25 |
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