CA2548039A1 - 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5 - Google Patents
5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5 Download PDFInfo
- Publication number
- CA2548039A1 CA2548039A1 CA002548039A CA2548039A CA2548039A1 CA 2548039 A1 CA2548039 A1 CA 2548039A1 CA 002548039 A CA002548039 A CA 002548039A CA 2548039 A CA2548039 A CA 2548039A CA 2548039 A1 CA2548039 A1 CA 2548039A1
- Authority
- CA
- Canada
- Prior art keywords
- tetrazol
- fluoro
- compounds
- cyano
- benzonitrile
- 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.)
- Abandoned
Links
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 title claims 6
- 239000003446 ligand Substances 0.000 title description 5
- LYOJURLAGFMSOQ-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)pyridine-3-carbonitrile Chemical class N#CC1=CC=CN=C1C1=NNN=N1 LYOJURLAGFMSOQ-UHFFFAOYSA-N 0.000 title 1
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- 238000000034 method Methods 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 230000008569 process Effects 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims description 40
- -1 chloro, bromo, iodo, methoxymethyl Chemical group 0.000 claims description 35
- 102000005962 receptors Human genes 0.000 claims description 30
- 108020003175 receptors Proteins 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 230000004913 activation Effects 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 230000001404 mediated effect Effects 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 208000002193 Pain Diseases 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- 150000001412 amines Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 208000020016 psychiatric disease Diseases 0.000 claims description 7
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 6
- 208000012902 Nervous system disease Diseases 0.000 claims description 6
- 208000025966 Neurological disease Diseases 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- XUICYRFPJOHKGW-UHFFFAOYSA-N 3-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]-5-(methoxymethyl)benzonitrile Chemical compound COCC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 XUICYRFPJOHKGW-UHFFFAOYSA-N 0.000 claims description 3
- 208000000094 Chronic Pain Diseases 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 208000005298 acute pain Diseases 0.000 claims description 3
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- AQGCLHIWIZUYPV-UHFFFAOYSA-N 3-(difluoromethoxy)-5-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]benzonitrile Chemical compound FC(F)OC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 AQGCLHIWIZUYPV-UHFFFAOYSA-N 0.000 claims description 2
- RNUMNUGYLBCCEU-UHFFFAOYSA-N 3-(ethylamino)-5-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]benzonitrile Chemical compound CCNC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 RNUMNUGYLBCCEU-UHFFFAOYSA-N 0.000 claims description 2
- SAWSSPISYVVUPP-UHFFFAOYSA-N 3-[5-(5-chloropyridin-2-yl)tetrazol-2-yl]-5-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(Cl)=CC=2)=C1 SAWSSPISYVVUPP-UHFFFAOYSA-N 0.000 claims description 2
- WQWFBZQKKNQGSY-UHFFFAOYSA-N 3-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]-5-(2-methoxyethoxy)benzonitrile Chemical compound COCCOC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 WQWFBZQKKNQGSY-UHFFFAOYSA-N 0.000 claims description 2
- UYRBZIYJANWFLG-UHFFFAOYSA-N 3-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]-5-(trifluoromethoxy)benzonitrile Chemical compound N1=CC(F)=CC=C1C1=NN(C=2C=C(C=C(OC(F)(F)F)C=2)C#N)N=N1 UYRBZIYJANWFLG-UHFFFAOYSA-N 0.000 claims description 2
- NDUDAERNMBXBRF-UHFFFAOYSA-N 3-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]-5-iodobenzonitrile Chemical compound N1=CC(F)=CC=C1C1=NN(C=2C=C(C=C(I)C=2)C#N)N=N1 NDUDAERNMBXBRF-UHFFFAOYSA-N 0.000 claims description 2
- HVPQJXMCMHHZHI-UHFFFAOYSA-N 3-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]-5-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 HVPQJXMCMHHZHI-UHFFFAOYSA-N 0.000 claims description 2
- UQCQFXVIFGQFRL-UHFFFAOYSA-N 3-fluoro-5-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]benzonitrile Chemical compound N1=CC(F)=CC=C1C1=NN(C=2C=C(C=C(F)C=2)C#N)N=N1 UQCQFXVIFGQFRL-UHFFFAOYSA-N 0.000 claims description 2
- IFOXWHQFTSCNQB-UHFFFAOYSA-N 5-aminopyridine-2-carbonitrile Chemical group NC1=CC=C(C#N)N=C1 IFOXWHQFTSCNQB-UHFFFAOYSA-N 0.000 claims description 2
- QJWNJNTZXKFBKG-UHFFFAOYSA-N 5-fluoro-2-[2-(3-fluoro-5-methoxyphenyl)tetrazol-5-yl]pyridine Chemical compound COC1=CC(F)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 QJWNJNTZXKFBKG-UHFFFAOYSA-N 0.000 claims description 2
- BHXHRMVSUUPOLX-UHFFFAOYSA-N 5-fluoropyridine-2-carbonitrile Chemical compound FC1=CC=C(C#N)N=C1 BHXHRMVSUUPOLX-UHFFFAOYSA-N 0.000 claims description 2
- RFXRMGATCPIUGX-UHFFFAOYSA-N 6-[2-(3-cyano-5-fluorophenyl)tetrazol-5-yl]pyridine-3-carbonitrile Chemical compound FC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(=CC=2)C#N)=C1 RFXRMGATCPIUGX-UHFFFAOYSA-N 0.000 claims description 2
- WLBDEBUYJGERNR-UHFFFAOYSA-N 6-[5-(3-cyano-5-fluorophenyl)tetrazol-2-yl]pyridine-3-carbonitrile Chemical compound FC1=CC(C#N)=CC(C2=NN(N=N2)C=2N=CC(=CC=2)C#N)=C1 WLBDEBUYJGERNR-UHFFFAOYSA-N 0.000 claims description 2
- 238000000354 decomposition reaction Methods 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- 230000000063 preceeding effect Effects 0.000 claims 4
- FBUHFQUZAYMTOM-UHFFFAOYSA-N pyridin-2-ylcyanamide Chemical compound N#CNC1=CC=CC=N1 FBUHFQUZAYMTOM-UHFFFAOYSA-N 0.000 claims 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims 3
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- GTANSZNHJARZLJ-UHFFFAOYSA-N 3-[2-(5-chloropyridin-2-yl)tetrazol-5-yl]-5-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC(C2=NN(N=N2)C=2N=CC(Cl)=CC=2)=C1 GTANSZNHJARZLJ-UHFFFAOYSA-N 0.000 claims 1
- TUVRMXKPGAJUGF-UHFFFAOYSA-N 3-amino-5-[5-(5-fluoropyridin-2-yl)tetrazol-2-yl]benzonitrile Chemical compound NC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(F)=CC=2)=C1 TUVRMXKPGAJUGF-UHFFFAOYSA-N 0.000 claims 1
- CKISQUUTFPIQAX-UHFFFAOYSA-N 3-fluoro-5-[2-(5-fluoropyridin-2-yl)tetrazol-5-yl]benzonitrile Chemical compound N1=CC(F)=CC=C1N1N=C(C=2C=C(C=C(F)C=2)C#N)N=N1 CKISQUUTFPIQAX-UHFFFAOYSA-N 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 238000010792 warming Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 14
- 235000013350 formula milk Nutrition 0.000 description 60
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 15
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 210000000111 lower esophageal sphincter Anatomy 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 230000004044 response Effects 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000000556 agonist Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229930195712 glutamate Natural products 0.000 description 10
- 229940049906 glutamate Drugs 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 230000009466 transformation Effects 0.000 description 10
- 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 9
- 239000007995 HEPES buffer Substances 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 8
- 210000003169 central nervous system Anatomy 0.000 description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 8
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 8
- 210000002569 neuron Anatomy 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 229940116592 central nervous system diagnostic radiopharmaceuticals Drugs 0.000 description 7
- 230000005284 excitation Effects 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- MTVWFVDWRVYDOR-UHFFFAOYSA-N 3,4-Dihydroxyphenylglycol Chemical compound OCC(O)C1=CC=C(O)C(O)=C1 MTVWFVDWRVYDOR-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001649 bromium compounds Chemical class 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 239000012954 diazonium Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 229960000367 inositol Drugs 0.000 description 6
- 150000004694 iodide salts Chemical class 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000000844 transformation Methods 0.000 description 6
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 150000001805 chlorine compounds Chemical class 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 208000002551 irritable bowel syndrome Diseases 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- HOOWCUZPEFNHDT-UHFFFAOYSA-N DHPG Natural products OC(=O)C(N)C1=CC(O)=CC(O)=C1 HOOWCUZPEFNHDT-UHFFFAOYSA-N 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
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 102100036834 Metabotropic glutamate receptor 1 Human genes 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000007975 buffered saline Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000001989 diazonium salts Chemical class 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 108010014719 metabotropic glutamate receptor type 1 Proteins 0.000 description 4
- 210000001589 microsome Anatomy 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 3
- FJHVWOFTAJCONF-UHFFFAOYSA-N 3-amino-5-fluorobenzonitrile Chemical compound NC1=CC(F)=CC(C#N)=C1 FJHVWOFTAJCONF-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical group OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 208000027520 Somatoform disease Diseases 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 102000014384 Type C Phospholipases Human genes 0.000 description 3
- 108010079194 Type C Phospholipases Proteins 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000005620 boronic acid group Chemical class 0.000 description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000003228 microsomal effect Effects 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 208000027753 pain disease Diseases 0.000 description 3
- 230000001242 postsynaptic effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000007306 turnover Effects 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 3
- AIJYIAZVEZVFPM-UHFFFAOYSA-N 3-cyano-5-(methoxymethyl)benzoic acid Chemical compound COCC1=CC(C#N)=CC(C(O)=O)=C1 AIJYIAZVEZVFPM-UHFFFAOYSA-N 0.000 description 2
- FMTHBNWQSHPQID-UHFFFAOYSA-N 3-methoxycarbonyl-5-(methoxymethyl)benzoic acid Chemical compound COCC1=CC(C(O)=O)=CC(C(=O)OC)=C1 FMTHBNWQSHPQID-UHFFFAOYSA-N 0.000 description 2
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 2
- IACCXWQKIQUVFQ-UHFFFAOYSA-N 5-fluoropyridine-2-carbaldehyde Chemical compound FC1=CC=C(C=O)N=C1 IACCXWQKIQUVFQ-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 108010000722 Excitatory Amino Acid Transporter 1 Proteins 0.000 description 2
- 102100031563 Excitatory amino acid transporter 1 Human genes 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 102000018899 Glutamate Receptors Human genes 0.000 description 2
- 108010027915 Glutamate Receptors Proteins 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- 206010019196 Head injury Diseases 0.000 description 2
- 241000167880 Hirundinidae Species 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- 238000006350 Schiemann fluorination reaction Methods 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 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 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- RWMLVMBSSADKRA-UHFFFAOYSA-L bismuth(2+);diacetate Chemical class [Bi+2].CC([O-])=O.CC([O-])=O RWMLVMBSSADKRA-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 201000006549 dyspepsia Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000037906 ischaemic injury Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229940073584 methylene chloride Drugs 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 150000003906 phosphoinositides Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000003518 presynaptic effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- XQVSJIPPURSOPX-UHFFFAOYSA-N tert-butyl n-[3-cyano-5-(methoxymethyl)phenyl]carbamate Chemical compound COCC1=CC(NC(=O)OC(C)(C)C)=CC(C#N)=C1 XQVSJIPPURSOPX-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 150000008648 triflates Chemical class 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- FSXLZUKMPRDBFO-UHFFFAOYSA-N (2-hydroxy-6-iodophenyl) 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=C(O)C=CC=C1I FSXLZUKMPRDBFO-UHFFFAOYSA-N 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- UHTQHHLSGVOGQR-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-4-ium-1-yl]ethanesulfonate Chemical compound OCCN1CCN(CCS(O)(=O)=O)CC1.OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 UHTQHHLSGVOGQR-UHFFFAOYSA-N 0.000 description 1
- JSHUFVVQNDIRNR-UHFFFAOYSA-N 3-[5-(5-bromopyridin-2-yl)tetrazol-2-yl]-5-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC(Br)=CC=2)=C1 JSHUFVVQNDIRNR-UHFFFAOYSA-N 0.000 description 1
- OSYFNYKMHRONSM-UHFFFAOYSA-N 3-[5-(5-bromopyridin-2-yl)tetrazol-2-yl]-5-fluorobenzonitrile 6-[2-(3-cyano-5-fluorophenyl)tetrazol-5-yl]pyridine-3-carbonitrile Chemical compound BrC=1C=CC(=NC1)C=1N=NN(N1)C=1C=C(C#N)C=C(C1)F.C(#N)C=1C=C(C=C(C1)F)N1N=C(N=N1)C1=NC=C(C#N)C=C1 OSYFNYKMHRONSM-UHFFFAOYSA-N 0.000 description 1
- CQEIAPVTSGNQNP-UHFFFAOYSA-N 3-amino-5-(methoxymethyl)benzonitrile Chemical compound COCC1=CC(N)=CC(C#N)=C1 CQEIAPVTSGNQNP-UHFFFAOYSA-N 0.000 description 1
- ZJQWXXSZXSTKHW-UHFFFAOYSA-N 3-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1.OOC(=O)C1=CC=CC(Cl)=C1 ZJQWXXSZXSTKHW-UHFFFAOYSA-N 0.000 description 1
- NNUSSUPIQZLYJW-UHFFFAOYSA-N 3-fluoro-5-(5-pyridin-2-yltetrazol-2-yl)benzonitrile Chemical compound FC1=CC(C#N)=CC(N2N=C(N=N2)C=2N=CC=CC=2)=C1 NNUSSUPIQZLYJW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YYLBDBOSXXSZQQ-UHFFFAOYSA-N 5-chloropyridine-2-carbaldehyde Chemical compound ClC1=CC=C(C=O)N=C1 YYLBDBOSXXSZQQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- ROWIMUXQCOPLPJ-UHFFFAOYSA-N COC(C1=CC(C(=O)OC)=CC(=C1)CBr)=O.COC(C1=CC(C(=O)OC)=CC(=C1)COC)=O Chemical compound COC(C1=CC(C(=O)OC)=CC(=C1)CBr)=O.COC(C1=CC(C(=O)OC)=CC(=C1)COC)=O ROWIMUXQCOPLPJ-UHFFFAOYSA-N 0.000 description 1
- 101100181929 Caenorhabditis elegans lin-3 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241001432959 Chernes Species 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102000006541 Ionotropic Glutamate Receptors Human genes 0.000 description 1
- 108010008812 Ionotropic Glutamate Receptors Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 201000008197 Laryngitis Diseases 0.000 description 1
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 1
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000036366 Sensation of pressure Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000006565 aromatic formylation reaction Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001626 borono group Chemical group [H]OB([*])O[H] 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 1
- 125000006006 difluoroethoxy group Chemical group 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SVXVCUVXGMLDJC-UHFFFAOYSA-N dimethyl 5-(bromomethyl)benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(CBr)=CC(C(=O)OC)=C1 SVXVCUVXGMLDJC-UHFFFAOYSA-N 0.000 description 1
- JMGDEIHUEMPLRO-UHFFFAOYSA-N dimethyl 5-(hydroxymethyl)benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(CO)=CC(C(=O)OC)=C1 JMGDEIHUEMPLRO-UHFFFAOYSA-N 0.000 description 1
- RQOUGOGXDAONID-UHFFFAOYSA-N dimethyl 5-(methoxymethyl)benzene-1,3-dicarboxylate Chemical compound COCC1=CC(C(=O)OC)=CC(C(=O)OC)=C1 RQOUGOGXDAONID-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 206010016165 failure to thrive Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- MSCIUSDXJVEIBZ-UHFFFAOYSA-M hydron;tetramethylazanium;difluoride Chemical compound [H+].[F-].[F-].C[N+](C)(C)C MSCIUSDXJVEIBZ-UHFFFAOYSA-M 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940028435 intralipid Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 230000020796 long term synaptic depression Effects 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- OASUQWPGKKANGK-UHFFFAOYSA-N methyl 3-carbamoyl-5-(methoxymethyl)benzoate Chemical compound COCC1=CC(C(N)=O)=CC(C(=O)OC)=C1 OASUQWPGKKANGK-UHFFFAOYSA-N 0.000 description 1
- WCQQTAZPFPQSLX-UHFFFAOYSA-N methyl 3-cyano-5-(methoxymethyl)benzoate Chemical compound COCC1=CC(C#N)=CC(C(=O)OC)=C1 WCQQTAZPFPQSLX-UHFFFAOYSA-N 0.000 description 1
- BBBFDXOHXIUUGE-UHFFFAOYSA-N methyl 3-cyano-5-(methoxymethyl)benzoate (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate Chemical compound FC(C(=O)OC(C(F)(F)F)=O)(F)F.COC(C1=CC(=CC(=C1)COC)C#N)=O BBBFDXOHXIUUGE-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 101150006061 neur gene Proteins 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007472 neurodevelopment Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical class OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- KEYZUMLVDCHSTP-UHFFFAOYSA-N pyridin-2-ylmethyl acetate Chemical compound CC(=O)OCC1=CC=CC=N1 KEYZUMLVDCHSTP-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- LFZRLONXXIASQC-UHFFFAOYSA-M sodium 5-fluoropyridine-2-carbonitrile nitrite Chemical compound [Na+].[O-]N=O.Fc1ccc(nc1)C#N LFZRLONXXIASQC-UHFFFAOYSA-M 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 238000000956 solid--liquid extraction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 230000004462 vestibulo-ocular reflex Effects 0.000 description 1
- 230000031836 visual learning Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Addiction (AREA)
- Vascular Medicine (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53063303P | 2003-12-19 | 2003-12-19 | |
| US60/530,633 | 2003-12-19 | ||
| PCT/US2004/041401 WO2005066155A1 (en) | 2003-12-19 | 2004-12-13 | 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2548039A1 true CA2548039A1 (en) | 2005-07-21 |
Family
ID=34748746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002548039A Abandoned CA2548039A1 (en) | 2003-12-19 | 2004-12-13 | 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US20070255061A1 (https=) |
| EP (1) | EP1713791B1 (https=) |
| JP (1) | JP2007514790A (https=) |
| KR (1) | KR20060126993A (https=) |
| CN (1) | CN1906187A (https=) |
| AR (1) | AR046768A1 (https=) |
| AT (1) | ATE393767T1 (https=) |
| AU (1) | AU2004312342A1 (https=) |
| BR (1) | BRPI0417308A (https=) |
| CA (1) | CA2548039A1 (https=) |
| DE (1) | DE602004013469T9 (https=) |
| ES (1) | ES2303969T3 (https=) |
| IL (1) | IL175909A0 (https=) |
| MX (1) | MXPA06006674A (https=) |
| NO (1) | NO20062533L (https=) |
| RU (1) | RU2006118021A (https=) |
| TW (1) | TW200524602A (https=) |
| UY (1) | UY28685A1 (https=) |
| WO (1) | WO2005066155A1 (https=) |
| ZA (1) | ZA200604681B (https=) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7723362B2 (en) * | 2004-01-08 | 2010-05-25 | Syngenta Crop Protection, Inc. | Pesticidal heterocyclic dihaloallyl compounds |
| AR058807A1 (es) | 2005-09-29 | 2008-02-27 | Astrazeneca Ab | 5-(fenilisoxazoletoxi)-triazol-3-il piridinas sustituidas, para el tratamiento de trastornos mediados por el receptor mglur5 |
| US8349852B2 (en) | 2009-01-13 | 2013-01-08 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
| US20120095056A1 (en) * | 2009-03-19 | 2012-04-19 | Neurosearch A/S | 2,5-disubstituted tetrazole derivatives and their use as nicotinic acetylcholine receptor modulators |
| WO2011073298A1 (en) * | 2009-12-18 | 2011-06-23 | Neurosearch A/S | Tetrazole derivatives as nicotinic acetylcholine receptor modulators |
| US20120309792A1 (en) * | 2009-12-18 | 2012-12-06 | Neurosearch A/S | Tetrazole derivatives as nicotinic acetylcholine receptor modulators |
| WO2011092290A1 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists |
| AR080056A1 (es) | 2010-02-01 | 2012-03-07 | Novartis Ag | Derivados de ciclohexil-amida como antagonistas de los receptores de crf |
| EP2531490B1 (en) | 2010-02-02 | 2014-10-15 | Novartis AG | Cyclohexyl amide derivatives as crf receptor antagonists |
| GB201312800D0 (en) | 2013-07-17 | 2013-08-28 | Heptares Therapeutics Ltd | mGlu5 modulators |
| WO2016001452A1 (en) | 2014-07-04 | 2016-01-07 | Universität Zürich | Compounds, in particular for use in the treatment of a disease or condition for which a bromodomain inhibitor is indicated |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6660753B2 (en) * | 1999-08-19 | 2003-12-09 | Nps Pharmaceuticals, Inc. | Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists |
| CN1853630A (zh) * | 2001-02-21 | 2006-11-01 | Nps制药公司 | 杂多环化合物及其在亲代谢的谷氨酸受体拮抗剂中的应用 |
| DE60226756D1 (de) * | 2001-10-04 | 2008-07-03 | Merck & Co Inc | Heteroarylsubstituierte tetrazolmodulatoren des metabotropischen glutamatrezeptors-5 |
-
2004
- 2004-12-13 BR BRPI0417308-2A patent/BRPI0417308A/pt not_active IP Right Cessation
- 2004-12-13 US US10/582,051 patent/US20070255061A1/en not_active Abandoned
- 2004-12-13 AT AT04813689T patent/ATE393767T1/de not_active IP Right Cessation
- 2004-12-13 ES ES04813689T patent/ES2303969T3/es not_active Expired - Lifetime
- 2004-12-13 WO PCT/US2004/041401 patent/WO2005066155A1/en not_active Ceased
- 2004-12-13 CN CNA2004800406448A patent/CN1906187A/zh active Pending
- 2004-12-13 CA CA002548039A patent/CA2548039A1/en not_active Abandoned
- 2004-12-13 RU RU2006118021/04A patent/RU2006118021A/ru not_active Application Discontinuation
- 2004-12-13 DE DE602004013469T patent/DE602004013469T9/de not_active Expired - Fee Related
- 2004-12-13 MX MXPA06006674A patent/MXPA06006674A/es unknown
- 2004-12-13 JP JP2006545760A patent/JP2007514790A/ja active Pending
- 2004-12-13 AU AU2004312342A patent/AU2004312342A1/en not_active Abandoned
- 2004-12-13 KR KR1020067011449A patent/KR20060126993A/ko not_active Withdrawn
- 2004-12-13 EP EP04813689A patent/EP1713791B1/en not_active Expired - Lifetime
- 2004-12-16 TW TW093139143A patent/TW200524602A/zh unknown
- 2004-12-16 AR ARP040104711A patent/AR046768A1/es unknown
- 2004-12-17 UY UY28685A patent/UY28685A1/es unknown
-
2006
- 2006-05-25 IL IL175909A patent/IL175909A0/en unknown
- 2006-06-01 NO NO20062533A patent/NO20062533L/no not_active Application Discontinuation
- 2006-06-07 ZA ZA200604681A patent/ZA200604681B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU2006118021A (ru) | 2007-12-10 |
| NO20062533L (no) | 2006-09-19 |
| AU2004312342A1 (en) | 2005-07-21 |
| AR046768A1 (es) | 2005-12-21 |
| IL175909A0 (en) | 2008-02-09 |
| CN1906187A (zh) | 2007-01-31 |
| UY28685A1 (es) | 2005-06-30 |
| EP1713791A1 (en) | 2006-10-25 |
| DE602004013469T9 (de) | 2009-09-24 |
| KR20060126993A (ko) | 2006-12-11 |
| BRPI0417308A (pt) | 2007-09-11 |
| HK1095598A1 (en) | 2007-05-11 |
| MXPA06006674A (es) | 2007-04-16 |
| ES2303969T3 (es) | 2008-09-01 |
| ATE393767T1 (de) | 2008-05-15 |
| DE602004013469T2 (de) | 2009-06-18 |
| EP1713791B1 (en) | 2008-04-30 |
| ZA200604681B (en) | 2007-04-25 |
| US20070255061A1 (en) | 2007-11-01 |
| TW200524602A (en) | 2005-08-01 |
| WO2005066155A1 (en) | 2005-07-21 |
| DE602004013469D1 (de) | 2008-06-12 |
| JP2007514790A (ja) | 2007-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2890981C (en) | Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn.alpha. responses | |
| JP5828201B2 (ja) | ナフタレン誘導体 | |
| CA2930060C (en) | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses | |
| NZ548693A (en) | Polyheterocyclic compounds and their use as metabotropic glutamate receptor antagonists | |
| EP1406877A1 (en) | Heterocyclic amines for the treatment of conditions associated with gsk-3 | |
| KR20130056345A (ko) | 피리딘 화합물 및 그의 용도 | |
| JP2009536209A (ja) | Ｍｇｌｕｒ５モジュレーターｉ | |
| CA2650255A1 (en) | Mglur5 modulators v | |
| CA2548039A1 (en) | 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5 | |
| JP2009536211A (ja) | Ｍｇｌｕｒ５モジュレーターｉｉｉ | |
| KR20040015716A (ko) | Ｃｒｆ1 조절자로서의 5-치환된-2-아릴피리딘 | |
| US20060235024A1 (en) | Acetylinic piperazine compounds and their use as metabotropic glutamate receptor antagonists | |
| US20050004130A1 (en) | New metabotropic glutamate receptor compounds | |
| US9078899B2 (en) | Pyrazolyl-based carboxamides II | |
| US7205411B2 (en) | Aminopyridine derivatives as mGluR5 antagonists | |
| HK1095598B (en) | 5-fluoro-and chloro-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5 | |
| US20090111823A1 (en) | Aminopyridine derivatives as modulators of mglur5 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |