CN1260226C - 用作mGluR1拮抗剂的四氢-(苯并或噻吩并)-氮杂䓬-吡嗪和三嗪衍生物 - Google Patents
用作mGluR1拮抗剂的四氢-(苯并或噻吩并)-氮杂䓬-吡嗪和三嗪衍生物 Download PDFInfo
- Publication number
- CN1260226C CN1260226C CNB018222099A CN01822209A CN1260226C CN 1260226 C CN1260226 C CN 1260226C CN B018222099 A CNB018222099 A CN B018222099A CN 01822209 A CN01822209 A CN 01822209A CN 1260226 C CN1260226 C CN 1260226C
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- chr
- azepine
- benzo
- 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.)
- Expired - Fee Related
Links
- 239000005557 antagonist Substances 0.000 title claims description 8
- 102100036834 Metabotropic glutamate receptor 1 Human genes 0.000 title claims description 7
- 108010014719 metabotropic glutamate receptor type 1 Proteins 0.000 title description 5
- 150000003918 triazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 230000001684 chronic effect Effects 0.000 claims abstract description 8
- 230000001154 acute effect Effects 0.000 claims abstract description 6
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 107
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 94
- BVCRYZCZHIUGTH-UHFFFAOYSA-N triazine-4-carbonitrile Chemical compound N#CC1=CC=NN=N1 BVCRYZCZHIUGTH-UHFFFAOYSA-N 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- -1 m-pyridyl Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000012434 nucleophilic reagent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002981 neuropathic effect Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 8
- 101710086716 Metabotropic glutamate receptor 1 Proteins 0.000 claims 4
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 abstract description 11
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 abstract description 11
- 238000011282 treatment Methods 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 3
- 208000012902 Nervous system disease Diseases 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 208000025966 Neurological disease Diseases 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 125000000217 alkyl group Chemical group 0.000 description 28
- 239000000203 mixture Substances 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 15
- 230000009467 reduction Effects 0.000 description 14
- 238000009834 vaporization Methods 0.000 description 14
- 230000008016 vaporization Effects 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- PHNQOKOZTVTGPL-UHFFFAOYSA-N 2h-thieno[3,2-b]azepine Chemical compound C1=CC=NC2=CCSC2=C1 PHNQOKOZTVTGPL-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical group [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229960002989 glutamic acid Drugs 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical class ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- XOXCGVGVMDZKLG-UHFFFAOYSA-N 1,2,4-triazine-6-carbonitrile Chemical compound N#CC1=CN=CN=N1 XOXCGVGVMDZKLG-UHFFFAOYSA-N 0.000 description 3
- GFQBSQXXHYLABK-UHFFFAOYSA-N 2-aminopropanediamide Chemical compound NC(=O)C(N)C(N)=O GFQBSQXXHYLABK-UHFFFAOYSA-N 0.000 description 3
- WGFCNCNTGOFBBF-UHFFFAOYSA-N 2-bromopyrazine Chemical class BrC1=CN=CC=N1 WGFCNCNTGOFBBF-UHFFFAOYSA-N 0.000 description 3
- OMCZEQIPFNFVEW-UHFFFAOYSA-N 3-bromo-5-(2-hydroxyethylamino)pyrazine-2-carbonitrile Chemical compound OCCNC1=CN=C(C#N)C(Br)=N1 OMCZEQIPFNFVEW-UHFFFAOYSA-N 0.000 description 3
- LCRXVZUADRMZHU-UHFFFAOYSA-N 3-bromo-5-chloropyrazine-2-carbonitrile Chemical compound ClC1=CN=C(C#N)C(Br)=N1 LCRXVZUADRMZHU-UHFFFAOYSA-N 0.000 description 3
- PVMFSFJXLROPKO-UHFFFAOYSA-N 3-chloro-5-ethyl-6-methylpyrazine-2-carbonitrile Chemical compound CCC1=NC(Cl)=C(C#N)N=C1C PVMFSFJXLROPKO-UHFFFAOYSA-N 0.000 description 3
- SDLFAEGTVBPHBK-UHFFFAOYSA-N 3-chloropyrazine-2-carbonitrile Chemical compound ClC1=NC=CN=C1C#N SDLFAEGTVBPHBK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 150000003921 pyrrolotriazines Chemical class 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JEKVPDBFXZHQRQ-UHFFFAOYSA-N 2h-thieno[2,3-d]azepin-2-ol Chemical compound C1=NC=CC2=CC(O)SC2=C1 JEKVPDBFXZHQRQ-UHFFFAOYSA-N 0.000 description 2
- XNLQAQYLXYAYNH-UHFFFAOYSA-N 3-chloro-6-ethyl-5-methylpyrazine-2-carbonitrile Chemical compound CCC1=NC(C#N)=C(Cl)N=C1C XNLQAQYLXYAYNH-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 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
- NFJPXNNWFCJQSO-UHFFFAOYSA-N C(C)C1=C(NC(C(=N1)C1=CC=CC=C1C(=O)N)=O)C Chemical class C(C)C1=C(NC(C(=N1)C1=CC=CC=C1C(=O)N)=O)C NFJPXNNWFCJQSO-UHFFFAOYSA-N 0.000 description 2
- GINUIUYFNFEWCL-UHFFFAOYSA-N CC=1NC(C(=NC1C1=CC=CC=C1)C1=CC=CC=C1C(=O)N)=O Chemical class CC=1NC(C(=NC1C1=CC=CC=C1)C1=CC=CC=C1C(=O)N)=O GINUIUYFNFEWCL-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010008748 Chorea Diseases 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010019196 Head injury Diseases 0.000 description 2
- 208000010496 Heart Arrest Diseases 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 206010057852 Nicotine dependence Diseases 0.000 description 2
- 208000021957 Ocular injury Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- 208000020339 Spinal injury Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000025569 Tobacco Use disease Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000012148 binding buffer Substances 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 230000003925 brain function Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 208000012601 choreatic disease Diseases 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003825 glutamate receptor antagonist Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 206010027175 memory impairment Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229940032007 methylethyl ketone Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000004081 narcotic agent Substances 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- XEEVLJKYYUVTRC-UHFFFAOYSA-N oxomalonic acid Chemical compound OC(=O)C(=O)C(O)=O XEEVLJKYYUVTRC-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- 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 1
- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- NKDRKWBQTPTBNL-UHFFFAOYSA-N 2-(triazin-4-yl)benzamide Chemical class NC(=O)C1=CC=CC=C1C1=CC=NN=N1 NKDRKWBQTPTBNL-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- NAHHNSMHYCLMON-UHFFFAOYSA-N 2-pyridin-3-ylethanamine Chemical compound NCCC1=CC=CN=C1 NAHHNSMHYCLMON-UHFFFAOYSA-N 0.000 description 1
- FSVRTOKNIQGMQP-UHFFFAOYSA-N 3-amino-5-chloropyrazine-2-carbonitrile Chemical compound NC1=NC(Cl)=CN=C1C#N FSVRTOKNIQGMQP-UHFFFAOYSA-N 0.000 description 1
- ASOXJSLMSXXLFK-UHFFFAOYSA-N 3-chloro-5-methyl-6-phenylpyrazine-2-carbonitrile Chemical compound CC1=NC(Cl)=C(C#N)N=C1C1=CC=CC=C1 ASOXJSLMSXXLFK-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- BPZIFGKPYYGCPV-UHFFFAOYSA-N C(C)C=1NC(C(=NC1C)C1=CC=CC=C1C(=O)N)=O Chemical class C(C)C=1NC(C(=NC1C)C1=CC=CC=C1C(=O)N)=O BPZIFGKPYYGCPV-UHFFFAOYSA-N 0.000 description 1
- GLNJJSZTPYVBEC-UHFFFAOYSA-N C(C)N1C(C(=NC=C1C)C1=CC=CC=C1C(=O)N)=O Chemical class C(C)N1C(C(=NC=C1C)C1=CC=CC=C1C(=O)N)=O GLNJJSZTPYVBEC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 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 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 description 1
- 102100036837 Metabotropic glutamate receptor 2 Human genes 0.000 description 1
- 102100038352 Metabotropic glutamate receptor 3 Human genes 0.000 description 1
- 102100038354 Metabotropic glutamate receptor 4 Human genes 0.000 description 1
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 description 1
- 102100038300 Metabotropic glutamate receptor 6 Human genes 0.000 description 1
- 102100038294 Metabotropic glutamate receptor 7 Human genes 0.000 description 1
- 102100037636 Metabotropic glutamate receptor 8 Human genes 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- RNJCXDJXPXWMDK-UHFFFAOYSA-N [AlH3].COCCO[Na] Chemical compound [AlH3].COCCO[Na] RNJCXDJXPXWMDK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001411 amidrazones Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling 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
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 1
- 108010038445 metabotropic glutamate receptor 3 Proteins 0.000 description 1
- 108010038422 metabotropic glutamate receptor 4 Proteins 0.000 description 1
- 108010038450 metabotropic glutamate receptor 6 Proteins 0.000 description 1
- 108010038449 metabotropic glutamate receptor 7 Proteins 0.000 description 1
- 108010038448 metabotropic glutamate receptor 8 Proteins 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002265 sensory receptor cell Anatomy 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- ZNJHFNUEQDVFCJ-UHFFFAOYSA-M sodium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OCCN1CCN(CCS(O)(=O)=O)CC1 ZNJHFNUEQDVFCJ-UHFFFAOYSA-M 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- 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
-
- 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
- A61P25/36—Opioid-abuse
-
- 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
- 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
- A61P9/10—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
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Addiction (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及通式(I)所示的化合物及其可药用盐,其中R<sup>1</sup>、R<sup>2</sup>、R<sup>3</sup>、R<sup>4</sup>、X和Y如说明书中所定义。本发明还涉及含有这些化合物的药物及其制备方法。该化合物对代谢型谷氨酸受体具有亲和性,因此可用于治疗或预防急性和/或慢性神经病学障碍。
Description
本发明涉及通式I的外消旋和旋光形式的1,2,4,5-四氢-苯并[d]氮杂_-吡嗪和三嗪衍生物和1,2,4,5-四氢-噻吩并[d]氮杂_-吡嗪和三嗪衍生物及其可药用盐:
其中
R1 表示氢、低级烷基、低级链烯基或未取代的苯基或在间位或对位
被一个或多个选自低级烷基、低级烷氧基或卤素的取代基取代的
苯基,
或者如果X是-N=或=N-,R1不存在;
R2 表示氢、低级烷基、低级链烯基、=O、-S-低级烷基,
-SO2-低级烷基或
-OR、-O(CHR)m+1-OR、-NR2、-NH-NR2、-N(R)(CHR)m+1-OR,
-N(R)(CHR)m-吡啶基基、-N(R)(CHR)n-(C3-C6)环烷基,
-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-低级烷基;
m 是1、2、3、4、5或6;
n 是0、1、2、3、4或5;
R 表示氢、低级烷基或低级链烯基,并且如果存在一个以上的R,它
们是彼此独立的;
X 表示-N=、=N-、>C=或=C<;并且虚线可以是键,Y 表示-CH=CH-、-CH=CR3-、-CR3=CH-、-CR3=CR4-或S;并且R3、R4彼此独立地表示氢、低级烷基、低级烷氧基或卤素,条件是如果Y
表示亚乙烯基,则在整个苯环上只存在一个R3基团和一个R4基
团。
我们惊奇地发现通式I的化合物是代谢型谷氨酸受体(metabotropicglutamate receptors)的拮抗剂。
在中枢神经系统(CNS),刺激的传导是通过由神经元释放的神经递质与神经受体之间的相互作用而发生的。
L-谷氨酸是CNS中最常见的神经递质,在大量的生理学过程中起着重要作用。谷氨酸依赖型刺激物受体分为两大组。第一大组形成配体控制的离子通道。代谢型谷氨酸受体(mGluR)属于第二大组,并且属于G-蛋白偶联的受体家族。
目前,已知有8种不同的mGluR成员,其中的一些甚至还有亚型。根据结构参数、不同的第二信使信号传导途径以及对低分子量化合物的不同亲和性,可将这8种受体再分成3个小组:mGluR1和mGluR5属于第I组,mGluR2和mGluR3属于第II组,mGluR4、mGluR6、mGluR7和mGluR8属于第III组。
第I组代谢型谷氨酸受体的配体可用于治疗或预防急性和/或慢性神经病学障碍例如癫痫、中风、慢性和急性疼痛、精神病、精神分裂症、阿尔茨海默病、认知障碍和记忆缺陷。
就此而言,其它可以治疗的适应症是由旁路手术或移植、脑供血不足、脊髓损伤、头部损伤、怀孕引起的缺氧、心脏停跳和低血糖引起的脑功能不足。其它可以治疗的适应症是杭廷顿舞蹈症、肌萎缩性侧索硬化症(ALS)、AIDS引起的痴呆、眼损伤、视网膜病、特发性帕金森病或由药物引起的帕金森病以及导致谷氨酸缺乏功能的情况例如肌肉痉挛、惊厥、偏头痛、尿失禁、尼古丁成瘾、麻醉药成瘾、焦虑、呕吐、运动障碍和抑郁。
本发明的目的是式I化合物及其可药用盐及其用作药物活性物质的用途。制备上述物质的方法和基于本发明化合物的药物及其生产方法以及本发明的化合物在控制或预防上述类型的疾病和生产相应药物中的用途也是本发明的目的。
在本发明的范围内,优选的式I化合物是具有下列通式的外消旋和旋光形式的化合物及其可药用盐:
其中
R1 表示氢、低级烷基、低级链烯基或未取代的苯基或在间位或对位
被一个或多个选自低级烷基、低级烷氧基或卤素的取代基取代的
苯基,
或者如果X是-N=或=N-,R1不存在;
R2 表示氢、低级烷基、低级链烯基、=O、-S-低级烷基,
-SO2-低级烷基或
-OR、-O(CHR)m+1-OR、-NR2、-NH-NR2、-N(R)(CHR)m+1-OR,
-N(R)(CHR)m-吡啶基、-N(R)(CHR)n-(C3-C6)环烷基,
-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-低级烷
基;
m 是1、2、3、4、5或6;
n 是0、1、2、3、4或5;
R 表示氢、低级烷基或低级链烯基,并且如果存在一个以上的R,
它们是彼此独立的;
X 表示-N=、=N-、>C=或=C<;并且
虚线可以是键。
在本发明的范围内,优选的式I-A化合物是如下化合物,其中R1不存在且X是-N=或=N-;并且R2是-NR2、-NH-NR2、-N(R)(CHR)m+1-OR、-N(R)(CHR)m-吡啶基,-N(R)(CHR)n-(C3-C6)环烷基、-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-低级烷基。
下面是这样的化合物的例子:
3-氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
3-(环丙基甲基-氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
3-(2-羟基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
(RS)-3-(2-羟基-丙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
3-肼基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
{2-[6-氰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-3-基氨基]-乙基}-氨基甲酸叔丁酯或
3-(2-吡啶-3-基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈。
特别优选的是如下式I-A的化合物,其中
R1不存在且X是-N=或=N-;并且
R2表示-N(R)(CHR)m+1-OR、-N(R)(CHR)m-吡啶基或-N(R)(CHR)n-(C3-C6)环烷基。
这样的化合物的例子如下:
3-(环丙基甲基-氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
3-(2-羟基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氨杂_-3-基)-[1,2,4]三嗪-6-甲腈,
(RS)-3-(2-羟基-丙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈或
3-(2-吡啶-3-基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈。
还优选其中的X表示>C=或=C<且R1和R2是低级烷基的式I化合物。
下面是这样的化合物的例子:
5-乙基-6-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈或6-乙基-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈。
特别优选的是其中的X表示>C=或=C<且R1表示乙基的式I化合物。
6-乙基-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈是这样的化合物的一个例子。
还优选其中的X表示>C=或=C<且R1表示未取代的苯基或在间位或对位被一个或多个选自低级烷基、低级烷氧基或卤素的取代基取代的苯基的式I化合物。
这样的化合物的例子是5-甲基-6-苯基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈。
其它优选的化合物是其中的X表示>C=或=C<且R2表示-N(R)(CHR)m+1-OR(R彼此独立地表示氢、低级烷基或低级链烯基)的化合物。
5-(2-羟基-乙基氨基)-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈是这样的化合物的一个例子。
在本说明书中使用的术语“低级烷基”是指含有1-7个碳子、优选1-4个碳原子的直链或支链的烃残基,例如甲基、乙基、正丙基、异丙基等。
在本说明书中使用的术语“低级链烯基”是指含有2-7个碳原子、优选2-4个碳原子的直链或支链的不饱和烃残基。
术语“低级烷氧基”是指连接到氧上的如上所定义的低级烷基。优选的烷氧基是甲氧基或乙氧基。
术语“环烷基”是指含有3至6个碳原子的饱和的碳环基团,优选环丙基、环戊基或环己基。
术语“卤素”包括氟、氯、溴和碘。
术语“在间位或对位被一个或多个选自低级烷基、低级烷氧基或卤素的取代基取代的苯基”是指在相对于连接到式I化合物的吡嗪环碳原子之一上的碳环原子的对位和/或间位被一个或多个选自低级烷基、低级烷氧基或卤素的取代基取代的同素六元芳环。
通式I的化合物及其可药用盐可通过如下方法生产:
a)将式I-2的化合物
与亲核试剂反应得到式I-1的化合物
其中R21表示-OR、-O(CHR)m+1-OR、-NR2、-NH-NR2、-N(R)(CHR)m+1-OR、-N(R)(CHR)m-吡啶基、-N(R)(CHR)n-(C3-C6)环烷基、-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-低级烷基,并且,如果需要的话,
将式I-1化合物中的R21官能团转化成另-种官能团以得到式I-1的另一种化合物,
并且,如果需要的话,
将式I-1化合物转化成可药用盐;或者
b)将式II-1的化合物
其中R22表示烷基,
与式III的化合物反应
得到式I-3的化合物
并且,如果需要,
将式I-3的化合物转化成可药用盐;或者
c)将式II-2的化合物
其中R5表示卤素,
与式III的化合物反应
得到式I-4的化合物
并且,如果需要,
将式I-4化合物中的R2官能团转化成另一种官能团得到式I-4的另一种化合物,
并且,如果需要,
将式I-4的化合物转化成可药用盐。
3-甲硫基-5-(1,2,4,5-四氢-苯并-或噻吩并-氮杂_-3-基)-[1,2,4]三嗪-6-甲腈(I-2)通过在碱如三乙胺或乙基-二异丙基胺的存在下、在溶剂如N,N-二甲 基甲酰胺、二甲基亚砜、甲基-乙基酮、乙醇、二噁烷或四氢呋喃中、在10至50℃下通过将3-(甲硫基)-5-氯-6-氰基-1,2,4-三嗪(J.J.Huang,J.Org.Chem.1985,50,2293-2298)与四氢-苯并-或噻吩并-氮杂_化合物III、例如2,3,4,5-四氢-1H-苯并[d]氮杂_盐酸盐(J.Heterocycl.Chem.1971,8(5),779-83)反应来制备。
化合物I-2中的Me-S-基团被任选取代的N-亲核试剂取代的反应可以在水、乙醇、N,N-二甲基甲酰胺、二甲基亚砜、1,2-二甲氧基乙烷、优选二噁烷中在升高的温度、优选100℃至160℃下进行。
在使用碱诸如氢化钠或氢化钾将相应的醇转化成醇盐之后,化合物I-2中的Me-S-基团被任选取代的O-亲核试剂取代的反应可以在惰性溶剂如醚类诸如1,2-二甲氧基乙烷或二噁烷中,在室温至120℃下进行。
O-和N-亲核试剂的官能团化还可以起到保护功能。因此,可以将R21-取代基的其它部分进行化学修饰,例如通过文献中记载的方法除去N-保护基诸如叔丁氧基羰基。
通式I-1的化合物还可通过按照已知的氧化方法(例如用3-氯过苯甲酸的二氯甲烷溶液)将硫醚I-2氧化成相应的砜,随后用硫醇盐、醇盐、胺或含水碱例如碳酸钠或碳酸氢钠进行处理来制备,由此得到基团R21。
其中的R22表示低级烷基的通式I-3的化合物可以通过在碱如三乙胺或乙基-二异丙基胺的存在下、在溶剂如N,N-二甲基甲酰胺、二甲基亚砜、甲基-乙基酮、乙醇、二噁烷或四氢呋喃中、在10至50℃下将中间体II-1与四氢-苯并-或噻吩并-氮杂_化合物III、例如2,3,4,5-四氢-1H-苯并[d]氮杂_盐酸盐(J.Heterocycl.Chem.1971,8(5),779-83)反应来制备。
中间体II-1可以按照与J.Org.Chem.1972,37(24),3958-3960中所述的方法相类似的方法来合成,将相应的氨基腙IV和氧代丙二酸甲酯或乙酯V进行缩合、接着进行酯VI的氨解、最后进行酰胺VII的脱水以及将羟基用氯取代(方案1)。
方案1
通式I-4的化合物
可以通过方案2、3和4所示的、如下所述的方法来制备。
将其中的R6和R7都彼此独立地表示氢、未取代的或取代的苯基、低级烷基或低级链烯基的1,2-二羰基化合物VIII与2-氨基-丙二酸二酰胺IX按照J.Amer.Chem.Soc.1949,71,78-81中的描述,在含水碱的存在下在0℃至60℃下、或者在溶剂如水或醇中在不存在碱的条件下在室温至120℃下反应形成两种3-氧代-3,4-二氢-吡嗪-2-甲酸酰胺Xa和Xb。在三乙胺或二乙基苯胺的存在下在40℃至120℃下用三氯氧化磷和任选地加入的五氯化磷分别处理Xa和Xb或者处理二者的混合物得到3-氯-吡嗪-2-甲腈II-3a和II-3b(方案2)。
方案2
将3-氯-吡嗪-2-甲腈II-3a和II-3b或者分别地、或者以混合物的形式与四氢-苯并-或噻吩并-氮杂_化合物III或其盐酸盐在溶剂如N,N-二甲基甲酰胺、乙腈、丙酮或二甲基亚砜中在碱如碳酸钾或叔胺诸如二异丙基-乙基胺的存在下在室温至80℃下发生反应形成所需的3-(四氢-苯并-或噻吩并-氮杂_-3-基)-吡嗪-2-甲腈I-5a和I-5b,可通过已知方法例如色谱法或结晶法将其分离。
在另一种方法中(方案3),式II-4的溴代吡嗪衍生物通过如下方法制备:将O-甲苯磺酰基肟基丙二腈XI与式XII的吗啉代烯胺(其中的R11表示低级烷基或低级链烯基)在碱如吡啶、三乙胺或二异丙基-乙基胺的存在下在惰性溶剂如乙醚、四氢呋喃或N,N-二甲基甲酰胺中在-20℃至60℃下反应得到(吗啉代链烯基亚氨基)丙二腈XIII(Helv.Chim.Acta 1986,49,793-802)来制备。将(吗啉代链烯基亚氨基)丙二腈XIII在室温至80℃下用氢溴酸在乙酸中进行处理引起生成溴代吡嗪II-4的环化反应(Helv.Chim.Acta 1990,73,1210-1214)。
方案3
将溴代吡嗪II-4与四氢-苯并或噻吩并-氮杂_化合物III或其盐酸盐在溶剂如N,N-二甲基甲酰胺、乙腈、丙酮或二甲基亚砜中在碱如碳酸钾或叔胺如二异丙基-乙基胺的存在下在室温至80℃下反应形成所需的3-(四氢-苯并-或噻吩并-氮杂_-3-基)-吡嗪-2-甲腈I-6。
式I-7的3-(四氢-苯并-或噻吩并-氮杂_-3-基)-吡嗪-2-甲腈可按照方案4制备。
在溶剂如乙腈或N,N-二甲基甲酰胺中、在溴化铜(II)的存在下在室温至95℃下用亚硝酸叔丁酯重氮化3-氨基-5-氯-2-氰基-吡嗪XIV(J.Org.Chem.1975,40,2341-2347)得到3-溴-5-氯-2-氰基-吡嗪II-5。将3-溴-5-氯-2-氰基-吡嗪II-5与1当量伯胺或仲胺反应得到其中的氯原子或溴原子被胺部分取代的两种产物。如果反应利用伯胺R8NH2在溶剂如二噁烷或四氢呋喃中在碱如三乙胺或二异丙基乙基胺的存在下、优选在室温下进行,则可以以合理的选择性得到氯原子被取代的化合物II-6。在第二步类似的反应中,将四氢-苯并-或噻吩并-氮杂_化合物III或其盐酸盐与II-6在溶剂如N,N-二甲基甲酰胺、四氢呋喃、二噁烷、乙腈、丙酮或二甲基亚砜中以及在碱如碳酸钾或叔胺如二异丙基-乙基胺的存在下在室温至80℃下反应得到化合物I-7。
方案4
取代的或未取代的1,2,4,5-四氢-苯并[d]氮杂_化合物III
可以按照欧洲专利申请EP 1 074 549 A2(2001)所述的方法制备。其中的R3和R4=H的5,6,7,8-四氢-4H-噻吩并[2,3-d]氮杂_是已知的(J.Heterocyclic Chem.1985,22,1011)。在噻吩环中带有取代基的类似的5,6,7,8-四氢-4H-噻吩并[2,3-d]氮杂_化合物可以按照与方案5中概述的方法相类似的方法制备。将在仲氮原子上带有优选是甲苯磺酰基氧基的保护官能团的前体酰氯XV在惰性溶剂如1,2-二氯乙烷、二氯甲烷或硝基苯中在Lewis酸催化剂如三氯化铝、四氯化锡或五氯化磷的存在下在-40℃至80℃下进行环化得到保护的酮XVI。通过用二(甲氧基乙氧基)氢化铝钠在甲苯中在回流下处理以同时将酮官能团还原并除去N-甲苯磺酰基保护官能团而得到羟基噻吩并[2,3-d]氮杂_XVII。在乙酸中在盐酸的存在下在室温至100℃下,用氯化亚锡将羟基噻吩并[2,3-d]氮杂_XVII进一步还原成5,6,7,8-四氢-4H-噻吩并[2,3-d]氮杂_XVIII。
方案5
制备通式I的化合物的方法更详细地记载于实施例1至15中。
可药用盐可以方便地按照本领域已知的方法并且根据被转化成盐的化合物的性质来生产。无机酸或有机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸或柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等适于形成式I的碱性化合物的可药用盐。含有碱金属或碱土金属例如钠、钾、钙、镁等、碱性胺或碱性氨基酸的化合物适于形成式I的酸性化合物的可药用盐。
如上所述,式I化合物及其可药用盐是代谢型谷氨酸受体拮抗剂,因此可用于治疗或预防由代谢型谷氨酸受体拮抗剂介导的疾病。式I化合物可用于治疗或预防急性和/或慢性神经障碍例如癫痫、中风、慢性和急性疼痛、精神病、精神分裂症、阿尔茨海默病、认知障碍和记忆缺陷。其它可以治疗的适应症是由旁路手术或移植、脑供血不足、脊髓损伤、头部损伤、怀孕引起的缺氧、心脏停跳和低血糖引起的脑功能不足。其它可以治疗的适应症是杭廷顿舞蹈症、ALS、AIDS引起的痴呆、眼损伤、视网膜病、特发性帕金森病或由药物引起的帕金森病以及导致谷氨酸缺乏功能的情况例如肌肉痉挛、惊厥、偏头痛、尿失禁、尼古丁成瘾、麻醉药成瘾、焦虑、呕吐、运动障碍和抑郁。该化合物尤其可用于治疗疼痛和偏头痛。
本发明的化合物是第I组mGluR的拮抗剂。它们的药理学活性可用如下方法进行测试:
用于鉴定mGluR 1拮抗特性的结合试验
用含氚的1-乙基-2-甲基-6-氧代-4-(1,1,2-三氚代-1,2,4,5-四氢-苯并[d]氮杂_-3-基)-1,6-二氢-嘧啶-5-甲腈进行的结合试验(欧洲专利申请EP 1 074549 A2):将HEK 293细胞用大鼠的mGluR1a受体瞬时转染。收集细胞并用PBS洗涤3次。将细胞沉积物在-80℃下冷冻。从用大鼠的mGluR1a受体转染的HEK 293细胞制备膜,在重新悬浮于HEPES NaOH 20mM,pH=7.4的结合缓冲液中之后,以10μg蛋白质/试验用于结合实验。以3nM 的最终浓度使用1-乙基-2-甲基-6-氧代-4-(1,1,2-三氚代-1,2,4,5-四氢-苯并[d]氮杂_-3-基)-1,6-二氢-嘧啶-5-甲腈(S.A 33.4Ci/mmol)。与不同浓度的潜在的抑制剂一起在室温下保温1小时,然后将保温的物质过滤到预先在0.1%的PEI中保温1小时的GF/B玻璃纤维滤纸上并用1ml冷的结合缓冲液洗涤3次。使用Topcount β计数器计数留在unifilter 96上的放射性。在校正非特异性结合后,将数据标准化并利用符合抑制曲线的4参数逻辑方程式计算IC50值。
优选化合物的IC50值为0.001-10.0μmol/l(B-IC50)。
下表中表示出了优选化合物的某些具体的活性数据:
实施例号 | B-IC50(μM) | |
3-(2-甲氧基-乙氧基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 1 | 3.0 |
3-氨基-5-(1,2,4,5-四氢-苯并[d]-氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 2 | 0.027 |
3-二甲基氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 3 | 1.38 |
3-(环丙基甲基-氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 4 | 0.005 |
3-(2-羟基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 5 | 0.031 |
(RS)-3-(2-羟基-丙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 6 | 0.027 |
3-肼基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 7 | 0.37 |
{2-[6-氰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-3-基氨基]-乙基}-氨基甲酸叔丁酯 | 8 | 0.027 |
3-(2-吡啶-3-基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈 | 9 | 0.029 |
6-乙基-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈 | 12 | 0.006 |
5-乙基-6-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈 | 12 | 0.103 |
3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈 | 13 | 0.47 |
5-甲基-6-苯基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈 | 14 | 0.045 |
5-(2-羟基-乙基氨基)-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈 | 15 | 0.5 |
式I化合物及其可药用盐可以以例如药物制剂的形式用作药物。药物制剂可以以例如片剂、包衣片、糖衣丸、硬和软明胶胶囊、溶液剂、乳液或混悬液的形式口服给药。但是,也可以以例如栓剂的形式直肠给药或者以例如注射溶液的形式胃肠外给药。
可将式I化合物及其可药用盐与药物惰性的无机或有机载体一起加工生产药物制剂。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等可用作片剂、包衣片剂、糖衣丸和硬明胶胶囊的载体。软明胶胶囊的适宜载体是,例如植物油、蜡、脂肪以及半固体和液体多元醇(然而,根据活性成分的性质,在软明胶胶囊的情况下通常不需要载体)。生产溶液剂和糖浆的适宜载体材料是,例如水、多元醇、蔗糖、转化糖、葡萄糖等。辅剂诸如醇、多元醇、甘油、植物油等可用于式I化合物的水溶性盐的注射水溶液。用于栓剂的适宜载体是例如天然或硬化油、蜡、脂肪和半液体或液体多元醇等。
另外,药物制剂可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂和抗氧化剂。它们还可以含有其它有治疗价值的物质。
如上所述,含有式I化合物或其可药用盐和治疗惰性的赋形剂的药物也是本发明的目的,并且生产所述药物的方法也是本发明的目的,该方法包括将一种或多种式I化合物或其可药用盐和,如果需要的话,一种或多种其它有治疗价值的物质以及一种或多种治疗惰性载体一起制成盖仑剂量形式。
剂量可以在宽的限度内变化,当然,在每一具体情况下,均应适合于个体的需要。一般地,对于所有上述的适应症,口服或胃肠外给药的有效剂量为0.01-20mg/kg/天,优选剂量为0.1-10mg/kg/天。对于体重为70kg的成人,每日剂量相应地为0.7-1400mg/天,优选7至700mg/天。
最后,如上所述,式I化合物及其可药用盐在制备药物、特别是用于控制或预防上述类型的急性和/或慢性神经病学障碍的药物中的用途也是本发明的目的。
提供以下实施例来说明本发明。不应该将它们认为是对本发明范围的限制,它们仅仅是本发明的代表性的例子。
实施例1
3-(2-甲氧基-乙氧基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲
腈
a)5-氯-3-甲硫基-[1,2,4]三嗪-6-甲腈
将500mg(2.7mmol)3-甲硫基-5-氧代-4,5-二氢-[1,2,4]三嗪-6-甲酸酰胺(J.J.Huang,J.Org.Chem.1985,50,2293-2298;H.Wang等人,Hua HsuehHsueh Pao 1964,30(2),183-192;CA Vol.61,8311b)的38ml(408mmol)三氯氧化磷溶液加热回流1.5小时。将深褐色反应混合物冷却后,减压蒸发过量的三氯氧化磷。为了破坏残余的三氯氧化磷并中和反应混合物,将形成的红褐色油状残余物溶于15ml甲苯,然后将溶液加入到冰冷的碳酸氢钠饱和水溶液中。将有机相用100ml二氯甲烷稀释,与水相分离,用硫酸钠干燥并减压蒸发。得到褐色油状的5-氯-3-甲硫基-[1,2,4]三嗪-6-甲腈,其不经进一步纯化即可用于随后的反应。
b)3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈
将395mg(2.7mmol)2,3,4,5-四氢-1H-3-苯并氮杂_盐酸盐[J.Heterocycl.Chem.1971,8(5),779-83]的5ml乙醇溶液在室温下用0.92ml(5.4mmol)Huenig碱处理,然后用501mg(2.7mmol)粗品5-氯-3-甲硫基-[1,2,4]三嗪-6-甲腈的5ml乙醇溶液处理。将深褐色的反应混合物在室温下搅拌18小时。为了进行后处理,将以纯净形式部分沉淀析出的产物过滤并将得到的母液减压蒸发。用己烷和乙酸乙酯的2∶1v/v混合物作为洗脱剂将残余物进行硅胶色谱。总共得到470mg(58.5%理论值)米色粉末状的3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:298M+H)+。
c)3-(2-甲氧基-乙氧基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-
甲腈
在氩气氛及0℃下,将25.6mg(0.34mmol)2-甲氧基-乙醇的2ml四氢呋喃溶液用15mg(0.34mmol)氢化钠(55%的精制油悬浮液)处理并搅拌15分钟。向该混合物中加入100mg(0.34mmol)3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈的3ml四氢呋喃溶液并在40℃下继续搅拌18小时。将黄色溶液减压蒸发,然后用二氯甲烷和甲醇的99∶1v/v混合物作为洗脱剂将残余物(141mg)进行硅胶色谱。由此得到10mg(9%理论值)浅黄色固体状的3-(2-甲氧基-乙氧基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:326(M+H)+。
实施例2
3-氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈
将200mg(0.67mmol)3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈(可以按照实施例1b所述的方法得到)和1.0ml氢氧化铵(1.34M)的分散液在搅拌下在密封试管中在140℃下加热过夜。为了完成反应,补加1.0ml氢氧化铵(1.34M)。在上述条件下继续加热18小时。将澄清溶液减压蒸发,然后用二氯甲烷和甲醇的95∶5v/v混合物作为洗脱剂将残余物进行硅胶色谱。得到40mg(22%理论值)浅黄色固体状的3-氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:267(M+H)+。
实施例3
3-二甲基氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈
按照与实施例2所述类似的方式,在密封试管中在110℃下,将3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈与二甲基胺(33%的无水乙醇溶液)反应得到浅褐色无定形固体状的3-二甲基氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:295(M+H)+。
实施例4
3-(环丙基甲基-氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲
腈
将150mg(0.50mmol)3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈(按照实施例1b制得)和74mg(1.0mmol)氨基甲基-环丙烷的混合物在5ml二噁烷中在120℃下搅拌过夜。将溶液减压蒸发,然后用二氯甲烷和甲醇的98∶2v/v混合物作为洗脱剂将残余物进行硅胶色谱。得到57mg(35%理论值)白色固体状的3-(环丙基甲基-氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:321(M+H)+。
实施例5
3-(2-羟基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲
腈
按照与实施例4所述类似的方法,将3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈与乙醇胺在二噁烷中在140℃下反应过夜得到浅黄色固体状的3-(2-羟基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:311(M+H)+。
实施例6
(RS)-3-(2-羟基-丙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪
-6-甲腈
按照与实施例4所述类似的方法,将3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈与(RS)-1-氨基-2-丙醇在二噁烷中在120℃下反应过夜得到白色固体状的(RS)-3-(2-羟基-丙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:325(M+H)+。
实施例7
3-肼基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈
按照与实施例4所述类似的方法,将3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈与水合肼在二噁烷中在140℃下反应3小时得到黄色无定形粉末状的3-肼基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:282(M+H)+。
实施例8
{2-[6-氰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-3-基氨基]-乙
基}-氨基甲酸叔丁酯
按照与实施例4所述类似的方法,将3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈与(2-氨基乙基)-氨基甲酸叔丁酯在二噁烷中在120℃下反应过夜得到白色固体状的{2-[6-氰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-3-基氨基]-乙基}-氨基甲酸叔丁酯;MS:410(M+H)+。
实施例9
3-(2-吡啶-3-基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪
-6-甲腈
将120mg(0.40mmol)3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈的5ml二氯甲烷溶液在室温下用109mg(0.44mmol)3-氯-过苯甲酸(70%)处理。2小时后,将反应混合物减压蒸发并且不经后处理以及特征分析,将形成的粗品3-甲磺酰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈直接用108mg(0.88mmol)3-(2-氨基乙基)吡啶的10ml二噁烷溶液处理。然后将反应混合物在80℃下搅拌过夜。然后将反应混合物减压蒸发,并用二氯甲烷、甲醇和氢氧化铵的95∶5∶0.1v/v/v混合物作为洗脱剂将得到的残余物直接进行硅胶色谱。得到55mg(37%理论值)白色无定形固体状的3-(2-吡啶-3-基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:372(M+H)+。
实施例10
3-羟基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈
将200mg(0.67mmol)3-甲硫基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈的10ml二氯甲烷溶液冷却至0℃并用332mg(1.35mmol)3-氯-过苯甲酸(70%)处理。将反应混合物升温至室温并搅拌过夜。为了进行后处理,将反应混合物用10ml二氯甲烷稀释,然后用10ml饱和的碳酸氢钠溶液萃取两次。将合并的有机相用硫酸钠干燥并减压蒸发。用二氯甲烷和甲醇的98∶2混合物作为洗脱剂,将形成的残余物(170mg黄色粉末)通过硅胶色谱纯化。得到154mg(86%理论值)浅黄色固体状的3-羟基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈;MS:266(M-H)。
实施例11
3-(2-氨基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲
腈三氟乙酸盐
向60mg(0.15mmol){2-[6-氰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-3-基氨基]-乙基}-氨基甲酸叔丁酯(按照实施例8制得)的2ml二氯甲烷溶液中加入0.2ml三氟乙酸。将反应混合物在室温下搅拌1小时,然后减压蒸发。将固体残余物在乙醚中形成分散液。将形成的固体过滤,得到30mg(47%理论值)灰白色固体状的3-(2-氨基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈三氟乙酸盐;MS:310(M+H)+。
实施例12
12-1)5-乙基-6-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈和
12-2)6-乙基-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈
a)5-乙基-6-甲基-3-氧代-3,4-二氢-吡嗪-2-甲酸酰胺和6-乙基-5-甲基-3-氧代
-3,4-二氢-吡嗪-2-甲酸酰胺
将8.32g(80.61mmol)2-氨基-丙二酸二酰胺和9.75g(83.26mmol)2,3-戊二酮的60ml水溶液加热回流18小时。冷却至室温后,通过过滤收集形成的结晶并真空干燥。由此得到9.52g(52.54mmol,65.2%理论值)黄色固体状的6-乙基-5-甲基-3-氧代-3,4-二氢-吡嗪-2-甲酸酰胺和5-乙基-6-甲基-3-氧代-3,4-二氢-吡嗪-2-甲酸酰胺的3∶2或2∶3混合物;MS:181(M)+。
b)3-氯-6-乙基-5-甲基-吡嗪-2-甲腈和3-氯-5-乙基-6-甲基-吡嗪-2-甲腈(两
种异构体的1∶1混合物)
将1.81g(10.0mmol)6-乙基-5-甲基-3-氧代-3,4-二氢-吡嗪-2-甲酸酰胺和5-乙基-6-甲基-3-氧代-3,4-二氢-吡嗪-2-甲酸酰胺的3∶2或2∶3混合物在4.2ml(30mmol)三乙胺中形成悬浮液。然后在0℃至5℃下缓慢加入30ml三氯氧化磷并将反应混合物加热回流3小时。然后将其冷却至20℃,加入5.3g(25mmol)五氯化磷并将反应混合物再次加热回流3小时。然后将其加入到水中,同时将温度维持在20℃至25℃。随后将水相用100ml乙醚萃取5次,将合并的乙醚相用饱和的碳酸氢钠溶液洗涤,用硫酸镁干燥并减压蒸发。用二氯甲烷和己烷的1∶1v/v混合物作为洗脱剂将形成的残余物进行硅胶色谱,得到1.0g(5.5mmol,55%理论值)橙红色油状的3-氯-6-乙基-5-甲基-吡嗪-2-甲腈和3-氯-5-乙基-6-甲基-吡嗪-2-甲腈的1∶1混合物;MS:181(M)+。
c)5-乙基-6-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈和6-乙基
-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈
将0.300g(1.65mmol)3-氯-6-乙基-5-甲基-吡嗪-2-甲腈和3-氯-5-乙基-6-甲基-吡嗪-2-甲腈的1∶1混合物、0.395g(1.30mmol)2,3,4,5-四氢-1H-苯并[d]氮杂_盐酸盐(J.Heterocycl.Chem.1971,8(5),779-83)和0.566g(2.60mmol)N-乙基-二异丙基胺的1.0ml N,N-二甲基甲酰胺溶液在室温下搅拌60小时,然后在60℃下搅拌18小时。随后将反应混合物倒入50ml冰/水混合物中并用50ml乙酸乙酯萃取3次。将合并的乙酸乙酯相用硫酸镁干燥并减压蒸发。然后用二氯甲烷作为洗脱剂将形成的残余物进行硅胶色谱,用二氯甲烷/戊烷结晶后得到0.086g(0.29mmol,18%理论值)浅黄色固体状的6-乙基-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈;MS:293(M+H)+;和0.074g(0.25mmol,15%理论值)浅黄色固体状的5-乙基-6-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈;MS:293(M+H)+。
实施例13
3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈
按照与实施例12所述类似的方法,将2-氯-3-氰基吡嗪(J.Chem.Soc.,Perkin Trans.I 1991,11,2877-81)用2,3,4,5-四氢-1H-苯并[d]氮杂_盐酸盐(J.Heterocycl.Chem.1971,8(5),779-83)和N-乙基-二异丙基胺在N,N-二甲基甲酰胺中在室温下处理,随后在60℃下处理得到浅黄色固体状的3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈;MS:251(M+H)+。
实施例14
5-甲基-6-苯基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈
按照与实施例12所述类似的方法,将1-苯基-1,2-丙二酮和2-氨基丙二酰胺在水溶液中加热得到5-甲基-3-氧代-6-苯基-3,4-二氢-吡嗪-2-甲酸酰胺。然后将5-甲基-3-氧代-6-苯基-3,4-二氢-吡嗪-2-甲酸酰胺用三乙胺和五氯化磷的三氯氧化磷溶液在回流下处理得到3-氯-5-甲基-6-苯基-吡嗪-2-甲腈。将3-氯-5-甲基-6-苯基-吡嗪-2-甲腈最后用2,3,4,5-四氢-1H-苯并[d]氮杂_盐酸盐(J.Heterocycl.Chem.1971,8(5),779-83)和N-乙基二异丙基胺在N,N-二甲基甲酰胺中在室温下处理得到黄色无定形固体状的5-甲基-6-苯基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈;MS:341(M+H)+。
实施例15
5-(2-羟基-乙基氨基)-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈
a)3-溴-5-氯-吡嗪-2-甲腈
将0.309g(2.00mmol)3-氨基-5-氯-吡嗪-2-甲腈(J.Org.Chem.1975,40,2341-2347)的5.0ml乙腈溶液在65℃下缓慢加入到0.903g(4.0mmol)溴化铜(II)和0.344g(3.0mmol)亚硝酸叔丁酯的20.0ml乙腈悬浮液中。将反应混合物在65℃下搅拌1小时,然后冷却至室温。随后将其倒入50ml冰/水混合物中并用50ml二氯甲烷萃取3次。将合并的二氯甲烷相用硫酸镁干燥并减压蒸发。用己烷和二氯甲烷的4∶1至0∶10v/v的梯度作为洗脱剂将形成的残余物进行硅胶色谱,得到0.333g(1.53mmol,76.2%理论值)浅黄色无定形固体状的3-溴-5-氯-吡嗪-2-甲腈;MS:218(M)+。
b)3-溴-5-(2-羟基-乙基氨基)-吡嗪-2-甲腈
将0.061g(1.00mmol)乙醇胺在室温下缓慢加入到0.218g(1.0mmol)3-溴-5-氯-吡嗪-2-甲腈和0.264g(2.0mmol)N-乙基二异丙基胺的15.0ml二噁烷溶液中。将反应混合物在室温下搅拌18小时。随后将其倒入50ml冰/水/碳酸氢钠的混合物中并用50ml乙酸乙酯萃取3次。将合并的乙酸乙酯相用硫酸镁干燥并减压蒸发。用二氯甲烷和甲醇的100∶0至95∶5v/v的梯度作为洗脱剂将形成的残余物进行硅胶色谱,得到0.131g(0.539mmol,53.9%理论值)黄色无定形固体状的3-溴-5-(2-羟基-乙基氨基)-吡嗪-2-甲腈;MS:243(M)+。
c)5-(2-羟基-乙基氨基)-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈
将0.415g(3.00mmol)碳酸钾在室温下缓慢加入到0.243g(1.0mmol)3-溴-5-(2-羟基-乙基氨基)-吡嗪-2-甲腈和0.220g(1.2mmol)2,3,4,5-四氢-1H-苯并[d]氮杂_盐酸盐(J.Heterocycl.Chem.1971,8(5),779-83)的10.0mlN,N-二甲基-甲酰胺溶液中。将反应混合物在室温下搅拌64小时并在80℃下搅拌5小时。随后将其倒50ml冰/水混合物中并用50ml二氯甲烷萃取3次。将合并的二氯甲烷相用硫酸镁干燥并减压蒸发。用己烷和乙酸乙酯的9∶1至0∶10v/v梯度作为洗脱剂将形成的残余物进行硅胶色谱,得到0.308g(1.0mmol,100%理论值)浅黄色无定形固体状的5-(2-羟基-乙基氨基)-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈;MS:310(M+H)+。
实施例A
以常规方式生产具有如下组成的片剂:
mg/片
活性成分 100
乳糖粉 95
白色玉米淀粉 35
聚乙烯吡咯烷酮 8
羧甲基淀粉钠 10
硬脂酸镁 2
片重250
实施例B
以常规方式生产具有如下组成的片剂:
mg/片
活性成分 200
乳糖粉 100
白色玉米淀粉 64
聚乙烯吡咯烷酮 12
羧甲基淀粉钠 20
硬脂酸镁 4
片重400
实施例C
生产具有如下组成的胶囊:
mg/胶囊
活性成分 50
结晶乳糖 60
微晶纤维素 34
滑石 5
硬脂酸镁 1
胶囊填充重量150
将具有适宜粒度的活性成分、结晶乳糖和微晶纤维素均匀地混合在一起,过筛然后混入滑石和硬脂酸镁。将最终的混合物填充到适宜大小的硬明胶胶囊中。
Claims (20)
1、通式I的化合物或其可药用盐:
其中
R1 表示氢、C1-C7烷基、C2-C7链烯基或未取代的苯基或在间位或对位被一个或多个选自C1-C7烷基、C1-C7烷氧基或卤素的取代基取代的苯基;
或者如果X是-N=或=N-,R1不存在;
R2 表示氢、C1-C7烷基、C2-C7链烯基、=O、-S-C1-C7烷基,-SO2-C1-C7烷基或
-OR、-O(CHR)m+1-OR、-NR2、-NH-NR2、-N(R)(CHR)m+1-OR,
-N(R)(CHR)m-吡啶基、-N(R)(CHR)n-(C3-C6)环烷基,
-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-C1-C7烷基;
m 是1、2、3、4、5或6;
n 是0、1、2、3、4或5;
R 表示氢、C1-C7烷基或C2-C7链烯基,并且如果存在一个以上的R,它们是彼此独立的;
X 表示-N=、=N-、>C=或=C<;并且虚线是键或不存在,
Y 表示-CH=CH-、-CH=CR3-、-CR3=CH-或-CR3=CR4-;并且R3,R4彼此独立地表示氢、C1-C7烷基、C1-C7烷氧基或卤素,条件是如果Y表示亚乙烯基,则在整个苯环上只存在一个基团R3和一个基团R4。
2、根据权利要求1所述的下列通式的化合物或其可药用盐:
其中
R1 表示氢、C1-C7烷基、C2-C7链烯基或未取代的苯基或在间位或对位被一个或多个选自C1-C7烷基、C1-C7烷氧基或卤素的取代基取代的苯基,
或者如果X是-N=或=N-,R1不存在;
R2 表示氢、C1-C7烷基、C2-C7链烯基、=O、-S-C1-C7烷基,-SO2-C1-C7烷基或
-OR、-O(CHR)m+1-OR、-NR2、-NH-NR2、-N(R)(CHR)m+1-OR,
-N(R)(CHR)m-吡啶基、-N(R)(CHR)n-(C3-C6)环烷基,
-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-C1-C7烷基;
m 是1、2、3、4、5或6;
n 是0、1、2、3、4或5;
R 表示氢、C1-C7烷基或C2-C7链烯基,并且如果存在一个以上的R,它们是彼此独立的;
X 表示-N=、=N-、>C=或=C<;并且虚线是键或不存在。
3、根据权利要求2所述的式I-A化合物,其中R1不存在并且X是-N=或=N-。
4、根据权利要求2或3所述的式I-A化合物,其中R2表示-NR2、-NH-NR2、-N(R)(CHR)m+1-OR、-N(R)(CHR)m-吡啶基,-N(R)(CHR)n-(C3-C6)环烷基、-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-C1-C7烷基。
5、根据权利要求4所述的式I-A化合物,所述化合物选自:
3-氨基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
3-肼基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈或
{2-[6-氰基-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-3-基氨基]-乙基}-氨基甲酸叔丁酯。
6、根据权利要求2或3所述的式I-A化合物,其中R2表示-N(R)(CHR)m+1-OR、-N(R)(CHR)m-吡啶基或-N(R)(CHR)n-(C3-C6)-环烷基。
7、根据权利要求6所述的式I-A化合物,所述化合物选自:
3-(环丙基甲基-氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
3-(2-羟基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈,
(RS)-3-(2-羟基-丙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈或
3-(2-吡啶-3-基-乙基氨基)-5-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-[1,2,4]三嗪-6-甲腈。
8、根据权利要求2所述的式I-A化合物,其中X表示>C=或=C<。
9、根据权利要求2或8所述的式I-A化合物,其中R1和R2是C1-C7烷基。
10、根据权利要求9所述的式I-A化合物,所述化合物选自:
5-乙基-6-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈或
6-乙基-5-甲基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈。
11、根据权利要求2或8所述的式I-A化合物,其中R1是乙基。
12、根据权利要求2或8所述的式I-A化合物,其中R1表示未取代的苯基或在间位或对位被一个或多个选自C1-C7烷基、C1-C7烷氧基或卤素的取代基取代的苯基。
13、根据权利要求12所述的式I-A化合物,该化合物是5-甲基-6-苯基-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈。
14、根据权利要求2或8所述的式I-A化合物,其中R2表示-N(R)(CHR)m+1-OR,其中R彼此独立地表示氢、C1-C7烷基或C2-C7链烯基。
15、根据权利要求14所述的式I-A化合物,所述化合物是5-(2-羟基-乙基氨基)-3-(1,2,4,5-四氢-苯并[d]氮杂_-3-基)-吡嗪-2-甲腈。
16、用于控制或预防由代谢型谷氨酸受体1拮抗剂介导的疾病的药物,该药物含有权利要求1至15中的任何一项所述的化合物或其可药用盐和可药用赋形剂。
17、权利要求16的药物,其中所述由代谢型谷氨酸受体1拮抗剂介导的疾病为急性或慢性神经病学障碍。
18、权利要求1至15中的任何一项所述的化合物或其可药用盐在生产用于控制或预防由代谢型谷氨酸受体1拮抗剂介导的疾病的药物中的用途。
19、权利要求18的用途,其中所述由代谢型谷氨酸受体1拮抗剂介导的疾病为急性或慢性神经病学障碍。
20、制备权利要求1所述的式I化合物或其可药用盐的方法,该方法包括:
a)将式I-2的化合物
其中Y、R3和R4与权利要求1中定义相同,与亲核试剂反应得到式I-1的化合物
其中Y、R3和R4与权利要求1中定义相同,R21表示-OR、-O(CHR)m+1-OR、-NR2、-NH-NR2、-N(R)(CHR)m+1-OR、-N(R)(CHR)m-吡啶基、-N(R)(CHR)n-(C3-C6)环烷基、-N(R)(CHR)m(CR2)-NR2或-N(R)(CHR)m+1-NH-C(O)-O-C1-C7烷基,其中m、n和R与权利要求1中定义相同,并且,
将或不将式I-1化合物中的R21官能团转化成另一种R21官能团以得到式I-1的另一种式I-1化合物,
并且,在制备可药用盐的情况下,将式I-1化合物转化成可药用盐;或者
b)将式II-1的化合物
其中R22表示C1-C7烷基,
与式III的化合物反应
其中Y、R3和R4与权利要求1中定义相同,得到式I-3的化合物
其中Y、R3和R4与权利要求1中定义相同,R22表示C1-C7烷基,并且,在制备可药用盐的情况下,将式I-3的化合物转化成可药用盐;或者
c)将式II-2的化合物
其中R1和R2与权利要求1中定义相同,R5表示卤素,
与式III的化合物反应
其中Y、R3和R4与权利要求1中定义相同,得到式I-4的化合物
其中Y、R1、R2、R3和R4与权利要求1中定义相同,并且,
将或不将式I-4化合物中的R2官能团转化成另一种R2官能团得到式I-4的另一种式I-4化合物,
并且,在制备可药用盐的情况下,将式I-4的化合物转化成可药用盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00128329 | 2000-12-22 | ||
EP00128329.0 | 2000-12-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1487831A CN1487831A (zh) | 2004-04-07 |
CN1260226C true CN1260226C (zh) | 2006-06-21 |
Family
ID=8170787
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018222099A Expired - Fee Related CN1260226C (zh) | 2000-12-22 | 2001-12-11 | 用作mGluR1拮抗剂的四氢-(苯并或噻吩并)-氮杂䓬-吡嗪和三嗪衍生物 |
Country Status (17)
Country | Link |
---|---|
US (1) | US6586422B2 (zh) |
EP (1) | EP1345609B1 (zh) |
JP (1) | JP4077319B2 (zh) |
KR (1) | KR100545906B1 (zh) |
CN (1) | CN1260226C (zh) |
AR (1) | AR032379A1 (zh) |
AT (1) | ATE297734T1 (zh) |
AU (1) | AU2002216095B2 (zh) |
BR (1) | BR0116378A (zh) |
CA (1) | CA2432077C (zh) |
DE (1) | DE60111568T2 (zh) |
DK (1) | DK1345609T3 (zh) |
ES (1) | ES2243400T3 (zh) |
MX (1) | MXPA03005515A (zh) |
PT (1) | PT1345609E (zh) |
WO (1) | WO2002051418A1 (zh) |
ZA (1) | ZA200304557B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009506069A (ja) | 2005-08-26 | 2009-02-12 | ブレインセルス,インコーポレイティド | ムスカリン性受容体調節による神経発生 |
EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
CA2625153A1 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
US20070112017A1 (en) | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
AU2007207508B2 (en) * | 2006-01-19 | 2011-08-18 | Athersys, Inc. | Thiophenyl and pyrrolyl azepines as serotonin 5-HT2c receptor ligands and uses thereof |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
EP2377531A2 (en) | 2006-05-09 | 2011-10-19 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
US7678808B2 (en) | 2006-05-09 | 2010-03-16 | Braincells, Inc. | 5 HT receptor mediated neurogenesis |
WO2008030651A1 (en) | 2006-09-08 | 2008-03-13 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
KR101100864B1 (ko) * | 2009-06-12 | 2012-01-02 | 양준호 | 자동차 광택기용 광택패드 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3136654A1 (de) | 1981-09-16 | 1983-03-31 | Zahnradfabrik Friedrichshafen Ag, 7990 Friedrichshafen | Linearverschieblicher arbeitsarm, insbesondere fuer handhabungsgeraete |
WO1999044639A1 (fr) * | 1998-03-03 | 1999-09-10 | Yamanouchi Pharmaceutical Co., Ltd. | Medicaments contre l'infarcissement du cerveau |
ID29095A (id) * | 1998-10-02 | 2001-07-26 | Novartis Ag Cs | Antagonis mglur5 untuk pengobatan rasa sakit dan kegelisahan |
GB9823847D0 (en) * | 1998-11-02 | 1998-12-23 | Lilly Co Eli | Pharmaceutical compounds |
DE60006618T2 (de) * | 1999-08-06 | 2004-09-23 | F. Hoffmann-La Roche Ag | Tetrahydro-benzo(d)azepine und deren Verwendung als metabotrope Glutamatrezeptor-Antagonisten |
EP1074549B1 (en) * | 1999-08-06 | 2003-11-19 | F. Hoffmann-La Roche Ag | Tetrahydro-benzo(d)azepines and their use as antagonists at metabotropic glutamate receptors |
-
2001
- 2001-12-11 CN CNB018222099A patent/CN1260226C/zh not_active Expired - Fee Related
- 2001-12-11 DE DE60111568T patent/DE60111568T2/de not_active Expired - Lifetime
- 2001-12-11 JP JP2002552562A patent/JP4077319B2/ja not_active Expired - Fee Related
- 2001-12-11 AU AU2002216095A patent/AU2002216095B2/en not_active Ceased
- 2001-12-11 CA CA2432077A patent/CA2432077C/en not_active Expired - Fee Related
- 2001-12-11 MX MXPA03005515A patent/MXPA03005515A/es active IP Right Grant
- 2001-12-11 PT PT01271999T patent/PT1345609E/pt unknown
- 2001-12-11 WO PCT/EP2001/014527 patent/WO2002051418A1/en active IP Right Grant
- 2001-12-11 BR BR0116378-7A patent/BR0116378A/pt not_active IP Right Cessation
- 2001-12-11 EP EP01271999A patent/EP1345609B1/en not_active Expired - Lifetime
- 2001-12-11 KR KR1020037008488A patent/KR100545906B1/ko not_active IP Right Cessation
- 2001-12-11 AT AT01271999T patent/ATE297734T1/de active
- 2001-12-11 DK DK01271999T patent/DK1345609T3/da active
- 2001-12-11 ES ES01271999T patent/ES2243400T3/es not_active Expired - Lifetime
- 2001-12-12 US US10/020,680 patent/US6586422B2/en not_active Expired - Fee Related
- 2001-12-20 AR ARP010105926A patent/AR032379A1/es unknown
-
2003
- 2003-06-11 ZA ZA200304557A patent/ZA200304557B/en unknown
Also Published As
Publication number | Publication date |
---|---|
EP1345609B1 (en) | 2005-06-15 |
ATE297734T1 (de) | 2005-07-15 |
PT1345609E (pt) | 2005-08-31 |
AU2002216095B2 (en) | 2005-12-01 |
CN1487831A (zh) | 2004-04-07 |
JP2004517850A (ja) | 2004-06-17 |
KR20030062444A (ko) | 2003-07-25 |
ES2243400T3 (es) | 2005-12-01 |
WO2002051418A1 (en) | 2002-07-04 |
MXPA03005515A (es) | 2003-09-25 |
BR0116378A (pt) | 2003-10-28 |
KR100545906B1 (ko) | 2006-01-26 |
EP1345609A1 (en) | 2003-09-24 |
DE60111568D1 (de) | 2005-07-21 |
AR032379A1 (es) | 2003-11-05 |
JP4077319B2 (ja) | 2008-04-16 |
CA2432077C (en) | 2011-01-18 |
ZA200304557B (en) | 2004-09-13 |
CA2432077A1 (en) | 2002-07-04 |
DK1345609T3 (da) | 2005-10-03 |
DE60111568T2 (de) | 2006-05-11 |
US20020123488A1 (en) | 2002-09-05 |
US6586422B2 (en) | 2003-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1260225C (zh) | 四氢吡啶基或哌啶基杂环衍生物 | |
CN1187358C (zh) | 四氢杂环吖庚因基嘧啶衍生物 | |
CN1094490C (zh) | 作为血清素拮抗剂的喹诺-2(1h)-酮衍生物 | |
CN1077891C (zh) | 作为5-ht4或h3受体配位体有效的5-苯基-3-(哌啶-4-基)-1,3,4-噁二唑-2(3h)-酮衍生物 | |
CN1260226C (zh) | 用作mGluR1拮抗剂的四氢-(苯并或噻吩并)-氮杂䓬-吡嗪和三嗪衍生物 | |
CN1054598A (zh) | 甲酰胺衍生物的制备方法 | |
CN1278819A (zh) | 作为促肾上腺皮质素释放激素拮抗剂、可用于治疗cns障碍和紧张相关性疾病的杂环基取代的环稠合吡啶和嘧啶 | |
CN1045781A (zh) | N-(3-羟基-4-哌啶基)(二氢苯并呋喃,二氢-2h-苯并吡喃或二氢苯并二英)甲酰胺衍生物 | |
CN1474820A (zh) | 作为gaba a受体调节剂的苯并二氮杂�衍生物 | |
CN1328560A (zh) | [1,2,4]三唑并[1,5-c]嘧啶衍生物 | |
CN1372547A (zh) | 用于治疗中枢神经系统疾病的氨基烷氧基咔唑 | |
CN1093859C (zh) | 新型吲哚-2,3-二酮-3-肟衍生物 | |
CN1030452C (zh) | 2-氨基嘧啶酮衍生物的制备方法 | |
CN1042133C (zh) | N-取代的氮杂双环庚烷衍生物及其用途 | |
CN1620290A (zh) | 作为5-羟色胺-6配体的吲哚基烷基胺衍生物 | |
CN87103504A (zh) | 杂环羧酰胺 | |
CN1058215A (zh) | 新的唑基衍生物 | |
CN1324358A (zh) | 具有因子xa抑制作用的咪唑并[4,5-c]吡啶-4-酮衍生物 | |
CN1114957A (zh) | 新(硫代)环烷基[b]吲哚化合物及制法和药物组合物 | |
CN100338074C (zh) | 杂环化合物和以其为有效成分的脑机能改善剂 | |
CN1029964C (zh) | 新的n-(4-哌啶基)双环缩合2-咪唑胺衍生物的制备方法 | |
CN1308325C (zh) | 新的芳基-{4-卤素-4-[(杂芳基甲氨基)甲基]-哌啶-1-基}甲酮衍生物、制备方法及其作为药物的用途 | |
CN1875016A (zh) | 咪唑衍生物 | |
CN1823054A (zh) | 咪唑衍生物ⅲ | |
CN1395567A (zh) | 新的咪唑类衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20060621 Termination date: 20111211 |