BRPI0612719A2 - derivados de pirazol [3,4-d] azepina como antagonistas de histamina h3 - Google Patents
derivados de pirazol [3,4-d] azepina como antagonistas de histamina h3 Download PDFInfo
- Publication number
- BRPI0612719A2 BRPI0612719A2 BRPI0612719-3A BRPI0612719A BRPI0612719A2 BR PI0612719 A2 BRPI0612719 A2 BR PI0612719A2 BR PI0612719 A BRPI0612719 A BR PI0612719A BR PI0612719 A2 BRPI0612719 A2 BR PI0612719A2
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- Prior art keywords
- mmol
- formula
- methanol
- mixture
- alkyl
- Prior art date
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- 239000003395 histamine H3 receptor antagonist Substances 0.000 title description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title 1
- 150000001538 azepines Chemical class 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 103
- 230000008569 process Effects 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 9
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 209
- -1 cyano, amino Chemical group 0.000 claims description 177
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000005418 aryl aryl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 284
- 239000005557 antagonist Substances 0.000 abstract description 7
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 208000020016 psychiatric disease Diseases 0.000 abstract description 3
- 230000000926 neurological effect Effects 0.000 abstract description 2
- 150000003217 pyrazoles Chemical class 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 747
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 448
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 174
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 132
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 108
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 96
- 229910021529 ammonia Inorganic materials 0.000 description 86
- 238000012799 strong cation exchange Methods 0.000 description 79
- 239000002904 solvent Substances 0.000 description 76
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical class N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 71
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 69
- 229910052786 argon Inorganic materials 0.000 description 66
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 57
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 49
- 238000003756 stirring Methods 0.000 description 46
- LPFTYOLVWHTSKV-UHFFFAOYSA-N 2H-azepine-6-carboxylic acid Chemical compound C1C=CC=C(C=N1)C(=O)O LPFTYOLVWHTSKV-UHFFFAOYSA-N 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 41
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 238000010992 reflux Methods 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 29
- 235000019341 magnesium sulphate Nutrition 0.000 description 29
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 27
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 19
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 16
- 235000011114 ammonium hydroxide Nutrition 0.000 description 16
- 239000012298 atmosphere Substances 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 15
- 125000002950 monocyclic group Chemical group 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 229960001340 histamine Drugs 0.000 description 13
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000002808 molecular sieve Substances 0.000 description 12
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 12
- 239000013058 crude material Substances 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 9
- 239000007983 Tris buffer Substances 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 8
- JTPZTKBRUCILQD-UHFFFAOYSA-N 1-methylimidazolidin-2-one Chemical compound CN1CCNC1=O JTPZTKBRUCILQD-UHFFFAOYSA-N 0.000 description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- KROXNGTXSOPSRS-UHFFFAOYSA-N 1-[4-(5,6,7,8-tetrahydro-4h-pyrazolo[3,4-d]azepin-2-yl)phenyl]pyrrolidin-2-one Chemical compound O=C1CCCN1C1=CC=C(N2N=C3CCNCCC3=C2)C=C1 KROXNGTXSOPSRS-UHFFFAOYSA-N 0.000 description 7
- TVUIYWDZNFGFTC-UHFFFAOYSA-N 1-benzyl-5-chloro-2,3,6,7-tetrahydroazepine-4-carbaldehyde Chemical compound C1CC(Cl)=C(C=O)CCN1CC1=CC=CC=C1 TVUIYWDZNFGFTC-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- BZJQQRCFYKSQKX-UHFFFAOYSA-N 1-(5-bromopyridin-2-yl)pyrrolidin-2-one Chemical compound N1=CC(Br)=CC=C1N1C(=O)CCC1 BZJQQRCFYKSQKX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004384 Histamine H3 receptors Human genes 0.000 description 6
- 108090000981 Histamine H3 receptors Proteins 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000005342 ion exchange Methods 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- QBLFZIBJXUQVRF-UHFFFAOYSA-N (4-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Br)C=C1 QBLFZIBJXUQVRF-UHFFFAOYSA-N 0.000 description 5
- BZQUQLBDAKYDCX-UHFFFAOYSA-N 1-[4-(6-benzyl-4,5,7,8-tetrahydropyrazolo[3,4-d]azepin-2-yl)phenyl]pyrrolidin-2-one Chemical compound O=C1CCCN1C1=CC=C(N2N=C3CCN(CC=4C=CC=CC=4)CCC3=C2)C=C1 BZQUQLBDAKYDCX-UHFFFAOYSA-N 0.000 description 5
- 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 208000010877 cognitive disease Diseases 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 5
- YNHBHIKWCYXZHS-UHFFFAOYSA-N n-[(1-benzyl-5-chloro-2,3,6,7-tetrahydroazepin-4-yl)methylidene]hydroxylamine Chemical compound C1CC(C=NO)=C(Cl)CCN1CC1=CC=CC=C1 YNHBHIKWCYXZHS-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229910052717 sulfur Chemical group 0.000 description 5
- 239000011593 sulfur Chemical group 0.000 description 5
- SWGKYHKUYIKLDC-UHFFFAOYSA-N 1-[4-(6-cyclobutyl-4,5,7,8-tetrahydropyrazolo[3,4-d]azepin-2-yl)phenyl]pyrrolidin-2-one Chemical compound O=C1CCCN1C1=CC=C(N2N=C3CCN(CCC3=C2)C2CCC2)C=C1 SWGKYHKUYIKLDC-UHFFFAOYSA-N 0.000 description 4
- JXMRRRVOKOPLCD-UHFFFAOYSA-N 1-[5-(6-benzyl-4,5,7,8-tetrahydropyrazolo[3,4-d]azepin-2-yl)pyridin-2-yl]pyrrolidin-2-one Chemical compound O=C1CCCN1C1=CC=C(N2N=C3CCN(CC=4C=CC=CC=4)CCC3=C2)C=N1 JXMRRRVOKOPLCD-UHFFFAOYSA-N 0.000 description 4
- TVIICJDDSIMWQT-UHFFFAOYSA-N 1-benzylazepan-4-one;hydrochloride Chemical compound Cl.C1CC(=O)CCCN1CC1=CC=CC=C1 TVIICJDDSIMWQT-UHFFFAOYSA-N 0.000 description 4
- WBYWWQLHAXLGPX-UHFFFAOYSA-N 1-methyl-3-[4-(5,6,7,8-tetrahydro-4h-pyrazolo[3,4-d]azepin-2-yl)phenyl]imidazolidin-2-one Chemical compound O=C1N(C)CCN1C1=CC=C(N2N=C3CCNCCC3=C2)C=C1 WBYWWQLHAXLGPX-UHFFFAOYSA-N 0.000 description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0513886.2 | 2005-07-06 | ||
| GBGB0513886.2A GB0513886D0 (en) | 2005-07-06 | 2005-07-06 | Novel compounds |
| PCT/EP2006/006613 WO2007025596A1 (en) | 2005-07-06 | 2006-07-04 | Pyrazolo [3 , 4-d] azepine derivatives as histamine h3 antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0612719A2 true BRPI0612719A2 (pt) | 2010-11-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0612719-3A BRPI0612719A2 (pt) | 2005-07-06 | 2006-07-04 | derivados de pirazol [3,4-d] azepina como antagonistas de histamina h3 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US7888347B2 (https=) |
| EP (1) | EP1899350B1 (https=) |
| JP (1) | JP5145218B2 (https=) |
| KR (1) | KR20080037651A (https=) |
| CN (1) | CN101258154B (https=) |
| AT (1) | ATE467636T1 (https=) |
| AU (1) | AU2006286897A1 (https=) |
| BR (1) | BRPI0612719A2 (https=) |
| CA (1) | CA2614232A1 (https=) |
| CR (1) | CR9622A (https=) |
| CY (1) | CY1110711T1 (https=) |
| DE (1) | DE602006014273D1 (https=) |
| DK (1) | DK1899350T3 (https=) |
| EA (1) | EA013600B1 (https=) |
| ES (1) | ES2345841T3 (https=) |
| GB (1) | GB0513886D0 (https=) |
| HR (1) | HRP20100401T1 (https=) |
| IL (1) | IL188184A0 (https=) |
| MA (1) | MA29623B1 (https=) |
| MX (1) | MX2008000383A (https=) |
| NO (1) | NO20080563L (https=) |
| PL (1) | PL1899350T3 (https=) |
| PT (1) | PT1899350E (https=) |
| SI (1) | SI1899350T1 (https=) |
| UA (1) | UA93047C2 (https=) |
| WO (1) | WO2007025596A1 (https=) |
| ZA (1) | ZA200710798B (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382174A (zh) | 2006-06-23 | 2013-11-06 | 雅培制药有限公司 | 作为组胺h3受体调节物的环丙胺衍生物 |
| US9108948B2 (en) | 2006-06-23 | 2015-08-18 | Abbvie Inc. | Cyclopropyl amine derivatives |
| KR20100059919A (ko) | 2007-09-24 | 2010-06-04 | 코멘티스, 인코포레이티드 | 치료를 위한 베타-세크레타제 억제제로서 (3-히드록시-4-아미노-부탄-2일)-3-(2-티아졸-2-일-피롤리딘-1-카르보닐) 벤즈아미드 유도체 및 관련 화합물 |
| US9186353B2 (en) * | 2009-04-27 | 2015-11-17 | Abbvie Inc. | Treatment of osteoarthritis pain |
| US8853390B2 (en) | 2010-09-16 | 2014-10-07 | Abbvie Inc. | Processes for preparing 1,2-substituted cyclopropyl derivatives |
| CN102952139B (zh) * | 2011-08-30 | 2016-08-10 | 上海药明康德新药开发有限公司 | 反式-3a-氟吡咯烷[3,4-C]并环化合物及其制备方法 |
| 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 |
| JO3407B1 (ar) | 2012-05-31 | 2019-10-20 | Eisai R&D Man Co Ltd | مركبات رباعي هيدرو بيرازولو بيريميدين |
| US9910887B2 (en) * | 2013-04-25 | 2018-03-06 | Facebook, Inc. | Variable search query vertical access |
| MX2018014034A (es) * | 2016-05-25 | 2019-08-29 | Akarna Therapeutics Ltd | Compuestos bicíclicos fusionados para el tratamiento de enfermedades. |
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| AU6018799A (en) * | 1998-09-09 | 2000-03-27 | Ishihara Sangyo Kaisha Ltd. | Fused-benzene derivatives useful as herbicides |
| JP2002542245A (ja) * | 1999-04-16 | 2002-12-10 | ノボ ノルディスク アクティーゼルスカブ | 置換イミダゾール、それらの製造および使用 |
| JP2001220390A (ja) | 2000-02-09 | 2001-08-14 | Yamanouchi Pharmaceut Co Ltd | 縮合ピラゾール誘導体 |
| ES2283768T3 (es) * | 2002-06-06 | 2007-11-01 | Novo Nordisk A/S | Hexahidropirrolo(1,2-a)piracinas, octahidropirido(1,2-a)piracinas y decahidropiracino(1,2-a)acepinas sustituidas. |
| US6770597B2 (en) | 2002-07-17 | 2004-08-03 | Ishihara Sangyo Kaisha, Ltd. | Benzohydrazide derivatives as herbicides and desiccant compositions containing them |
| JP2005537290A (ja) | 2002-07-25 | 2005-12-08 | ファルマシア・イタリア・エス・ピー・エー | キナーゼ阻害剤として活性なビシクロピラゾール類、その製造方法、およびそれを含有する薬学的組成物 |
| EP1539704A1 (en) * | 2002-08-20 | 2005-06-15 | Eli Lilly And Company | Substituted azepines as histamine h3 receptor antagonists, preparation and therapeutic uses |
| GB0224083D0 (en) | 2002-10-16 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
| GB0224557D0 (en) | 2002-10-22 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
| EP2133340B1 (en) | 2002-12-20 | 2013-01-16 | Glaxo Group Limited | Novel benzazepine derivatives |
| SI1668014T1 (sl) * | 2003-09-17 | 2009-06-30 | Janssen Pharmaceutica Nv | Kondenzirane heterociklične spojine kot modulatorji serotoninskih receptorjev |
| GB0329214D0 (en) | 2003-12-17 | 2004-01-21 | Glaxo Group Ltd | Novel compounds |
| GB0405628D0 (en) | 2004-03-12 | 2004-04-21 | Glaxo Group Ltd | Novel compounds |
| GB0408083D0 (en) | 2004-04-08 | 2004-05-12 | Glaxo Group Ltd | Novel compounds |
| WO2005123723A1 (en) | 2004-06-18 | 2005-12-29 | Glaxo Group Limited | 3-cycloalkylbenzazepines as histamine h3 antagonists |
| GB0418267D0 (en) | 2004-08-16 | 2004-09-15 | Glaxo Group Ltd | Novel compounds |
| RU2007125648A (ru) | 2004-12-07 | 2009-01-20 | Глэксо Груп Лимитед (GB) | Инденильные производные и их применение для лечения неврологических расстройств |
| US20080161289A1 (en) | 2005-03-14 | 2008-07-03 | Glaxo Group Limited | Fused Thiazole Derivatives Having Affinity for the Histamine H3 Receptor |
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2005
- 2005-07-06 GB GBGB0513886.2A patent/GB0513886D0/en not_active Ceased
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2006
- 2006-07-04 JP JP2008519862A patent/JP5145218B2/ja not_active Expired - Fee Related
- 2006-07-04 HR HR20100401T patent/HRP20100401T1/hr unknown
- 2006-07-04 AU AU2006286897A patent/AU2006286897A1/en not_active Abandoned
- 2006-07-04 AT AT06818218T patent/ATE467636T1/de active
- 2006-07-04 BR BRPI0612719-3A patent/BRPI0612719A2/pt not_active IP Right Cessation
- 2006-07-04 ES ES06818218T patent/ES2345841T3/es active Active
- 2006-07-04 PL PL06818218T patent/PL1899350T3/pl unknown
- 2006-07-04 EP EP06818218A patent/EP1899350B1/en not_active Not-in-force
- 2006-07-04 US US11/994,689 patent/US7888347B2/en not_active Expired - Fee Related
- 2006-07-04 MX MX2008000383A patent/MX2008000383A/es active IP Right Grant
- 2006-07-04 UA UAA200800190A patent/UA93047C2/ru unknown
- 2006-07-04 CN CN2006800322776A patent/CN101258154B/zh not_active Expired - Fee Related
- 2006-07-04 EA EA200800264A patent/EA013600B1/ru not_active IP Right Cessation
- 2006-07-04 WO PCT/EP2006/006613 patent/WO2007025596A1/en not_active Ceased
- 2006-07-04 DE DE602006014273T patent/DE602006014273D1/de active Active
- 2006-07-04 CA CA002614232A patent/CA2614232A1/en not_active Abandoned
- 2006-07-04 SI SI200630733T patent/SI1899350T1/sl unknown
- 2006-07-04 KR KR1020087000265A patent/KR20080037651A/ko not_active Ceased
- 2006-07-04 PT PT06818218T patent/PT1899350E/pt unknown
- 2006-07-04 DK DK06818218.7T patent/DK1899350T3/da active
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2007
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- 2007-12-17 IL IL188184A patent/IL188184A0/en unknown
- 2007-12-20 CR CR9622A patent/CR9622A/es not_active Application Discontinuation
-
2008
- 2008-01-09 MA MA30562A patent/MA29623B1/fr unknown
- 2008-01-30 NO NO20080563A patent/NO20080563L/no not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| ES2345841T3 (es) | 2010-10-04 |
| CN101258154A (zh) | 2008-09-03 |
| JP2009500366A (ja) | 2009-01-08 |
| WO2007025596A1 (en) | 2007-03-08 |
| EA200800264A1 (ru) | 2008-06-30 |
| SI1899350T1 (sl) | 2010-09-30 |
| MX2008000383A (es) | 2008-03-07 |
| CY1110711T1 (el) | 2015-06-10 |
| JP5145218B2 (ja) | 2013-02-13 |
| NO20080563L (no) | 2008-02-01 |
| EA013600B1 (ru) | 2010-06-30 |
| US7888347B2 (en) | 2011-02-15 |
| DE602006014273D1 (de) | 2010-06-24 |
| CN101258154B (zh) | 2011-01-19 |
| CR9622A (es) | 2008-04-10 |
| HRP20100401T1 (hr) | 2010-09-30 |
| IL188184A0 (en) | 2008-03-20 |
| UA93047C2 (ru) | 2011-01-10 |
| ATE467636T1 (de) | 2010-05-15 |
| DK1899350T3 (da) | 2010-09-06 |
| CA2614232A1 (en) | 2007-03-08 |
| GB0513886D0 (en) | 2005-08-10 |
| EP1899350A1 (en) | 2008-03-19 |
| PL1899350T3 (pl) | 2010-10-29 |
| PT1899350E (pt) | 2010-07-21 |
| EP1899350B1 (en) | 2010-05-12 |
| MA29623B1 (fr) | 2008-07-01 |
| AU2006286897A1 (en) | 2007-03-08 |
| ZA200710798B (en) | 2008-11-26 |
| KR20080037651A (ko) | 2008-04-30 |
| US20080176832A1 (en) | 2008-07-24 |
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