CN1496262A - 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 - Google Patents
三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 Download PDFInfo
- Publication number
- CN1496262A CN1496262A CNA028063031A CN02806303A CN1496262A CN 1496262 A CN1496262 A CN 1496262A CN A028063031 A CNA028063031 A CN A028063031A CN 02806303 A CN02806303 A CN 02806303A CN 1496262 A CN1496262 A CN 1496262A
- Authority
- CN
- China
- Prior art keywords
- triazol
- furyl
- pyrimidine
- amine
- methyl
- 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.)
- Pending
Links
- 239000000111 purinergic antagonist Substances 0.000 title description 2
- 229940121374 purinergic receptor antagonist Drugs 0.000 title description 2
- GIIGHSIIKVOWKZ-UHFFFAOYSA-N 2h-triazolo[4,5-d]pyrimidine Chemical class N1=CN=CC2=NNN=C21 GIIGHSIIKVOWKZ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 144
- 125000003118 aryl group Chemical group 0.000 claims abstract description 105
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 59
- 238000011282 treatment Methods 0.000 claims abstract description 45
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 26
- 150000002367 halogens Chemical class 0.000 claims abstract description 26
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 102000009346 Adenosine receptors Human genes 0.000 claims abstract description 17
- 108050000203 Adenosine receptors Proteins 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 14
- 208000002193 Pain Diseases 0.000 claims abstract description 13
- 102000000033 Purinergic Receptors Human genes 0.000 claims abstract description 13
- 108010080192 Purinergic Receptors Proteins 0.000 claims abstract description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 10
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 9
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims abstract description 9
- 150000001721 carbon Chemical class 0.000 claims abstract description 5
- 206010027175 memory impairment Diseases 0.000 claims abstract description 5
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 4
- 230000001154 acute effect Effects 0.000 claims abstract description 4
- 208000005298 acute pain Diseases 0.000 claims abstract description 4
- 230000002265 prevention Effects 0.000 claims abstract description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 357
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 claims description 275
- -1 heterocyclic radical Chemical class 0.000 claims description 193
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 129
- 238000000034 method Methods 0.000 claims description 116
- 201000010099 disease Diseases 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 31
- 230000033001 locomotion Effects 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002541 furyl group Chemical group 0.000 claims description 17
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 13
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 13
- 230000000324 neuroprotective effect Effects 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 230000003111 delayed effect Effects 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 230000000302 ischemic effect Effects 0.000 claims description 8
- 230000007971 neurological deficit Effects 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 150000003456 sulfonamides Chemical class 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- TYQRKUKKCLHFOS-UHFFFAOYSA-N tert-butyl formate 1H-indole Chemical compound C(C)(C)(C)OC=O.N1C=CC2=CC=CC=C12 TYQRKUKKCLHFOS-UHFFFAOYSA-N 0.000 claims description 7
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 5
- 206010008748 Chorea Diseases 0.000 claims description 5
- 208000003098 Ganglion Cysts Diseases 0.000 claims description 5
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 5
- 208000005400 Synovial Cyst Diseases 0.000 claims description 5
- 208000012601 choreatic disease Diseases 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 206010003694 Atrophy Diseases 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 claims description 4
- 206010024264 Lethargy Diseases 0.000 claims description 4
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 4
- 208000018839 Wilson disease Diseases 0.000 claims description 4
- 230000037444 atrophy Effects 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 208000018198 spasticity Diseases 0.000 claims description 4
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical class NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 3
- 239000012964 benzotriazole Substances 0.000 claims description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 230000019771 cognition Effects 0.000 claims description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 3
- 230000000142 dyskinetic effect Effects 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 230000001898 pallidal effect Effects 0.000 claims description 3
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 2
- 208000014094 Dystonic disease Diseases 0.000 claims description 2
- 206010033799 Paralysis Diseases 0.000 claims description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 208000013044 corticobasal degeneration disease Diseases 0.000 claims description 2
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 2
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 claims description 2
- 208000010118 dystonia Diseases 0.000 claims description 2
- 206010014599 encephalitis Diseases 0.000 claims description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
- IMNDHOCGZLYMRO-UHFFFAOYSA-N n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC=C1 IMNDHOCGZLYMRO-UHFFFAOYSA-N 0.000 claims description 2
- 231100000614 poison Toxicity 0.000 claims description 2
- 239000002574 poison Substances 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims 4
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 3
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 claims 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 1
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical class NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims 1
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- YBTJYDBEEZJCCA-UHFFFAOYSA-N C1=CC2=C(C(=C(C=C2)C3=CC=CO3)CN4C=CN=N4)N=C1 Chemical compound C1=CC2=C(C(=C(C=C2)C3=CC=CO3)CN4C=CN=N4)N=C1 YBTJYDBEEZJCCA-UHFFFAOYSA-N 0.000 claims 1
- CJLGRVPSBUHFIK-UHFFFAOYSA-N C1=COC(=C1)C2=CC(=CC3=C2NN=C3)CN4C=CN=N4 Chemical compound C1=COC(=C1)C2=CC(=CC3=C2NN=C3)CN4C=CN=N4 CJLGRVPSBUHFIK-UHFFFAOYSA-N 0.000 claims 1
- PJMDVMKIYVTAMW-UHFFFAOYSA-N C1=COC(=C1)C2=CC3=C(C=C2)C=CC(=N3)CN4C=CN=N4 Chemical compound C1=COC(=C1)C2=CC3=C(C=C2)C=CC(=N3)CN4C=CN=N4 PJMDVMKIYVTAMW-UHFFFAOYSA-N 0.000 claims 1
- 241000790917 Dioxys <bee> Species 0.000 claims 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 1
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical compound C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 claims 1
- WVWZECQNFWFVFW-UHFFFAOYSA-N methyl 2-methylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C WVWZECQNFWFVFW-UHFFFAOYSA-N 0.000 claims 1
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 claims 1
- AHTBSQOOXCUCBM-UHFFFAOYSA-N pyrimidin-5-amine;2,2,2-trifluoroacetic acid Chemical compound NC1=CN=CN=C1.OC(=O)C(F)(F)F AHTBSQOOXCUCBM-UHFFFAOYSA-N 0.000 claims 1
- JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 claims 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical class NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 claims 1
- 150000003673 urethanes Chemical class 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 9
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 208000010877 cognitive disease Diseases 0.000 abstract description 4
- 208000035475 disorder Diseases 0.000 abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 101150051188 Adora2a gene Proteins 0.000 abstract 1
- 208000028698 Cognitive impairment Diseases 0.000 abstract 1
- 101100134922 Gallus gallus COR5 gene Proteins 0.000 abstract 1
- 208000016285 Movement disease Diseases 0.000 abstract 1
- 208000018737 Parkinson disease Diseases 0.000 abstract 1
- 230000001149 cognitive effect Effects 0.000 abstract 1
- 201000003631 narcolepsy Diseases 0.000 abstract 1
- 230000004112 neuroprotection Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 783
- 239000000243 solution Substances 0.000 description 99
- 239000007787 solid Substances 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 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 65
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- 238000003756 stirring Methods 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 34
- 229960005305 adenosine Drugs 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000002585 base Substances 0.000 description 30
- 238000010561 standard procedure Methods 0.000 description 30
- 229910004298 SiO 2 Inorganic materials 0.000 description 29
- 238000011097 chromatography purification Methods 0.000 description 27
- 238000001035 drying Methods 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 208000035126 Facies Diseases 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000000605 extraction Methods 0.000 description 20
- 230000014759 maintenance of location Effects 0.000 description 19
- 238000001914 filtration Methods 0.000 description 18
- 102000005962 receptors Human genes 0.000 description 18
- 108020003175 receptors Proteins 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 16
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 238000012545 processing Methods 0.000 description 15
- 239000007788 liquid Substances 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000002464 receptor antagonist Substances 0.000 description 12
- 238000010790 dilution Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 238000011161 development Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000003513 alkali Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 210000003169 central nervous system Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229960003638 dopamine Drugs 0.000 description 8
- 229960003878 haloperidol Drugs 0.000 description 8
- 229950007908 piconol Drugs 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 6
- 229960001948 caffeine Drugs 0.000 description 6
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 5
- 208000009132 Catalepsy Diseases 0.000 description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 208000006011 Stroke Diseases 0.000 description 5
- 206010047853 Waxy flexibility Diseases 0.000 description 5
- 229960003116 amyl nitrite Drugs 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 5
- 229960004046 apomorphine Drugs 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 206010008118 cerebral infarction Diseases 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000003709 fluoroalkyl group Chemical group 0.000 description 4
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 210000001577 neostriatum Anatomy 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 4
- 150000003230 pyrimidines Chemical class 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000001117 sulphuric acid Substances 0.000 description 4
- 235000011149 sulphuric acid Nutrition 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 3
- 101100256910 Drosophila melanogaster sick gene Proteins 0.000 description 3
- 208000012661 Dyskinesia Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920005372 Plexiglas® Polymers 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 229940121359 adenosine receptor antagonist Drugs 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 208000029028 brain injury Diseases 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229960003914 desipramine Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000010829 isocratic elution Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000037023 motor activity Effects 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- MDOGCUPGRYNLQG-UHFFFAOYSA-N 2-(1-methoxypropyl)-6-methylpyridine Chemical compound CCC(OC)C1=CC=CC(C)=N1 MDOGCUPGRYNLQG-UHFFFAOYSA-N 0.000 description 2
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 2
- PLDJBBLAQSTSKA-UHFFFAOYSA-N 7-fluoro-5-methyl-1h-indole-2,3-dione Chemical compound FC1=CC(C)=CC2=C1NC(=O)C2=O PLDJBBLAQSTSKA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- 208000025480 CHILD syndrome Diseases 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000028603 Interstitial lung disease specific to childhood Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- UTLPKQYUXOEJIL-UHFFFAOYSA-N LSM-3822 Chemical compound N1=CC=2C3=NC(C=4OC=CC=4)=NN3C(N)=NC=2N1CCC1=CC=CC=C1 UTLPKQYUXOEJIL-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- 241001590997 Moolgarda engeli Species 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 229940072107 ascorbate Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000005518 carboxamido group Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 230000006999 cognitive decline Effects 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000011790 ferrous sulphate Substances 0.000 description 2
- 235000003891 ferrous sulphate Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 150000004688 heptahydrates Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 206010020765 hypersomnia Diseases 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- QQHNOQIBTQVLTA-UHFFFAOYSA-N n-[2-amino-6-(furan-2-yl)-5-nitropyrimidin-4-yl]-6-chloropyridine-3-carboxamide Chemical compound [O-][N+](=O)C=1C(C=2OC=CC=2)=NC(N)=NC=1NC(=O)C1=CC=C(Cl)N=C1 QQHNOQIBTQVLTA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 210000002569 neuron Anatomy 0.000 description 2
- 208000002040 neurosyphilis Diseases 0.000 description 2
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 239000012053 oil suspension Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 2
- 230000001696 purinergic effect Effects 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000007958 sleep Effects 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 208000020685 sleep-wake disease Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 208000002025 tabes dorsalis Diseases 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- CIUYJYRQKYGNQP-UHFFFAOYSA-N (3-nitrophenyl)methanamine Chemical compound NCC1=CC=CC([N+]([O-])=O)=C1 CIUYJYRQKYGNQP-UHFFFAOYSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical compound C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 description 1
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 1
- JHFAEUICJHBVHB-UHFFFAOYSA-N 1h-indol-2-ol Chemical compound C1=CC=C2NC(O)=CC2=C1 JHFAEUICJHBVHB-UHFFFAOYSA-N 0.000 description 1
- IQNHBUQSOSYAJU-UHFFFAOYSA-N 2,2,2-trifluoro-n-methylacetamide Chemical compound CNC(=O)C(F)(F)F IQNHBUQSOSYAJU-UHFFFAOYSA-N 0.000 description 1
- YSSWCSYAQLKZNM-UHFFFAOYSA-N 2-(bromomethyl)-1-fluoro-4-iodobenzene Chemical compound FC1=CC=C(I)C=C1CBr YSSWCSYAQLKZNM-UHFFFAOYSA-N 0.000 description 1
- HDNPQSSQQYCVMP-UHFFFAOYSA-N 2-(bromomethyl)-4,6-di(propan-2-yl)pyridine Chemical compound CC(C)C1=CC(CBr)=NC(C(C)C)=C1 HDNPQSSQQYCVMP-UHFFFAOYSA-N 0.000 description 1
- CZTCOXQVCBNPKF-UHFFFAOYSA-N 2-(bromomethyl)-4-methylpyridine Chemical compound CC1=CC=NC(CBr)=C1 CZTCOXQVCBNPKF-UHFFFAOYSA-N 0.000 description 1
- OUGUTAUSQAZEJH-UHFFFAOYSA-N 2-(bromomethyl)-4-nitropyridine Chemical compound [O-][N+](=O)C1=CC=NC(CBr)=C1 OUGUTAUSQAZEJH-UHFFFAOYSA-N 0.000 description 1
- PJMAUBJLWARFCM-UHFFFAOYSA-N 2-(bromomethyl)-5-ethylthiophene Chemical compound CCC1=CC=C(CBr)S1 PJMAUBJLWARFCM-UHFFFAOYSA-N 0.000 description 1
- DQLAPDXPSFFWRE-UHFFFAOYSA-N 2-(bromomethyl)-6-(2-methoxyethyl)pyridine Chemical compound COCCC1=CC=CC(CBr)=N1 DQLAPDXPSFFWRE-UHFFFAOYSA-N 0.000 description 1
- DHBBDAPZQVATGR-UHFFFAOYSA-N 2-(bromomethyl)-6-ethenylpyridine Chemical compound BrCC1=CC=CC(C=C)=N1 DHBBDAPZQVATGR-UHFFFAOYSA-N 0.000 description 1
- SROQIKSXGIUWIU-UHFFFAOYSA-N 2-(bromomethyl)-6-ethylpyridine Chemical compound CCC1=CC=CC(CBr)=N1 SROQIKSXGIUWIU-UHFFFAOYSA-N 0.000 description 1
- XHWDFGQAXHSIMH-UHFFFAOYSA-N 2-(bromomethyl)-6-methoxypyridine Chemical compound COC1=CC=CC(CBr)=N1 XHWDFGQAXHSIMH-UHFFFAOYSA-N 0.000 description 1
- YVNDNIOLHPZZJX-UHFFFAOYSA-N 2-(bromomethyl)-6-methyl-4-nitropyridine Chemical compound CC1=CC([N+]([O-])=O)=CC(CBr)=N1 YVNDNIOLHPZZJX-UHFFFAOYSA-N 0.000 description 1
- DNFLPQFSDKFUCX-UHFFFAOYSA-N 2-(bromomethyl)-6-propan-2-ylpyridine Chemical compound CC(C)C1=CC=CC(CBr)=N1 DNFLPQFSDKFUCX-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- ZQEXBVHABAJPHJ-UHFFFAOYSA-N 2-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C(F)=C1 ZQEXBVHABAJPHJ-UHFFFAOYSA-N 0.000 description 1
- ZZWCZVKPIXUMCY-UHFFFAOYSA-N 2-methyl-1h-pyridine-2-carbaldehyde Chemical compound O=CC1(C)NC=CC=C1 ZZWCZVKPIXUMCY-UHFFFAOYSA-N 0.000 description 1
- HWPIDHRDNNZJSY-UHFFFAOYSA-N 2-methyl-4-nitropyridine Chemical compound CC1=CC([N+]([O-])=O)=CC=N1 HWPIDHRDNNZJSY-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- YCAIYRWHKSJKEB-UHFFFAOYSA-N 3-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=CC(C(Cl)=O)=C1 YCAIYRWHKSJKEB-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XLDLRRGZWIEEHT-UHFFFAOYSA-N 3-hydroxy-4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C(O)=C1 XLDLRRGZWIEEHT-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- DXTYEQRLURNLGL-UHFFFAOYSA-N 4-(bromomethyl)-1-nitro-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC(CBr)=CC=C1[N+]([O-])=O DXTYEQRLURNLGL-UHFFFAOYSA-N 0.000 description 1
- WZNDYHIBMJITOD-UHFFFAOYSA-N 4-(bromomethyl)-2-ethyl-1-nitrobenzene Chemical compound CCC1=CC(CBr)=CC=C1[N+]([O-])=O WZNDYHIBMJITOD-UHFFFAOYSA-N 0.000 description 1
- VXBCENSSPUOYEF-UHFFFAOYSA-N 4-(bromomethyl)-2-ethylpyridine Chemical compound CCC1=CC(CBr)=CC=N1 VXBCENSSPUOYEF-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- UKWUOTZGXIZAJC-UHFFFAOYSA-N 4-nitrosalicylic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1O UKWUOTZGXIZAJC-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- FLDSMVTWEZKONL-AWEZNQCLSA-N 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxamide Chemical compound CC1(CC2=C(NN=C2C(=O)N[C@@H]2C(N(C3=C(OC2)C=CC=C3)C)=O)CCO1)C FLDSMVTWEZKONL-AWEZNQCLSA-N 0.000 description 1
- LNPXQWSVYVUJHJ-UHFFFAOYSA-N 5-(bromomethyl)-2-propan-2-ylpyridine Chemical compound CC(C)C1=CC=C(CBr)C=N1 LNPXQWSVYVUJHJ-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- FXYZKNWQYGOZEC-UHFFFAOYSA-N 6-(1-bromopropyl)-2,3-dimethylpyridine Chemical class CCC(Br)C1=CC=C(C)C(C)=N1 FXYZKNWQYGOZEC-UHFFFAOYSA-N 0.000 description 1
- NFCAXMYSRSNRRA-UHFFFAOYSA-N 6-(5-methylfuran-2-yl)pyrimidine-2,4,5-triamine Chemical compound O1C(C)=CC=C1C1=NC(N)=NC(N)=C1N NFCAXMYSRSNRRA-UHFFFAOYSA-N 0.000 description 1
- FMEBIWNKYZUWFV-UHFFFAOYSA-N 6-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)N=C1 FMEBIWNKYZUWFV-UHFFFAOYSA-N 0.000 description 1
- AORDVAXRGDICNT-UHFFFAOYSA-N 7-fluoro-5-methyl-1h-indole Chemical compound CC1=CC(F)=C2NC=CC2=C1 AORDVAXRGDICNT-UHFFFAOYSA-N 0.000 description 1
- KGWPHCDTOLQQEP-UHFFFAOYSA-N 7-methylindole Chemical compound CC1=CC=CC2=C1NC=C2 KGWPHCDTOLQQEP-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 229940122614 Adenosine receptor agonist Drugs 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000009017 Athetosis Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OQDYOCKNPAIWSG-UHFFFAOYSA-N C1=CC=C(C=C1)C(=O)C2=C(C=CC(=C2)CO)[N+](=O)[O-] Chemical compound C1=CC=C(C=C1)C(=O)C2=C(C=CC(=C2)CO)[N+](=O)[O-] OQDYOCKNPAIWSG-UHFFFAOYSA-N 0.000 description 1
- QGKIZLFFHITBKT-UHFFFAOYSA-N CC(C)COC1=CC=CC(N1)(C)CBr Chemical compound CC(C)COC1=CC=CC(N1)(C)CBr QGKIZLFFHITBKT-UHFFFAOYSA-N 0.000 description 1
- GUUPMNWIAMHEDQ-UHFFFAOYSA-N CC(C)COC1=CC=CC(N1)(C)CO Chemical compound CC(C)COC1=CC=CC(N1)(C)CO GUUPMNWIAMHEDQ-UHFFFAOYSA-N 0.000 description 1
- XJRKKRRVBAEDGV-UHFFFAOYSA-N CC(C)OC1=CC=CC(N1)(C)CBr Chemical compound CC(C)OC1=CC=CC(N1)(C)CBr XJRKKRRVBAEDGV-UHFFFAOYSA-N 0.000 description 1
- QPTZBLWQRWQMFG-UHFFFAOYSA-N CC(C)OC1=CC=CC(N1)(C)CO Chemical compound CC(C)OC1=CC=CC(N1)(C)CO QPTZBLWQRWQMFG-UHFFFAOYSA-N 0.000 description 1
- YURNUQQDKASIIJ-UHFFFAOYSA-N CCOClC Chemical compound CCOClC YURNUQQDKASIIJ-UHFFFAOYSA-N 0.000 description 1
- PAOANWZGLPPROA-RQXXJAGISA-N CGS-21680 Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(NCCC=3C=CC(CCC(O)=O)=CC=3)=NC(N)=C2N=C1 PAOANWZGLPPROA-RQXXJAGISA-N 0.000 description 1
- FKDJWPNZLPRUPO-UHFFFAOYSA-N COBrCC1=CC=CC=C1 Chemical compound COBrCC1=CC=CC=C1 FKDJWPNZLPRUPO-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010013486 Distractibility Diseases 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- 206010014498 Embolic stroke Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 206010065952 Hyperpathia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 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
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 206010022773 Intracranial pressure increased Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000006264 Korsakoff syndrome Diseases 0.000 description 1
- 241001484259 Lacuna Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 206010028570 Myelopathy Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- NZEJODZWNAVWKS-UHFFFAOYSA-N N-(2H-pyrimidin-1-yl)formamide Chemical compound O=CNN1CN=CC=C1 NZEJODZWNAVWKS-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- SETHSKIRVBKZTB-UHFFFAOYSA-N NC([O])=O Chemical compound NC([O])=O SETHSKIRVBKZTB-UHFFFAOYSA-N 0.000 description 1
- 206010028923 Neonatal asphyxia Diseases 0.000 description 1
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 208000001738 Nervous System Trauma Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 244000170916 Paeonia officinalis Species 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010037779 Radiculopathy Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VWZTTXIZVLKLOW-UHFFFAOYSA-N S1N=C(C=C1)C1=C(N=NO1)C=1OC=CN1 Chemical compound S1N=C(C=C1)C1=C(N=NO1)C=1OC=CN1 VWZTTXIZVLKLOW-UHFFFAOYSA-N 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 208000002667 Subdural Hematoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 201000008485 Wernicke-Korsakoff syndrome Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- VUEFLRVJQMLJGN-UHFFFAOYSA-N [6-(2-methoxyethyl)pyridin-2-yl]methanol Chemical compound COCCC1=CC=CC(CO)=N1 VUEFLRVJQMLJGN-UHFFFAOYSA-N 0.000 description 1
- WWFMINHWJYHXHF-UHFFFAOYSA-N [6-(hydroxymethyl)pyridin-2-yl]methanol Chemical compound OCC1=CC=CC(CO)=N1 WWFMINHWJYHXHF-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000006550 alkoxycarbonyl aryl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 1
- 229960000911 benserazide Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 208000003906 hydrocephalus Diseases 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000005027 hydroxyaryl group Chemical group 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 201000009941 intracranial hypertension Diseases 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000003151 isocoumarinyl group Chemical group C1(=O)OC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000007937 lozenge Substances 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- CUUYGSBOZFZTQY-UHFFFAOYSA-M methoxy(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(OC)C1=CC=CC=C1 CUUYGSBOZFZTQY-UHFFFAOYSA-M 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000028412 nervous system injury Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 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
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- UQZKYYIKWZOKKD-UHFFFAOYSA-N orphenadrine hydrochloride Chemical compound [Cl-].C=1C=CC=C(C)C=1C(OCC[NH+](C)C)C1=CC=CC=C1 UQZKYYIKWZOKKD-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- QIIPQYDSKRYMFG-UHFFFAOYSA-N phenyl hydrogen carbonate Chemical compound OC(=O)OC1=CC=CC=C1 QIIPQYDSKRYMFG-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003214 pyranose derivatives Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 208000032253 retinal ischemia Diseases 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 208000012672 seasonal affective disease Diseases 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- BBDNZMUIQBRBJH-UHFFFAOYSA-N sulfurochloridic acid;toluene Chemical compound OS(Cl)(=O)=O.CC1=CC=CC=C1 BBDNZMUIQBRBJH-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005306 thianaphthenyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/14—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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Ophthalmology & Optometry (AREA)
- Emergency Medicine (AREA)
- Anesthesiology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
式(I)化合物或其可药用盐或其前药在治疗或预防其中阻断嘌呤受体,特别是腺苷受体,更特别是A2A受体可对其有益的病症中的应用,其中R1选自H、烷基、芳基、烷氧基、芳氧基、烷硫基、芳硫基、卤素、CN、NR5R6、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7;R2选自经由不饱和碳连接的芳基;R3选自H、烷基、COR5、CO2R7、CONR5R6、CONR4NR5R6和SO2R7;R4、R5和R6独立地选自H、烷基和芳基,或者当R5和R6在NR5R6基团中时,R5和R6可连接以形成杂环基,或者当R4、R5和R6在(CONR4NR5R6)基团中时,R4和R5可连接以形成杂环基;且R7选自烷基和芳基,特别是其中所述病症是运动病症例如帕金森氏病,或者所述病症是抑郁症、认知或记忆减损、急性或慢性疼痛、ADHD或嗜眠症,或所述化合物用于个体中的神经保护;用于治疗的式(I)化合物;和新的式(I)化合物自身。
Description
技术领域
本发明涉及三唑并[4,5-d]嘧啶衍生物及其在治疗中的应用。特别是,本发明涉及其中降低嘌呤能(purinergic)神经传递可对其有益的疾病的治疗。本发明尤其涉及阻断腺苷受体、特别是腺苷A2A受体,和治疗运动病症例如帕金森氏病。
背景技术
运动病症是严重的健康问题,尤其是在老年人当中更是如此。这些运动病症经常是脑损伤的结果。导致运动病症的涉及基底神经节的病症包括帕金森氏病、亨廷顿氏舞蹈病和Wilson′s病。此外,运动障碍经常作为脑缺血和其它神经病症的后遗症出现。
帕金森氏病有4类典型的症状:震颤、僵硬、运动不能和姿势改变。该疾病通常还与抑郁症、痴呆和总体认知衰退有关。帕金森氏病的发病率为占总人口的千分之一。对于年龄超过60岁的人,发病率增高至百分之一。黑质中的多巴胺能神经元变性以及随后纹状体中多巴胺间质浓度的降低对于帕金森氏病的发展是决定性的。在帕金森氏病的临床症状表现出之前,有80%的黑质细胞需要被破坏。
目前治疗帕金森氏病的策略是基于递质替代治疗(L-二羟基苯基乙酸(L-DOPA))、抑制单胺氧化酶(例如Deprenyl)、多巴胺受体激动剂(例如溴隐亭和阿朴吗啡)和抗胆碱能剂(例如苯托品、邻甲苯海拉明)。当发展成“开关”症状时,递质替代治疗特别不提供持续的临床益处,尤其是长期治疗后更是如此,并且这种治疗还与手足徐动症和舞蹈病的不随意运动、恶心和呕吐有关。此外,目前的疗法不治疗导致患者持续认知衰退的基础性神经变性病症。尽管批准了新的药物,但是在医疗上仍然需要对运动病症、尤其是帕金森氏病的改进的治疗。特别是需要要求较少给药次数的有效治疗、带来较不严重副作用的有效治疗和控制或逆转基础性神经变性病症的有效治疗。
最近,A2腺苷受体阻断已牵涉在运动病症例如帕金森氏病的治疗中(Richardson,P.J.等人,Trends Pharmacol.Sci.1997,18,338-344)和脑缺血的治疗中(Gao,Y.和Phillis,J.W.,Life Sci.1994,55,61-65)。最近已有人综述性地描述了腺苷A2A受体拮抗剂在运动病症例如帕金森氏病的治疗中的潜在用途(Mally,J.和Stone,T.W.,CNS Drugs,1998,10,311-320)。
腺苷是天然嘌呤核苷,其具有多种充分证明的调节功能和生理作用。由于嘌呤能剂对CNS病症的治疗可能性,内源性核苷的中枢神经系统(CNS)作用在药物开发中吸引了特别的注意(Jacobson,K.A.等人,J.Med.Chem.1992,35,407-422)。最近,这种治疗可能性已经使得在腺苷受体激动剂和拮抗剂领域中付出了相当的研究努力(Bhagwhat,S.S.;Williams,M.Exp.Opin.Ther.Patents 1995,5,547-558)。
腺苷受体代表称为嘌呤受体的嘌呤核苷酸和核苷受体组当中的一个亚类(P1)。主要的药理不同的腺苷受体亚型称为A1、A2A、A2B(高和低亲和力)和A3(Fredholm,B.B.,等人,Pharmacol.Rev.1994,46,143-156)。腺苷受体存在于CNS中(Fredholm,B.B.,News Physiol.Sci.,1995,10,122-128)。
已有人综述性地描述了P1受体介导的活性剂的设计(Jacobson,K.A.,Suzuki,F.,Drug Dev.Res.,1997,39,289-300;Baraldi,P.G.等人,Curr.Med.Chem.1995,2,707-722),并且声称这样的化合物可用于治疗脑缺血或神经变性病症例如帕金森氏病(Williams,M.和Burnstock,G.Purinergic Approaches Exp.Ther.(1997),3-26.Editor:Jacobson,Kenneth A.;Jarvis,MichaelF.Publisher:Wiley-Liss,New York,N.Y.)。
据推测,黄嘌呤衍生物例如咖啡因可给注意涣散多动症(ADHD)提供一定形式的治疗。有很多研究证实了咖啡因在控制ADHD症状方面的有益作用(Garfinkel,B.D.等人,Psychiatry,1981,26,395-401)。据信,拮抗腺苷受体是咖啡因在人体中的大部分有益作用的原因,并且因此腺苷A2A受体被阻断可能是在ADHD患者观察到的咖啡因的作用的原因。因此,选择性A2A受体拮抗剂可给ADHD提供有效治疗,但是没有目前的治疗所带来的不需要的副作用。
人们已经认识到腺苷受体在睡眠模式的调节中起重要作用,并且实际上,腺苷拮抗剂例如咖啡因产生很强的刺激作用,并且可用于延长不眠(Porkka-Heiskanen,T.等人,Science,1997,276,1265-1268)。最近的证据表明,腺苷调节睡眠的作用有相当一部分是经由腺苷A2A受体介导的(Satoh,S.,等人,Proc.Natl.Acad.Sci.,USA,1996)。因此,选择性A2A受体拮抗剂可有益地在睡眠障碍例如睡眠过度或嗜眠症中对抗过度睡意。
最近已经观察到,重性抑郁症患者对腺苷激动剂诱导的血小板刺激作用表现出迟钝的反应,这意味着在抑郁症期间可发生A2A受体功能的失调(Berk,M.等人,2001,Eur.Neuropsychopharmacol.11,183-186)。动物模型中的实验证据表明,阻断A2A受体功能带来了抗抑郁剂活性(El Yacoubi,M等人Br.J.Pharmacol.2001,134,68-77)。因此,A2A受体拮抗剂可给重性抑郁症和其它情感性病症患者提供新的疗法。
已经有人综述性地描述了腺苷A2A受体的药理作用(Ongini,E.;Fredholm,B.B.Trends Pharmacol.Sci.1996,17(10),364-372)。在上述通过阻断A2腺苷受体来进行的运动病症的治疗中,一种可能的基础机制是,有证据表明,在CNS中,在腺苷A2A受体与多巴胺D2受体之间有功能联系。某些早期研究(例如Ferre,S.等人,刺激高亲和力腺苷A2A受体降低大鼠纹状体膜中多巴胺D2受体的亲和力.Proc.Natl.Acad.Sci.U.S.A.1991,88,7238-41)已经总结在两篇更近期的文章中(Fuxe,K.等人,Adenosine Adenine Nucleotides Mol.Biol.Integr.Physiol.,[Proc.Int.Symp.],5th(1995),499-507.Editors:Belardinelli,Luiz;Pelleg,Amir.Publisher:Kluwer,Boston,Mass.;Ferre,S.等人,Trends Neurosci.1997,20,482-487)。
作为这些对腺苷A2A受体在CNS中的功能作用的研究,尤其是将A2受体与僵住症联系起来的体内研究的结果(Ferre等人,Neurosci.Lett.1991,130,162-4;Mandhane,S.N.等人,Eur.J.Pharmacol.1997,328,135-141),已经对选择性结合腺苷A2A受体,从而可能有效治疗帕金森氏病的活性剂进行了研究。
虽然许多有可能治疗帕金森氏病的药物已在运动病症的治疗中表现出有益作用,但是腺苷A2A拮抗剂治疗的优点是还可以治疗基础神经变性病症。已经有人综述性地描述了腺苷A2A拮抗剂的神经保护作用(Ongini,E.;Adami,M.;Ferri,C.;Bertorelli,R.,Ann.N.Y.Acad.Sci.1997,825(神经保护剂),30-48)。特别是,最近有强有力的证据表明,阻断A2A受体功能在小鼠中提供了抗MPTP诱导的神经毒性的神经保护作用(Chen,J-F.,J.Neurosci.2001,21,RC143)。此外,最近有几项研究已表明,通过饮食摄取咖啡因—一种已知的腺苷A2A受体拮抗剂可降低人中帕金森氏病的危险性(Ascherio,A.等人,Ann Neurol.,2001,50,56-63;Ross G W,等人,JAMA,2000,283,2674-9)。因此,A2A受体拮抗剂可提供新的治疗,以在神经变性疾病例如帕金森氏病中提供神经保护作用。
黄嘌呤衍生物已作为可用于治疗由腺苷A2受体机能亢进所引起的各种疾病例如帕金森氏病的腺苷A2受体拮抗剂被公开过(参见例如EP-A-565377)。
一种卓越的黄嘌呤衍生的腺苷A2A选择性拮抗剂是CSC[8-(3-氯苯乙烯基)咖啡因](Jacobson等人,FEBS Lett.,1993,323,141-144)。
茶碱(1,3-二甲黄嘌呤)—一种支气管扩张药物,其是作用于腺苷A1和A2A受体的混合拮抗剂,已经在临床上对其研究过。为了确定该腺苷受体拮抗剂的制剂是否有治疗帕金森氏病的价值,对15名帕金森氏病患者进行了开放试验,其中是用缓释经口茶碱制剂(150mg/天)治疗最高达12周,1周后产生了4.44mg/L的血清茶碱水平。患者在平均目标病废得分方面表现出了显著改善,有11名患者报告有中等或显著主观改善(Mally,J.,Stone,T.W.J.Pharm.Pharmacol.1994,46,515-517)。
KF 17837[(E)-8-(3,4-二甲氧基苯乙烯基)-1,3-二丙基-7-甲基黄嘌呤]是选择性腺苷A2A受体拮抗剂,在经口给药时,其显著改善通过脑室内施用腺苷A2A受体激动剂CGS 21680所诱导的僵住症反应。KF17837还减轻由氟哌啶醇和利血平引起的僵住症。此外,KF 17837增强阈下剂量的L-DOPA加苄丝肼的抗僵住症作用,这意味着KF 17837是中枢活性的腺苷A2A受体拮抗剂,并且腺苷A2A受体拮抗剂增强了黑质纹状体途径的多巴胺功能(Kanda,T.等人,Eur.J.Pharmacol.1994,256,263-268)。KF 17837的构效关系(SAR)已经公开过(Shimada,J.等人,Bioorg.Med.Chem.Lett.1997,7,2349-2352)。最近还提供了关于腺苷A2A受体拮抗剂KW-6002的数据(Kuwana,Y等人,Soc.Neurosci.Abstr.1997,23,119.14;和Kanda,T.等人,Ann.Neurol.1998,43(4),507-513)。
共享这些药理性质的新的非黄嘌呤结构包括SCH 58261及其衍生物(Baraldi,P.G.等人,吡唑并[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶衍生物:强效且选择性的A2A腺苷拮抗剂.J.Med.Chem.1996,39,1164-71)。据报道,SCH 58261(7-(2-苯基乙基)-5-氨基-2-(2-呋喃基)-吡唑并[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶)能有效地治疗运动病症(Ongini,E.Drug Dev.Res.1997,42(2),63-70),并且随后又开发了一系列化合物(Baraldi,P.G.等人,J.Med.Chem.1998,41(12),2126-2133)。
上述讨论表明,人运动病症的可能有效治疗应当包括起腺苷A2A受体拮抗剂作用的活性剂。
发明内容
现在已经发现,在结构上与已知腺苷受体拮抗剂无关的三唑并[4,5-d]嘧啶衍生物对于腺苷(P1)受体,特别是腺苷A2A受体表现出意料不到的拮抗剂结合亲和力。因此,这样的化合物可用于治疗其中阻断嘌呤受体,特别是腺苷受体,更特别是腺苷A2A受体可对其有益的病症。特别是,这样的化合物可适于治疗运动病症,例如导致运动障碍的基底神经节病症。特别感兴趣的病症包括帕金森氏病、阿尔茨海默氏病、痉挛状态、亨廷顿氏舞蹈病和Wilson′s病。
这样的化合物还可以特别适于治疗抑郁症、认知或记忆减损,包括阿尔茨海默氏病、急性或慢性疼痛、ADHD和嗜眠症,或适于神经保护。
本发明提供了式(I)化合物或其可药用盐或其前药在制备用于治疗或预防其中阻断嘌呤受体,特别是腺苷受体,更特别是A2A受体可对其有益的病症的药物中的应用:
其中
R1选自H、烷基、芳基、烷氧基、芳氧基、烷硫基、芳硫基、卤素、CN、NR5R6、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7;
R2选自经由不饱和碳连接的芳基;
R3选自H、烷基、COR5、CO2R7、CONR5R6、CONR4NR5R6和SO2R7;
R4、R5和R6独立地选自H、烷基和芳基,或者当R5和R6在NR5R6基团中时,R5和R6可连接以形成杂环基,或者当R4、R5和R6在(CONR4NR5R6)基团中时,R4和R5可连接以形成杂环基;且R7选自烷基和芳基。
本文所用术语“烷基”是指支链或直链、环状或开链、饱和或不饱和(例如链烯基或炔基)烃基,并且可以取代或未取代的。当是环状时,烷基优选为C3-C12,更优选C5-C10,更优选C5、C6或C7。当是开链的时,烷基优选是C1-C10,更优选C1-C6,更优选是甲基、乙基、丙基(正丙基或异丙基)、丁基(正丁基、异丁基或叔丁基)或戊基(包括正戊基和异戊基),更优选甲基。因此应当理解,本文所用的术语“烷基”包括烷基(支链或直链)、链烯基(支链或直链)、炔基(支链或直链)、环烷基、环烯基和环炔基。
本文所用术语“低级烷基”是指甲基、乙基、丙基(正丙基或异丙基)或丁基(正丁基、异丁基或叔丁基)。
本文所用术语“芳基”是指芳族基团例如苯基或萘基,或含有一个或多个杂原子的杂芳基例如吡啶基、吡咯基、喹啉基、呋喃基、噻吩基、噁二唑基、噻二唑基、噻唑基、噁唑基、异噁唑基、吡唑基、三唑基、咪唑基、嘧啶基、吲哚基、吡嗪基和吲唑基。
本文所用术语“杂芳基”是指含有一个或多个优选选自N、O和S的杂原子的芳族基团,例如吡啶基、吡咯基、喹啉基、呋喃基、噻吩基、噁二唑基、噻二唑基、噻唑基、噁唑基、异噁唑基、吡唑基、三唑基、咪唑基、嘧啶基、吲哚基、吡嗪基和吲唑基。
本文所用术语“非芳族杂环基”是指含有一个或多个优选选自N、O和S的杂原子的非芳族环状基团,例如环状氨基(包括氮杂环丙烷基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基)或环状醚(包括四氢呋喃基)。
本文所用术语“烷氧基”是指烷基-O-。本文所用术语“芳氧基”是指芳基-O-。
本文所用术语“卤素”是指氟、氯、溴或碘基团。
本文所用术语“前药”是指本发明化合物的任何可药用前药。
当依据如上所定义的式(I),任何R1-R14选自烷基、烷氧基和烷硫基,特别是选自烷基和烷氧基时,则烷基或烷氧基或烷硫基的烷基可以是取代或未取代的。当依据如上所定义的式(I),任何R1-R14选自芳基、芳氧基和芳硫基,特别是选自芳基和芳氧基时,则所述芳基或芳氧基的芳基可以是取代或未取代的。当R5与R6或者R4与R5连接以形成杂环基时,所述杂环基可以是取代或未取代的。当被取代时,一般存在1-3个取代基,优选1个取代基。取代基可包括:
含碳基团例如
烷基,
芳基(例如取代和未取代的苯基(包括烷基苯基、烷氧基苯基和卤代苯基),
芳基烷基(例如取代和未取代的苄基);
卤素原子和含有卤素的基团例如
卤代烷基(例如三氟甲基),
卤代芳基(例如氯苯基);
含有氧的基团例如
醇(例如羟基、羟基烷基、羟基芳基、(芳基)(羟基)烷基),
醚(例如烷氧基、芳氧基、烷氧基烷基、芳氧基烷基、烷氧基芳基、芳氧基芳基),
醛(例如甲醛),
酮(例如烷基羰基、芳基羰基、烷基羰基烷基、烷基羰基芳基、芳基羰基烷基、芳基羰基芳基、芳基烷基羰基、芳基烷基羰基烷基、芳基烷基羰基芳基),
酸(例如羧基、羧基烷基、羧基芳基),
酸衍生物例如酯
(例如烷氧基羰基、芳氧基羰基、烷氧基羰基烷基、芳氧基羰基烷基、烷氧基羰基芳基、芳氧基羰基芳基、烷基羰基氧基、烷基羰基氧基烷基),
酰胺
(例如氨基羰基、一-或二烷基氨基羰基、环氨基羰基、氨基羰基烷基、一-或二烷基氨基羰基烷基、芳基氨基羰基或芳基烷基氨基羰基、烷基羰基氨基、芳基羰基氨基或芳基烷基羰基氨基),
氨基甲酸酯
(例如烷氧基羰基氨基、芳氧基羰基氨基、芳基烷氧基羰基氨基、氨基羰基氧基、一-或二-烷基氨基羰基氧基、芳基氨基羰基氧基或芳基烷基氨基羰基氧基)
和脲(例如一-或二-烷基氨基羰基氨基、芳基氨基羰基氨基或芳基烷基氨基羰基氨基);
含氮基团例如
胺(例如氨基、一-或二-烷基氨基、环氨基、芳基氨基、氨基烷基、一-或二-烷基氨基烷基),
叠氮化物,
腈(例如氰基、氰基烷基),
硝基,
磺酰胺(例如氨基磺酰基、一-或二-烷基氨基磺酰基、一-或二-芳基氨基磺酰基、烷基-或芳基-磺酰基氨基、烷基-或芳基-磺酰基(烷基)氨基、烷基-或芳基-磺酰基(芳基)氨基);
含硫基团例如
硫醇、硫醚、亚砜和砜
(例如烷硫基、烷基亚磺酰基、烷基磺酰基、烷硫基烷基、烷基亚磺酰基烷基、烷基磺酰基烷基、芳硫基、芳基亚磺酰基、芳基磺酰基、芳硫基烷基、芳基亚磺酰基烷基、芳基磺酰基烷基)和含有一个或多个、优选一个杂原子的杂环基
(例如噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、噁二唑基、噻二唑基、氮杂环丙烷基、氮杂环丁烷基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、四氢呋喃基、吡喃基、吡喃酮基、吡啶基、吡嗪基、哒嗪基、哌啶基、六氢氮杂基、哌嗪基、吗啉基、硫茚基、苯并呋喃基、异苯并呋喃基、吲哚基、羟吲哚基、异吲哚基、吲唑基、二氢吲哚基、7-氮杂吲哚基、苯并吡喃基、香豆素基、异香豆素基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、吡啶并吡啶基、苯并噁嗪基、喹喔啉基、色烯基、色满基、异色满基、酞嗪基(phthalazinyl)和咔啉基)。
当任何R1-R14选自芳基或选自含有芳基的基团例如芳氧基或芳硫基时,优选的取代基选自卤素、烷基(取代或未取代的;其中取代的烷基特别选自烷氧基烷基、羟基烷基、氨基烷基和卤代烷基)、羟基、烷氧基、CN、NO2、胺(包括氨基、一-和二-烷基氨基)、烷氧基羰基、氨基羰基、羧酰氨基、磺酰氨基、烷氧基羰基氨基和芳基,特别选自未取代的烷基、取代的烷基(包括烷氧基烷基和氨基烷基)、卤素和胺。
在一个实施方案中,当任何R1-R14被烷基取代基或含有烷基的取代基(例如烷氧基或烷基羰基氨基)直接取代时,则直接连接在任何R1-R14上的取代基的烷基部分可被上述取代基进一步取代,特别是被卤素、羟基、烷氧基、CN、胺(包括氨基、一-和二-烷基氨基)和芳基进一步取代。
在另一个实施方案中,当任何R1-R14被芳基取代基或含有芳基的取代基(例如芳氧基或芳基氨基羰基氨基)直接取代时,则直接连接在任何R1-R14上的取代基的芳基部分可被上述取代基进一步取代,特别是被下列基团进一步取代:卤素、烷基(取代或未取代的;其中取代的烷基特别选自烷氧基烷基、羟基烷基、氨基烷基和卤代烷基)、羟基、烷氧基、CN、NO2、胺(包括氨基、一-和二-烷基氨基)、烷氧基羰基、氨基羰基、羧酰氨基、磺酰氨基、烷氧基羰基氨基和芳基。在另一个实施方案,所述芳基部分被下列基团取代:卤素、烷基(包括CF3)、羟基、烷氧基、CN、胺(包括氨基、一-和二-烷基氨基)和NO2。在另一个实施方案中,所述芳基部分被下列基团取代:未取代的烷基、取代的烷基(特别是烷氧基烷基和氨基烷基)、卤素和胺。
本文所用术语“直接取代”和“直接连接”是指取代基直接键合到任何R1-R14上,而没有任何介于中间的二价原子或基团。
在式(I)化合物中,R1选自H、烷基(包括支链和直链烷基、取代和未取代的烷基、和环状以及开链的烷基)、芳基(包括杂芳基)、烷氧基、芳氧基、烷硫基、芳硫基、卤素、CN、NR5R6(包括NH2)、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7。
在一个实施方案中,式(I)化合物是定义如下的那些:其中R1选自烷基(包括支链和直链烷基、取代和未取代的烷基、和环状以及开链的烷基)、芳基(包括杂芳基)、烷氧基、芳氧基、烷硫基、芳硫基、卤素、CN,NR5R6(包括NH2)、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7。
R1优选选自烷基(包括支链和直链烷基、取代和未取代的烷基、和环状以及开链的烷基)、烷氧基、烷硫基、NR5R6(包括NH2)、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7,更优选选自NR5R6(包括NH2)、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7,更优选选自NR5R6(包括NH2)和NR4COR5,更优选选自NR5R6(包括NH2),最优选选自NH2。
当R1选自NR5R6时,在一个实施方案中,R5和R6独立地选自氢、烷基和芳基,优选选自氢。
当R1选自NR4COR5时,在一个实施方案中,R4是氢。
当R1选自烷基时,R1优选为C1-6烷基,更优选为C1-6饱和烷基,更优选为低级烷基。在一个实施方案中,R1选自取代的烷基,特别是卤代烷基(包括CF3)和芳基烷基(包括杂芳基烷基),特别是卤代烷基(包括CF3)。
R2优选是杂芳基,优选是连接在式(I)嘧啶环上的杂芳基,这样至少有一个杂原子与连接在所述嘧啶环上的不饱和碳原子相邻。R2优选是含有N、O或S的杂芳基。R2可含有一个或多个选自N、O和S的杂原子。
在一个实施方案中,R2的芳基(包括其中R2是杂芳基)不是邻位,邻位-二取代的。优选地,R2的芳基(包括其中R2是杂芳基)不在任一个邻位上被取代。本文所用的R2基团的邻位取代是指相对于R2与式(I)嘧啶部分的连接点的R2基团的邻位。
在优选的实施方案中,R2选自呋喃基(包括2-呋喃基)、噻吩基(包括2-噻吩基)、吡啶基(包括2-吡啶基)、噻唑基(包括2-和5-噻唑基)、吡唑基(包括3-吡唑基)、三唑基(包括4-三唑基)、吡咯基(包括2-吡咯基)和噁唑基(包括5-噁唑基)。在另一个实施方案中,R2选自2-呋喃基、2-噻吩基、2-噻唑基、2-吡啶基、3-吡唑基、2-吡咯基、4-三唑基和5-噁唑基。在另一个优选的实施方案中,R2选自呋喃基、噻吩基、吡啶基、噻唑基和吡唑基,特别选自2-呋喃基、2-噻吩基、2-噻唑基、2-吡啶基和3-吡唑基。在另一个实施方案中,R2选自呋喃基、噻吩基和吡啶基,优选选自2-呋喃基、2-噻吩基和2-吡啶基。在一个特别优选的实施方案中,R2选自呋喃基,优选选自取代或未取代的2-呋喃基。
当R2不是杂芳基时,R2优选为苯基。
在式(I)化合物中,R3选自H、烷基(包括支链和直链烷基、取代和未取代的烷基、环状和开链的烷基)、COR5、CO2R7、CONR5R6、CONR4NR5R6和SO2R7。
当R3选自烷基时,R3优选为开链烷基,优选开链C1-6烷基(包括链烯基和炔基),优选开链C1-6饱和烷基,优选低级烷基。在一个实施方案中,R3选自取代或未取代的甲基、乙基和丙基(正丙基或异丙基)。
当R3选自烷基,特别是选自饱和开链C1-6烷基,特别选自低级烷基,尤其是选自甲基、乙基和丙基时,R3优选是取代的烷基。优选的取代基是芳基(包括杂芳基)、环烷基、非芳族杂环基、CN、COR5、CO2R5、CONR5R6、CONR4NR5R6和C(=NR4)NR5R6,优选是芳基(包括杂芳基)、CONR5R6、CO2R5和COR5(特别是其中R5是芳基),更优选为芳基(包括杂芳基)、CONR5R6和CO2R5,更优选为芳基(包括杂芳基)和CONR5R6,最优选是芳基(包括杂芳基)。
当R3选自芳基烷基(包括杂芳基烷基)时,芳基(包括杂芳基)可以是未取代的,或者如下文在描述基团R11时所详细定义的那样被取代。芳基烷基(包括杂芳基烷基)优选是芳基甲基(包括杂芳基甲基)。下文在描述基团Ar时详细列出了优选的芳基。
当R3选自CONR5R6时,R5和R6选自H、烷基(包括取代的烷基例如芳基烷基(包括杂芳基烷基))和芳基(包括杂芳基),或者R5和R6可以连接以形成杂环。在一个实施方案中,R5和R6选自未取代的烷基和芳基烷基(包括杂芳基烷基)。所述芳基可以是取代或未取代的。在优选的实施方案中,R5和R6当中有一个是氢。在另一个优选的实施方案中,R5是H,且R6选自芳基烷基(包括杂芳基烷基),优选芳基甲基(包括杂芳基甲基)。
在优选的实施方案中,R3选自H和取代的烷基,优选地,其中所述烷基被芳基(包括杂芳基)或CONR5R6取代,优选被芳基(包括杂芳基)取代,更优选被取代的芳基(包括杂芳基)取代。在一个实施方案中,R3选自(CR9R10)nR8,其中n是1-6(n优选为1、2或3,n优选是1),R9和R10独立地选自H、烷基和芳基,且R8选自芳基(包括杂芳基)、环烷基、非芳族杂环基、CN、COR5、CO2R5、CONR5R6、CONR4NR5R6和C(=NR4)NR5R6,优选选自芳基(包括杂芳基)、CONR5R6、CO2R5和COR5(优选其中R5是芳基),更优选选自芳基(包括杂芳基)、CONR5R6和CO2R5,更优选选自芳基(包括杂芳基)和CONR5R6,最优选选自芳基(包括杂芳基)。优选地,R9和R10独立地选自H和烷基(优选开链饱和C1-6烷基,优选低级烷基,优选甲基、乙基或丙基),更优选选自H。优选地,R9和R10当中至少有一个是H,R9和R10两者优选都是氢。
当R8是芳基(包括杂芳基)时,所述芳基(包括杂芳基)可以是未取代的,或者如下文在描述R11时所详细定义的那样被取代。下文在描述基团Ar时详细列出了优选的芳基。
当R8选自CONR5R6时,R5和R6选自H、烷基(包括取代的烷基例如芳基烷基(包括杂芳基烷基))和芳基(包括杂芳基),或者R5和R6可以连接以形成杂环。在一个实施方案中,R5和R6当中有一个或两个都选自未取代的烷基和芳基烷基(包括杂芳基烷基)。在另一个实施方案中,R5和R6中至少一个选自芳基(包括杂芳基)。所述芳基可以是取代或未取代的。在优选的实施方案中,R5和R6当中有一个是氢。
当R8选自COR5时,R5优选为芳基(包括杂芳基)。
当R8选自CO2R5时,R5优选为烷基或芳基。
在另一个优选的实施方案中,R3选自H和(CR9R10)nR8,更优选选自(CH2)nR8,优选其中R8选自芳基(包括杂芳基)和CONR5R6,更优选其中R8选自芳基(包括杂芳基),更优选其中R8选自取代的芳基(包括杂芳基)。
在另一个实施方案中,R3选自(CR9R10)nR11,其中R9、R10和n如上所定义,且R11选自取代的芳基(包括杂芳基),优选由式Ar(R12)a(R13)b(R14)c所代表的一-、二-或三-取代的芳基(包括杂芳基),其中Ar是芳基(包括杂芳基);其中R12、R13和R14是相同或不同的取代基;且其中a、b和c是0或1,条件是a+b+c≥1。
在一个实施方案中,基团Ar选自苯基。在另一个实施方案中,基团Ar选自杂芳基例如上文所述的杂芳基,优选选自单环或二环杂芳基,更优选选自吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基,优选2-吡啶基),吲哚基(包括2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基、6-吲哚基和7-吲哚基)、呋喃基(包括2-呋喃基和3-呋喃基,优选2-呋喃基)、噻吩基(包括2-噻吩基和3-噻吩基,优选2-噻吩基)、异吲哚基、二氢吲哚基、异噁唑基、噁唑基、噻唑基、吡嗪基、嘧啶基、喹啉基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、吲唑基、苯并间二氧杂环戊烯基和二氢苯并呋喃基,优选选自吡啶基(优选2-吡啶基)、吲哚基、呋喃基(优选2-呋喃基)和噻吩基(优选2-噻吩基),最优选选自吡啶基(优选2-吡啶基)、呋喃基(优选2-呋喃基)和噻吩基(优选2-噻吩基)。
在一个实施方案中,基团Ar选自苯基、吡啶基(优选2-吡啶基)、呋喃基(优选2-呋喃基)、噻吩基(优选2-噻吩基)和吲哚基,特别选自苯基、吡啶基(优选2-吡啶基)、呋喃基(优选2-呋喃基)和噻吩基(优选2-噻吩基)。
取代基R12、R13和R14可选自上文所述的任何取代基。
在一个优选的实施方案中,R12、R13和R14选自NR5R6(包括NH2和NHR5)、烷基(取代或未取代的;优选C1-6开链烷基)、烷氧基(包括氟烷氧基)、卤素(包括F、Cl、Br和I)、NO2、CN、羟基、NHOH、CHO、CONR5R6、CO2R5、NR4COR5(优选NHCOR5)、NR4CO2R7(优选NHCO2R7)、NR4SO2R7(优选NHSO2R7)、OCO2R7和芳基(包括杂芳基)。
在更优选的实施方案中,R12、R13和R14选自NR5R6(包括NH2和NHR5)、烷基(取代或未取代的;优选C1-6开链饱和烷基)、和卤素(优选F或Cl,特别是F)。
在特别优选的实施方案中,R12、R13和R14选自NR5R6(包括NH2和NHR5,优选是NH2)和烷基(取代或未取代的;优选C1-6开链饱和烷基)。
当R12、R13和R14选自取代的烷基时,所述烷基优选选自烷氧基烷基、羟基烷基、氨基烷基(包括NH2-烷基、一-烷基氨基烷基和二-烷基氨基烷基)、卤代烷基(特别是氟烷基(包括CF3))、氰基烷基、烷硫基烷基、烷基羧基氨基烷基、烷氧基羰基氨基烷基和烷基磺酰基氨基,更优选选自烷氧基烷基、羟基烷基、氨基烷基和卤代烷基(特别是氟烷基(包括CF3)),最优选选自烷氧基烷基和氨基烷基。
在一个实施方案中,取代基R12、R13和R14选自卤素、烷基(包括CF3)、羟基、烷氧基、烷硫基、CN、胺(包括氨基、一-和二-烷基氨基)和NO2。
当Ar基团是苯基时,苯环可以是一-、二-或三-取代的,优选其中取代基选自如上所述的NR5R6、烷基、烷氧基、卤素、NO2、CN、羟基、CONR5R6、CO2R5、NR4COR5、NR4CO2R7、NR4SO2R7和OCO2R7,更优选选自NR5R6(包括NH2和NHR5,优选为NH2)、烷基(取代或未取代的;优选C1-6开链饱和烷基;当是取代的烷基时,其优选选自烷氧基烷基、羟基烷基、氨基烷基和卤代烷基(特别是氟烷基(包括CF3)),更优选选自烷氧基烷基和氨基烷基)和卤素(优选F或Cl,特别是F)。当(a+b+c)是2或3时,优选至少有一个取代基是NR5R6,特别是NH2。
当Ar基团是吡啶基时,吡啶基(优选是2-吡啶基)优选是单取代的,优选是6-取代的。优选的取代基选自如上所述的烷基(包括取代和未取代的、饱和和不饱和的(例如链烯基,包括乙烯基);优选是C1-6开链烷基)、烷氧基、卤素、芳基、NO2、NHOH和CHO,更优选选自烷基(取代或未取代的;优选C1-6开链饱和烷基;当是取代的烷基时,其优选选自烷氧基烷基、羟基烷基、氨基烷基和卤代烷基(特别是氟烷基(包括CF3)),更优选选自烷氧基烷基和氨基烷基)。
在优选的实施方案中,R3选自CHR9R11,其中R9和R11如上所定义,优选其中Ar是取代的吡啶基或取代的苯基。当Ar是取代的苯基时,优选地,R12和R13当中至少有一个,或者R12、R13和R14当中至少有一个是NR5R6,优选是NH2。
在式(I)化合物中,R4、R5和R6独立地选自H、烷基(包括支链和直链烷基、取代和未取代的烷基、环状和开链的烷基)和芳基(包括杂芳基),或者当R5和R6在任何NR5R6中时,R5和R6可连接以形成杂环,或者当R4、R5和R6在(CONR4NR5R6)基团中时,R4和R5可连接以形成杂环。
在式(I)化合物中,R7选自烷基(包括支链和直链烷基、取代和未取代的烷基、环状和开链的烷基)和芳基(包括杂芳基)。
当R4-R7独立地选自烷基时,优选地,R4-R7选自C1-6烷基,优选选自C1-6饱和烷基,更优选选自低级烷基。
当R5和R6或者R4和R5连接以形成杂环时,所述杂环可以是饱和、部分不饱和或芳族的,优选是饱和的。所述杂环优选是5、6或7元环,优选是5或6元环,并且可含有一个或多个优选选自N、O和S的另外的杂原子。
在优选的实施方案中,R1是NH2,R2是2-呋喃基,且R3是芳基甲基(包括杂芳基甲基)。
在一个本发明实施方案中,式(I)化合物选自如权利要求41所述的那些。
在另一个本发明实施方案中,式(I)化合物选自如权利要求42所述的那些。
当是手性的时,式(I)化合物可以是成对的对映体的外消旋混合物形式,或者是对映体纯的形式。
依据本发明的另一个方面,本发明提供了治疗或预防其中阻断嘌呤受体,特别是腺苷受体,更特别是腺苷A2A受体可对其有益的病症的方法,所述方法包括给需要这样的治疗的个体施用有效剂量的式(I)化合物或其可药用盐或前药。
所述病症可由于嘌呤受体的机能亢进引起。
特别值得关注的病症是其中阻断嘌呤受体,特别是腺苷受体,更特别是腺苷A2A受体可对其有益的那些。这些病症可包括运动病症例如帕金森氏病、药物诱导的帕金森神经功能障碍、脑炎后帕金森神经功能障碍、由中毒(例如MPTP、锰、一氧化碳)引起的帕金森神经功能障碍和创伤后帕金森氏病(拳击手酩酊样状态综合征)。
其中阻断嘌呤受体可对其有益的其它运动病症包括进行性核上(supernuclear)麻痹、亨廷顿氏舞蹈病、多发性全身萎缩、皮质基底变性、Wilsons病、Hallerrorden-Spatz病、进行性苍白球萎缩、多巴反应性张力障碍帕金森神经功能障碍、痉挛状态或导致异常动作或姿势的其它基底神经节病症。本发明还能有效地治疗具有开关现象的帕金森氏病;具有冷冻(剂量恶化结束时)的帕金森氏病;和具有显著运动障碍的帕金森氏病。
式(I)化合物可以与用于治疗运动病症的一种或多种其它药物例如L-DOPA或多巴胺激动剂联合使用或给药,这些组分可在相同制剂中或者在单独的制剂中以同时或依次给药。
其中阻断嘌呤受体,特别是腺苷受体,更特别是腺苷A2A受体可对其有益的其它病症包括急性和慢性疼痛;例如神经病性疼痛、癌症疼痛、三叉神经痛、偏头痛以及与头痛有关的其它病症、原发性和继发性痛觉过敏、炎性疼痛、感受伤害疼痛、脊髓痨、幻肢疼痛、脊髓损伤疼痛、中枢疼痛、疱疹后疼痛和HIV疼痛;情感性病症,包括心境障碍例如双相性精神障碍、季节性情感障碍、抑郁症、躁狂抑郁症、非典型抑郁症和单抑郁(monodepressive)病;中枢和外周神经系统变性病症,包括皮层基底变性、脱髓鞘疾病(多发性硬化、弥散性硬化)、Freidrich′s共济失调、运动神经元疾病(肌萎缩性侧索硬化、进行性延髓萎缩)、多发性全身萎缩、脊髓病、神经根病、外周神经病(糖尿病性神经病、脊髓痨、药物引起的神经病、维生素缺乏)、全身性红斑狼疮、肉芽肿性疾病、橄榄体脑桥小脑萎缩、进行性苍白球萎缩、进行性核上麻痹、痉挛状态;精神分裂症和相关精神病(pyshoses);认知病症,包括痴呆、阿尔茨海默氏病、额颞痴呆、多梗塞性痴呆、AIDS痴呆、与亨廷顿氏舞蹈病有关的痴呆、雷维小体痴呆、老年痴呆、与年龄有关的记忆减损、与痴呆有关的认知减损、Korsakoff综合征、痴呆pugilans;注意力病症例如注意缺乏活动过强疾病(ADHD)、注意缺乏病症、小(minimal)脑机能障碍、脑损伤儿童综合征、运动过度反应儿童期和活动过强儿童综合征;中枢神经系统损伤,包括创伤性脑损伤、神经外科手术(手术创伤)、用于脑损伤的神经保护、颅内压增高、脑水肿、脑积水、脊髓损伤;脑缺血,包括短暂性缺血发作、中风(血栓性中风、缺血性中风、栓塞性中风、出血性中风、腔隙中风)、蛛网膜下出血、脑血管痉挛、用于中风的神经保护、围生期窒息、淹溺、心搏停止、硬膜下血肿、心肌缺血;肌肉缺血;睡眠障碍例如睡眠过度和嗜眠症;眼睛病症例如视网膜缺血再灌注损伤和糖尿病性神经病;心血管病症例如跛行和低血压;和糖尿病及其并发症。
依据本发明另一个方面,本发明提供了式(I)化合物或其可药用盐或前药在制备用于治疗或预防个体中运动病症的药物中的应用。
依据本发明另一个方面,本发明提供了治疗或预防运动病症的方法,包括给需要这样的治疗的个体施用有效剂量的本发明式(I)化合物或其可药用盐或前药。
依据本发明另一个方面,本发明提供了式(I)化合物或其可药用盐或前药在制备用于个体神经保护的药物中的应用。
依据本发明另一个方面,本发明提供了神经保护的方法,包括给需要这样的治疗的个体施用有效剂量的式(I)化合物或其可药用盐或前药。
用于神经保护的药物或方法可用于治疗患有神经变性病症例如运动病症或有患所述病症危险的个体。
依据本发明另一个方面,本发明提供了式(I)化合物或其可药用盐或前药在治疗中的应用。
本发明可用于人或动物个体,更优选哺乳动物,更优选人个体。
依据本发明另一个方面,本发明提供了式(I)化合物自身,不包括其中R1是H,且R3选自甲基的化合物,更优选不包括其中R1是H,且R3选自未取代的低级烷基的化合物,更优选不包括其中R1是H,且R3选自未取代的烷基的化合物,更优选不包括其中R1是H的化合物。
依据本发明另一个方面,本发明提供了式(I)化合物自身,不包括其中R3是甲基的化合物,优选不包括其中R3是未取代的低级烷基的化合物,更优选不包括其中R3是未取代的烷基的化合物。
依据本发明另一个方面,本发明提供了制备新的式(I)化合物的方法。式(I)化合物可依据常规合成方法制得。例如,其中R1是NH2的式(I)化合物可通过标准方法例如在反应方案1中举例说明的方法合成。
反应方案1
其中R3是烷基(包括芳基烷基、杂芳基烷基和(CR9R10)nCO2R5)的式(4)化合物可由式(3)化合物通过标准方法例如在合适的碱例如氢化钠存在下与合适的烷基卤或取代的烷基卤反应来制得。
其中R3是(CR9R10)nCONR5R6或(CR9R10)nCONR4NR5R6的式(4)化合物可由其中R3是(CR9R10)nCO2R5的式(4)化合物通过标准方法例如与合适的胺或肼直接反应来制得,或者通过首先将酯基CO2R5水解成羧酸,然后与合适的胺或肼在标准偶联试剂例如DCC存在下反应来制得。
其中R3是(CR9R10)nC(=NR4)NR5R6的式(4)化合物可由其中R3是(CR9R10)nCN的式(4)化合物通过标准方法例如在三甲基铝存在下用合适的胺处理来制得。
其中R3是(CR9R10)nCN的式(4)化合物可由式(3)化合物通过标准方法例如在合适的碱如氢化钠存在下用合适的取代的烷基卤处理来制得。
其中R3是CONR5R6或CONR4NR5R6的式(4)化合物可由式(3)化合物通过标准方法例如用合适的异氰酸酯(R5NCO或R6NCO)或氨基甲酰氯(R5R6NCOCl或R5R6NR4NCOCl)处理来制得。
其中R3是COR5、CO2R7或SO2R7的式(4)化合物可由式(3)化合物通过标准方法例如在合适的碱如三乙胺存在下用合适的酰氯(R5COCl)、氯甲酸酯(ClCO2R7)或磺酰氯(R7SO2Cl)处理来制得。
式(3)化合物可由已知的式(2)氯化合物通过标准方法例如芳基或杂芳基偶联反应来制得。合适的芳基或杂芳基偶联反应包括在合适的催化剂例如钯络合物存在下与合适的芳基或杂芳基硼酸衍生物、芳基或杂芳基三烷基锡烷衍生物或芳基或杂芳基卤化锌衍生物的反应。
式(3)化合物还可以由式(7)化合物通过标准方法例如用亚硝酸异戊酯处理来制得。式(7)化合物是文献中已知的,或者可由式(6)化合物通过标准方法例如在适宜的催化剂如Pd存在下用氢还原来制得。式(6)化合物是文献中已知的或者可由已知的式(5)化合物通过标准方法例如上述芳基或杂芳基偶联反应来制得。
其中R1是NR5R6的式(1)化合物可由式(4)化合物通过标准方法例如用合适的醛或酮进行还原胺化或者通过在合适的碱存在下用合适的烷基卤处理来获得。
其中R1是NR4CONR5R6,R4是H的式(1)化合物可由式(4)化合物通过标准方法例如用合适的异氰酸酯(R5NCO或R6NCO)或氨基甲酰氯(R5R6NCOCl)处理来制得。其中R1是NR4CONR5R6,其中R4是烷基的式(1)化合物可通过首先进行如上所述的附加的烷基化步骤而如上所述制得。
其中R1是NR4COR5、NR4CO2R7或NR4SO2R7,其中R4是H的式(1)化合物可由式(4)化合物通过标准方法例如在合适的碱存在下用合适的酰氯(R5COCl)、氯甲酸酯(ClCO2R7)或磺酰氯(R7SO2Cl)处理来制得。其中R1是NR4COR5、NR4CO2R7或NR4SO2R7,R4是烷基的式(1)化合物可通过首先进行如上所述的附加的烷基化步骤而如上所述制得。
其中R1是NH2的式(1)化合物可通过标准方法例如在反应方案2中举例说明的方法合成。
反应方案2
其中R3是烷基(包括芳基烷基、杂芳基烷基和(CR9R10)nCO2R5)的式(4)化合物可由式(10)化合物通过标准方法例如上述芳基或杂芳基偶联反应来制得。其中R3是烷基的式(10)化合物是文献中已知的,或者可通过类似于文献中描述的方法制得。例如,其中R3是烷基的式(10)化合物可由其中R3是烷基的式(9)化合物通过标准方法例如用亚硝酸异戊酯处理来制得。其中R3是烷基的式(9)化合物是文献中已知的,或者可通过类似于文献中描述方法制得,例如通过在合适的溶剂中,优选在高温下用合适的胺处理已知的式(8)化合物来制得。
其中R1是NH2的式(1)化合物还可以通过标准方法例如在反应方案3中举例说明的方法合成。
反应方案3
其中R3是烷基(包括芳基烷基、杂芳基烷基和(CR9R10)nCO2R5)的式(4)化合物可由其中R3是烷基的式(15)化合物通过标准方法例如用亚硝酸异戊酯处理来制得。其中R3是烷基的式(15)化合物可由其中R3是烷基的式(14)化合物通过标准方法例如在合适的催化剂如Pd存在下用氢还原来制得。其中R3是烷基的式(14)化合物是文献中已知的,或者可由其中X是合适的离去基团例如甲苯磺酸酯或三氟甲磺酸酯基的式(13)化合物通过标准方法例如在合适的碱如三乙胺存在下用合适的胺处理来制得。其中X是合适的离去基团的式(13)化合物是文献中已知的,或者可由式(12)化合物通过标准方法例如在合适的碱如三乙胺或2,6-二甲基吡啶存在下用甲苯磺酰氯或三氟甲磺酸酐处理来制得。式(12)化合物是文献中已知的,或者可由式(11)化合物通过标准方法例如上述芳基或杂芳基偶联反应来制得。
其它式(1)化合物可通过标准方法例如反应方案4中举例说明的方法来制得。
反应方案4
其中R1是H、烷基或芳基的式(1)化合物可由其中R1是H、烷基或芳基的式(16)化合物通过标准方法例如上述芳基或杂芳基偶联反应来制得。其中R1是H、烷基或芳基的式(16)化合物是文献中已知的,或者可通过类似于文献中描述的方法制得。
其中R1是烷氧基、芳氧基、烷硫基、芳硫基、CN或NR5R6的式(1)化合物可由其中R1是卤素的式(1)化合物通过标准方法例如使用合适的亲核试剂(如果需要的话在合适的碱存在下)如醇、硫醇、氰化物或胺(HNR5R6)进行亲核取代来制得。其中R1是卤素的式(1)化合物可由如上所述的其中R1是卤素的式(16)化合物制得。其中R1是卤素的式(16)化合物是文献中已知的,或者可通过类似于文献中描述的方法制得。
其中R1是NR4CONR5R6、NR4COR5、NR4CO2R7或NR4SO2R7,其中R4是烷基或芳基的式(1)化合物可由其中R1是NR5R6,R5是H,且R6是烷基或芳基的式(1)化合物通过上述方法制得。
在一些情况下,制备其中选择R3以行使保护基的功能的式(1)化合物可能是有利的,例如,合适的保护基将是苄基或取代的苄基例如3,4-二甲氧基苄基。这种性质的化合物可如上所述制得,并且可通过标准方法例如用例如TFA处理来除去保护基R3,以生成其中R3是H的式(1)化合物。之后可使用其中R3是H的式(1)化合物来通过上述方法制备其中R3如上所定义的其它式(1)化合物。
在式(1)化合物中,基团R1、R2和R3可如上所定义被进一步取代,并且本领域技术人员应当理解,合适的取代基可依据上述方法直接引入,或者可通过将自身是直接引入的取代基进一步官能化来引入。例如,当基团R1、R2或R3含有硝基取代基时,可通过标准方法将其还原成氨基。之后可通过本领域技术人员已知的各种标准方法将所得氨基进一步转化成其它官能团;例如酰胺、脲、氨基甲酸酯、磺酰胺或烷基胺。
依据本发明另一个方面,本发明提供了包含式(I)化合物和可药用载体或赋形剂的药物组合物,以及制备所述组合物的方法,该方法包括将式(I)化合物与可药用载体或赋形剂混合。
本发明所用的药物组合物包含本发明化合物或其可药用盐或前药,并且还包含可药用载体和任选本领域技术人员已知的其它治疗组分。术语“可药用盐”是指用可药用无毒酸,包括无机酸和有机酸制得的盐。
当式(I)化合物是碱性的时,盐可以用可药用无毒酸,包括无机酸和有机酸制得。这样的酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、马尿酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、草酸、对甲苯磺酸等。特别优选的是盐酸、氢溴酸、磷酸和硫酸,最特别优选的是盐酸盐。
可采用任意合适的给药途径以给患者提供有效剂量的本发明化合物。例如,可采用经口、直肠、非胃肠道(静脉内、肌内)、透皮、皮下、等给药途径。剂型包括片剂、锭剂、分散液、悬浮液、溶液、胶囊、贴剂等。在任何给定情况下,最合适的途径将取决于所治疗病症的严重程度。本发明最优选的给药途径是经口途径。方便起见,组合物可以在单位剂型中提供,并且可通过药物领域众所周知的任何方法制得。
在实际应用中,可依据常规药物混合技术将本发明化合物作为活性组分与药物载体充分混合。根据给药例如经口或非胃肠道(例如静脉内)给药所需的制剂形式,载体可呈多种不同的形式。在制备用于经口剂型的组合物中,对于经口液体制剂(例如悬浮液、溶液和酏剂)或气雾剂,可使用任何常规药物介质作为载体,例如水、二醇、油、醇、矫味剂、防腐剂、着色剂等;或者,对于经口固体制剂例如粉剂、胶囊和片剂,可使用载体例如淀粉、糖、微晶纤维素、纤维素、稀释剂、制粒剂、润滑剂、粘合剂、崩解剂等,其中相对于液体制剂,固体经口制剂是优选的。最优选的固体经口制剂是片剂。
因为其易于给药,片剂和胶囊代表最有利的经口剂量单位形式,其中使用固体药物载体。如果需要的话,可通过标准水或非水技术将片剂包衣。
除了上述常规剂型以外,化合物还可以通过控释手段和/或递送装置例如在下列美国专利中描述的那些来给药:3,845,770;3,916,899;3,536,809;3,598,123;3,630,200;4,008,719;4,687,660;和4,769,027,将这些专利的公开内容引入本发明以作参考。
适于经口给药的本发明所用的药物组合物可以作为分别含有预定量活性组分的不连续单位例如胶囊、扁囊剂或片剂或气雾剂喷剂,作为粉剂或粒剂,在水液体中的溶液或悬浮液,水包油乳剂或油包水液体乳剂来提供。这样的组合物可通过任何制药方法来制备,但是所有方法都包括将活性组分与构成一种或多种必需组分的载体混合的步骤。一般情况下,组合物是这样制得的:将活性组分与液体载体或细分散的固体载体或二者均匀且充分地混合,然后如果需要的话,将产物制成所需递送形状。
例如,片剂可通过任选与一种或多种辅助成分压缩或模制来制得。压制片可通过将可自由流动形式例如粉末或颗粒形式的任选与粘合剂、润滑剂、惰性稀释剂和/或表面活性剂或分散剂混合的活性组分在合适的机器中压片来制得。模制片可通过将用惰性液体稀释剂润湿的化合物粉末的混合物在合适的机器中模制来获得。
可用下列实施例来进一步定义本发明。对于本领域技术人员显而易见的是,可在不背离本发明目的和实质的情况下对材料和方法作许多改变。
具体实施方式
实施例
合成实施例
可用如表1所示的下列实施例来举例说明本发明。
表1
用于制备这些实施例的一般合成方法在下文中作为方法A-BH列出。表2列出了每个实施例所用的方法以及分析数据。
使用下列条件进行HPLC:柱:Waters Xterra RP18(50×4.6mm);粒径5μM;流动相:MeOH:10mM NH4OAc水溶液(pH7缓冲液);梯度:50∶50等度(isocratic)洗脱1分钟,然后50∶50至80∶20的线性梯度5分钟,之后是80∶20等度洗脱3分钟;流速:2.0mL/分钟;检测波长λ=230nM。提供保留时间。
方法A
7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例1)
将7-氯-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(570mg,3.34mmol)在N-甲基-2-吡咯烷酮(4mL)中的溶液用PdCl2(PPh3)2(117mg,0.17mmol)和2-(三丁基锡烷基)呋喃(1.05mL,1mmol)处理,在80℃搅拌5小时,用EtOAc稀释,经由二氧化硅垫过滤,并真空浓缩。用乙醚研制残余物,分离出了本标题化合物,为黄色固体(438mg,65%)。
方法B
3-(2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例3)
在0℃,将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(101mg,0.5mmol)在DMF(2mL)中的溶液用NaH(20mg,60%,0.5mmol)处理,搅拌20分钟,然后用2-氟苄基溴(60μl,0.5mmol)处理。让该反应混合物温热至室温,搅拌1小时用水中止反应,用EtOAc萃取,干燥(MgSO4)并真空浓缩。通过色谱法纯化粗产物(EtOAc∶庚烷,1∶4-EtOAc∶庚烷,2∶1),获得了N,N-二(2-氟苄基)-3-(2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例2)(28mg,11%),为黄色固体,和本标题化合物(34mg,22%),为黄色固体。
方法C
3-(3-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例5)
在50℃,将7-(2-呋喃基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(152mg,0.45mmol)在EtOH(2mL)中的溶液用SnCl2(305mg,1.35mmol)在浓盐酸(0.7mL)中的溶液处理,搅拌2小时,冷却,用水稀释,碱化至pH 10(5-M,NaOH),并过滤,获得了本标题化合物(127mg,92%),为白色固体。
方法D
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)甲基)苯基-(1-甲基-1H-咪唑-4-基)磺酰胺(实施例9)
将3-(3-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(125mg,0.41mmol)在DMF(2mL)中的溶液用Et3N(85μL,0.61mmol)和1-甲基咪唑-4-磺酰氯(74mg,0.41mmol)处理,在室温搅拌过夜,倒入水内,用EtOAc萃取,干燥(MgSO4)并真空浓缩。通过色谱法纯化粗产物[SiO2;EtOAc∶MeOH(1∶10)],获得了本标题化合物(26mg,14%),为膏状固体。
方法E
5-氨基-N-苄基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲酰胺(实施例10)
将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(202mg,1.0mmol)在DMF(3mL)中的溶液用异氰酸苄酯(123μL,1.0mmol)和催化量的DMAP处理,在室温搅拌过夜,用EtOAc稀释,并过滤,获得了本标题化合物(62mg,19%),为桃色固体。
方法F
5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基乙酸乙酯(实施例14)
将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(101mg,0.5mmol)在DMF(4mL)中的溶液用4-(N,N-二甲基氨基)吡啶(5mg,0.04mmol)和溴乙酸乙酯(55μL,0.5mmol)处理,在室温搅拌16小时,并通过色谱法直接纯化[SiO2;EtOAc∶庚烷(1∶2)],获得了本标题化合物(50mg,35%),为白色固体。
方法G
7-(2-呋喃基)-3-(3-羟基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例18)
在0℃,将7-(2-呋喃基)-3-(3-甲氧基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(119mg,0.37mmol)在二氯甲烷(20mL)中的溶液用三溴化硼(1-M二氯甲烷溶液,8.8mL,8.8mmol)以3天的时间分批处理,真空浓缩,并通过过滤分离,获得了本标题化合物(114mg,100%),为黄色固体。
方法H
6-(5-甲基-2-呋喃基)-5-硝基嘧啶-2,4-二胺
将6-氯-5-硝基嘧啶-2,4-二胺(10g,60%纯度,32mmol)在THF(300mL)中的溶液用饱和碳酸氢钠水溶液(75mL)、5-甲基呋喃-2-硼酸(7.33g,0.058mol)和Pd(PPh3)4(1g,0.865mmol)处理,并在氩气氛下剧烈搅拌回流过夜。将该混合物冷却至室温,用EtOAc(400mL)和水(300mL)稀释,过滤以除去不溶物,用EtOAc(2×100mL)萃取滤液。将合并的有机相干燥(MgSO4),真空浓缩,用二氯甲烷研制所得固体并过滤,获得了本标题化合物(6g,72%),为黄色固体;
mp 196.3-196.9℃;IRνmax(Nujol)/cm-1 3442,3169,2930,1629,1463,1377,1027,and 790;NMRδH(400MHz,DMSO)7.40(2H,brs),7.09(2H,brs),6.87(1H,dd,J 0.5,3.2Hz),6.26(2H,dd,J1.0,3.3Hz)和2.28(3H,s).
方法I
6-(5-甲基-2-呋喃基)嘧啶-2,4,5-三胺
将6-(5-甲基-2-呋喃基)-5-硝基嘧啶-2,4-二胺(6.6g,29.6mmol)和10%Pd/C(0.66g)在MeOH(100mL)中的悬浮液于40℃和氢气氛下加热3小时,冷却至室温,经由硅藻土过滤,并真空浓缩,获得了本标题化合物(5.8g,99%),为灰白色固体;
IRνmax(DR)/cm-13333,2237,1634,1458,1237,1025,963 and 828;NMRδH(400MHz,DMSO)6.77(1H,dd,J0.5,3.2Hz),6.21-6.17(3H,m),5.14(2H,s),4.21(2H,s),和2.35(3H,s).
方法J
7-(5-甲基-2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例19)
将6-(5-甲基-2-呋喃基)嘧啶-2,4,5-三胺(5.8g,30.1mmol)在二氧杂环己烷(116mL)中的溶液用亚硝酸异戊酯(4.1mL,30.5mmol)处理,在80℃加热3.5小时,冷却至室温,过滤所得沉淀,用二氧杂环己烷(10mL)和庚烷(2×15mL)洗涤,然后用庚烷研制并过滤,获得了本标题化合物(4.7g,77%),为沙状固体。
方法K
7-(1H-吡唑-3-基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例21)
将7-(1-(2-(三甲基甲硅烷基)乙氧基甲基)-1H-吡唑-3-基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(120mg,0.361mmol)在MeOH(2mL)中的溶液用HCl(4-M的二氧杂环己烷溶液,1mL)处理,搅拌2小时,过滤并用乙醚洗涤所得固体,获得了本标题化合物(76mg,100%),为黄色固体。
方法L
4-甲基苯磺酸(2-氨基-6-(2-呋喃基)-5-硝基嘧啶-4-基)酯
将2-氨基-6-(2-呋喃基)-5-硝基嘧啶-4(1H)-酮(1.00g,4.50mmol)在二氯甲烷(50mL)中的悬浮液用三乙胺(0.941mL,6.75mmol)和对甲苯磺酰氯(944mg,4.95mmol)处理,搅拌1小时,用二氯甲烷(50mL)稀释,用2-M HCl(20mL)洗涤,干燥(MgSO4),真空浓缩,通过色谱法纯化[SiO2;异己烷∶EtOAc(2∶1)],获得了本标题化合物(410mg,24%),为黄色固体;
NMR δH(400MHz,CDCl3)7.95(2H,d,J8.5Hz),7.59-7.57(1H,m),7.39(2H,d,J 8.5Hz),7.23-7.21(1H,m),6.59-6.51(1H,m),539(2H,brs),2.48(3H,s);
保留时间5.68分钟。
方法M
6-(2-呋喃基)-5-硝基-N4-(2-吡啶基甲基)嘧啶-2,4-二胺
将4-甲基苯磺酸(2-氨基-6-(2-呋喃基)-5-硝基嘧啶-4-基)酯(478mg,1.27mmol)在二甲氧基乙烷(15mL)中的溶液用三乙胺(0.531mL,3.81mmol)和2-吡啶甲基胺(0.393mL,3.81mmol)处理,搅拌16小时,倒入水(100mL)中,将所得固体过滤,获得了本标题化合物(275mg,69%),为黄色固体;
NMR δH(400MHz,CDCl3)8.70-8.58(2H,m),7.70-7.66(1H,m),7.55-7.54(1H,m),7.28(1H,d,J 8.0Hz),7.24-7.20(1H,m),7.07-7.06(1H,m),6.54-6.52(1H,m),5.26(2H,brs)和4.83(2H,d,J 5.0Hz);
保留时间1.44分钟。
方法N
7-(2-呋喃基)-3-(2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例24)
将6-(2-呋喃基)-5-硝基-N4-(2-吡啶基甲基)嘧啶-2,4-二胺(270mg,0.864mmol)和10%Pd/C(92mg,0.086mmol)在EtOH(30mL)和EtOAc(10mL)中的溶液于氢气氛下搅拌1小时,经由硅藻土过滤,并真空浓缩。将所得黄色油状物溶解在二氧杂环己烷(25mL)中,用亚硝酸异戊酯(0.109mL,0.815mmol)处理,在100℃搅拌6小时,冷却至室温,经由硅藻土过滤,真空浓缩,用乙醚研制,获得了本标题化合物(110mg,46%),为黄色固体。
方法O
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)乙酸(实施例26)
将5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基乙酸乙酯(547mg,1.89mmol)在MeOH(5mL)中的溶液用NaOH水溶液(2mL,2-M,4mmol)处理,回流10分钟,冷却,用盐酸水溶液(1-M)酸化,过滤并干燥,获得了本标题化合物(417mg,85%),为白色固体。
方法P
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-N-(3-氯苯基)乙酰胺(实施例31)
将(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)乙酸(140mg,0.5mmol)在DMF(1mL)中的悬浮液用羰基二咪唑(81mg,0.5mmol)处理,在室温搅拌1小时,用3-氯苯胺(53μL,0.5mmol)处理,将该混合物在50℃加热16小时。将该反应混合物冷却,用水(3mL)稀释并过滤,获得了本标题化合物(94mg,48%),为膏状固体。
方法Q
3-(2-氟苄基)-7-(2-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例34)
在-78℃、氩气氛下,将噻唑(0.10mL,1.43mmol)在无水THF(5mL)中的搅拌溶液用n-BuLi(0.9mL,1.6-M的己烷溶液,1.43mmol)处理,搅拌30分钟,用ZnCl2溶液(1.8mL,1-M的Et2O溶液,1.80mmol)处理,并让其逐渐温热至室温。将该混合物用7-氯-3-(2-氟苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(200mg,0.714mmol)和Pd(PPh3)4(50mg)处理,回流2小时,并在饱和NH4Cl(20mL)与EtOAc(20mL)之间分配。将有机相干燥(MgSO4),真空浓缩,并通过色谱法纯化[SiO2;异己烷∶EtOAc(1∶1)],获得了本标题化合物(70mg,30%),为膏状固体。
方法R
N-(2-氨基-6-(2-呋喃基)-5-硝基嘧啶-4-基)-6-氯吡啶-3-甲酰胺
将6-(2-呋喃基)-5-硝基嘧啶-2,4-二胺(500mg,2.26mmol)在吡啶(10mL)中的溶液用6-氯烟酰氯(438mg,2.49mmol)处理,在80℃搅拌16小时,冷却至室温,倒入水(100mL)中,用EtOAc(2×25mL)萃取,将合并的有机相干燥(MgSO4),真空浓缩,通过色谱法纯化[SiO2;异己烷∶EtOAc(3∶2)],获得了本标题化合物(430mg,82%),为黄色固体;
NMR δH(400MHz,DMSO)11.14(1H,s),8.86(1H,d,J 2.5Hz),8.27(1H,dd,J 8.5,2.5Hz),7.93(1H,m),7.77(2H,brs),7.65(1H,d,J 7.5Hz),7.09(1H,d,J 4.5Hz),6.72-6.70(1H,m);
保留时间2.41分钟。
方法T
6-氯-N-(7-(2-呋喃基)-1H-[1,2,3]三唑并[45-d]嘧啶-5-基)吡啶-3-甲酰胺(实施例44)
将N-(2-氨基-6-(2-呋喃基)-5-硝基嘧啶-4-基)-6-氯吡啶-3-甲酰胺(153mg,0.423mmol)和10%Pd/C(82mg,42.3μmol)在EtOH(20mL)和EtOAc(5mL)中的溶液于氢气氛下搅拌3小时,经由硅藻土过滤,真空浓缩,获得了N-(2,5-二氨基-6-(2-呋喃基)嘧啶-4-基)-6-氯吡啶-3-甲酰胺,为黄色油状物。在0℃向该产物在EtOH(5mL)和2-M HCl(5mL)内的溶液中滴加亚硝酸钠(87mg,1.27mmol)在水(2mL)中的冰冷溶液。将该混合物在0℃搅拌1小时,在室温搅拌1小时,用5-M NaOH中和,搅拌16小时,将所得固体过滤,获得了本标题化合物(40mg,28%),为棕色固体。
方法U
6-氯-N4-(3-硝基苄基)嘧啶-2,4,5-三胺
将4,6-二氯嘧啶-2,5-二胺(700mg,3.91mmol)、3-硝基苄基胺盐酸盐(885mg,4.69mmol)和三乙胺(1.6mL,11.7mmol)在n-BuOH(20mL)中的混合物回流17小时,真空浓缩,将残余物在EtOAc(10mL)与H2O(5mL)之间分配。将有机相干燥(MgSO4)并真空浓缩,获得了本标题化合物,为橙色固体(906mg,76%),其不用进一步纯化直接用于下一反应;
NMR δH(400MHz,CDCl3)8.16(1H,s),8.10(1H,d, J 8.0Hz),7.80(1H,d,J 7.5Hz),7.62(1H,t,J 7.5Hz),7.25(1H,t,J 6.0Hz),5.69(2H,s),4.67(2H,d,J 6.0Hz)和3.93(2H,brs).
方法V
3-氯甲基-N,N-二甲基苯甲酰胺
将3-(氯甲基)苯甲酰氯(426μL,3mmol)和Et3N(626μL,4.5mmol)在THF(5mL)中的溶液用二甲胺(1.5mL,2-M的THF溶液,3mmol)处理,在室温搅拌1小时,倒入水内,用EtOAc萃取,干燥(MgSO4)并真空浓缩,获得了本标题化合物(580mg,98%),为无色油状物;
NMR δH(400MHz,CDCl3)7.46-7.34(4H,m),4.59(2H,s),3.11(3H,s)和2.98(3H,s);元素分析C12H12N6O2·0.2H2O的计算值C,49.38;H,4.28,N,28.79.
实测值:C,49.25;H,4.09;N,28.47.
方法W
7-(2-呋喃基)-3-(2-甲氧基-5-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例66)
在0℃,将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(606mg,3mmol)在DMF(5mL)中的溶液用CsCO3(977mg,3mmol)处理,搅拌1小时,用2-甲氧基-5-硝基苄基溴(738mg,3mmol)处理,并在室温搅拌1小时。用水(10mL)稀释该反应混合物,过滤并通过色谱法纯化所得固体[SiO2;EtOAc∶庚烷(2∶1)],获得了本标题化合物(279mg,25%),为黄色固体。
方法X
3-(2-氟苄基)-7-(5-噁唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例69)
在-78℃、氩气氛下,将噁唑(138mg,2.0mmol)在无水THF(10mL)中的搅拌溶液用n-BuLi(1.25mL,1.6-M的己烷溶液,2.0mmol)处理,搅拌30分钟,用ZnCl2溶液(2.0mL,1-M的Et2O溶液,2.0mmol))处理,让其逐渐温热至室温。将该混合物用7-氯-3-(2-氟苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(280mg,1.0mmol)和Pd(PPh3)4(100mg)处理,回流4小时,并在饱和NH4Cl溶液(10mL)与EtOAc(10mL)之间分配。将有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(1∶1),然后仅用EtOAc],获得了本标题化合物(6mg,2%),为米色固体。
方法Y
3-(2-氟苄基)-7-(1H-三唑-4-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例80)
将7-氯-3-(2-氟苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(145mg,0.50mmol)、三丁基1-(2-(三甲基甲硅烷基)乙氧基甲基)-1H-三唑-5-基锡烷(336mg,0.75mmol)和Pd(PPh3)2Cl2(35mg,0.05mmol)在DMF(2mL)中的混合物于80℃振摇17小时,然后通过色谱法直接纯化[SiO2;异己烷∶EtOAc(2∶1)],获得了3-(2-氟苄基)-7-(1-(2-三甲基甲硅烷基)乙氧基甲基)-1H-三唑-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,为无色油状物。将所得产物溶解在MeOH(1mL)中,用HCl溶液(0.5mL,4-M的二氧杂环己烷溶液)处理,搅拌17小时,真空浓缩并用乙醚研制残余物,获得了本标题化合物(16mg,10%),为灰白色固体。
方法Z
3-(4-羟基氨基-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例87)
将7-(5-甲基-2-呋喃基)-3-(4-硝基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(60mg,0.17mmol)在EtOH(40mL)、MeOH(20mL)和水(15mL)中的溶液用氯化铵(280mg,5.23mmol)和锌(138mg,2.05mmol)处理,搅拌1小时,经由硅藻土过滤,真空浓缩至约20mL,用盐水(20mL)稀释,用EtOAc(3×20mL)萃取,将合并的有机相干燥(MgSO4)并真空浓缩,获得了本标题化合物(40mg,73%),为黄色固体。
方法AA
3-(3-氨基甲基苄基)-7-(1H-吡唑-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例101)
将7-(1-(2-(三甲基甲硅烷基)乙氧基甲基)-1H-吡唑-5-基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(330mg,1mmol)在无水DMF(5mL)中的搅拌溶液用NaH(40mg,60%油悬浮液,1mmol)处理,搅拌15分钟,用N-(3-(溴甲基)苄基)氨基甲酸叔丁酯(300mg,1mmol)处理,并搅拌1小时。将该混合物在EtOAc(20mL)与H2O(20mL)之间分配,将有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(1∶1)]。将所得黄色浆状物溶解在MeOH(3mL)中,用HCl(2mL,4-M的二氧杂环己烷溶液)处理,搅拌17小时,将所得固体过滤,获得了本标题化合物(258mg,80%),为膏状固体。
方法AB
2-溴甲基-6-(甲氧基甲基)吡啶
在0℃,将6-甲氧基甲基-2-吡啶甲醇(860mg,5.64mmol)和三苯基膦(1.78g,6.77mmol)在二氯甲烷(40mL)中的溶液分批用CBr4(2.80g,8.43mmol)处理,搅拌1小时,真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(3∶1)],获得了本标题化合物(1.20g,99%),为无色油状物;(1.20g,99%)as a colourless oil;NMR δH(400MHz,CDCl3)7.71(1H,t,J 8.0Hz),7.35(2H,d,J 8.0Hz),4.58(2H,s)和4.54(2H,s).
通过方法AB由合适的醇还合成了下列新化合物。
2-溴甲基-4-甲基吡啶NMR δH(400MHz,CDCl3)8.43(1H,d,J 5.0Hz),7.26-7.25(1H,m),7.03(1H,d,J 5.0Hz),4.51(2H,s)和2.36(3H,s).
2-溴甲基-6-乙基吡啶NMR δH(400MHz,CDCl3)7.60(1H,t,J 7.5Hz),7.26(1H,d,J 7.5Hz),7.08(1H,d,J7.5Hz),4.53(2H,s),2.82(2H,q,J 7.5HZ)和1.30(3H,t,J 7.5Hz).
4-溴甲基-2-乙基吡啶NMR δH(400MHz,CDCl3)8.51(1H,d,J 5.0Hz),7.17-7.16(1H,m),7.13-7.11(1H,m),4.37(2H,s),2.84(2H,q,J 7.5Hz)和1.32(3H,t,J 7.5Hz).
(4-溴甲基-3,5-二氟苯基)碳酸叔丁酯NMR δH(400MHz,CDCl3)6.80(2H,m),4.49(2H,s)和1.56(9H,s).
2-氟-5-碘苄基溴NMR δH(400MHz,DMSO)7.94-7.91(1H,dd,J 2.5,7.5Hz),7.76-7.71(1H,m),7.12-7.06(1H,dd,J 8.5,10.0Hz)和4.66-4.64(2H,s).
2-烯丙氧基甲基-6-溴甲基吡啶NMR δH(400MHz,CDCl3)7.71(1H,t,J 7.5Hz),7.40(1H,d,J 7.5Hz),7.34(1H,d,J7.5Hz),6.03-5.93(1H,m),5.37-5.32(1H,M),5.26-5.22(1H,m),4.64(2H,s),4.54(2H,s)和4.14-4.12(2H,m).
4-硝基-2-(2-三甲基甲硅烷基乙氧基)甲氧基苄基溴NMR δH(400MHz,CDCl3)7.99(1H,d,J 2.0Hz),7.84(1H,dd,J 8.4,2.0Hz),7.49(1H,d,J 8.4Hz),5.41(2H,s),4.55(2H,s),3.82(2H,m),0.96(2H,m)和0.01(9H,s).
2-溴甲基-4,6-二异丙基吡啶NMR δH(400MHz,CDCl3)7.12(1H,s),6.93(1H,s),4.52(2H,s),3.03(1H,sept,J 7.0Hz),2.87(1H,sept,J 7.0Hz),1.29(6H,d,J 7.0Hz)和1.25(6H,d,J 7.0Hz).
2-溴甲基-6-异丙基吡啶NMR δH(400MHz,CDCl3)7.63-7.59(1H,m),7.27-7.25(1H,m),7.10-7.08(1H,m),4.54(2H,s),3.06(1H,sept,J 7.0Hz)和1.30(6H,d,J 7.0Hz).
2-溴甲基-6-乙烯基吡啶NMR δH(400MHz,CDCl3)7.66(1H,t,J 7.5Hz),7.34-7.28(2H,m),6.81(1H,dd,J10.5,17.5Hz),6.22(1H,dd,J 1.0,17.5Hz),5.51(1H,dd,J 1.0,10.5Hz)和4.55(2H,s).
2-溴甲基-5-乙基噻吩NMR δH(400MHz,DMSO)6.85-6.82(1H,d,J 3.5Hz),6.71-6.68(1H,d,J 3.5Hz),4.59-4.55(2H,s),2.81-2.75(2H,m)和1.25-1.20(3H,m).
2-溴甲基-6-正丙基吡啶NMR δH(400MHz,CDCl3)7.59(1H,t,J 7.5Hz),7.26(1H,d,J 7.5Hz),7.06(1H,d,J7.5Hz),4.53(2H,s),2.76(2H,t,J 7.5Hz),1.74(2H,sext,J 7.5Hz)和0.97(3H,t,J 7.5Hz).
2-溴甲基-6-异丁氧基甲基吡啶NMR δH(400MHz,CDCl3)7.71(1H,t,J 7.5Hz),7.41(1H,d,J 7.5Hz),7.33(1H,d,J7.5Hz),4.62(2H,s),4.53(2H,s),3.33(2H,d,J 6.5Hz),1.91-2.01(1H,m)和0.96(6H,d,J 6.5Hz).
5-溴甲基-2-异丙基吡啶NMR δH(400MHz,CDCl3)8.54(1H,m),7.65(1H,dd,J 2.5,8.0Hz),7.16(1H,d,J 8.0Hz),4.47(2H,s),3.07(1H,sept,J 7.0Hz)和1.30(6H,d,J 7.0Hz).
2-溴甲基-6-异丙氧基甲基吡啶NMR δH(400MHz,CDCl3)7.71-7.67(1H,m),7.42-7.40(1H,m),7.33-7.31(1H,m),4.63(2H,s),4.53(2H,s),3.75(1H,sept,J 6.0Hz)和1.25(6H,d,J 6.0Hz).
方法AC
2-溴甲基-4-硝基吡啶
将2-甲基-4-硝基吡啶(1.79g,13.0mmol)在CCl4(30mL)中的溶液用N-溴琥珀酰亚胺(2.31g,13.0mmol)和过氧化苯甲酰(420mg,1.30mmol)处理,在80℃搅拌16小时,冷却至室温,经由硅藻土过滤,真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(15∶1)],获得了本标题化合物(700mg,25%),为无色油状物;
NMR δH(400MHz,CDCl3)8.89(1H,d,J5.0Hz),8.19(1H,d,J 2.0Hz),7.96(1H,dd,J 5.0,2.0Hz)and 4.66(2H,s).
通过使用方法AC溴化合适的芳基烷基化合物,还合成了下列新化合物。
2-溴甲基-6-甲基-4-硝基吡啶NMR δH(400MHz,CDCl3)7.99-7.98(1H,m),7.79(1H,d,J 2.0Hz),4.60(2H,s)和2.71(3H,s).
7-溴甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.57(1H,d,J 4.0Hz),7.55(1H,dd,J 8.0,1.5Hz),7.27(1H,d,J 7.5Hz),7.19(1H,t,J 7.5Hz),6.58(1H,d,J 3.5Hz),5.24(2H,s)和1.68(9H,s).
5-溴甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)8.11(1H,brd,J 8.5Hz),6.72(1H,d,J 3.5Hz),7.59(1H,d,J1.5Hz),7.35(1H,dd,J 8.5,1.5Hz),6.54(1H,d,J 4.0Hz),4.64(2H,s)和1.67(9H,s).
7-溴甲基-5-氯吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.58(1H,d,J 3.5Hz),7.51(1H,d,J 2.0Hz),7.27(1H,m),6.52(1H,d,J 3.5Hz),5.15(2H,s),和1.67(9H,s).
7-溴甲基-5-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.53(1H,d,J 4.0Hz),7.32(1H,s),7.09(1H,s),6.49(1H,d,J 3.5Hz),5.21(2H,s),2.41(3H,s)和1.66(9H,s).
5-溴甲基-7-氟吲哚-1-甲酸叔丁酯NMR δH(CDCl3)7.65(1H,d,J 4.0Hz),7.35(1H,d,J 1.5Hz),7.07(1H,dd,J 13.0,1.5Hz),6.56(1H,dd,J 3.5,1.5Hz),4.56(2H,s)和1.65(9H,s).
5-溴甲基-4-氯吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)8.03(1H,d,J 8.5Hz),7.63(1H,d,J 4.0Hz),7.36(1H,d,8.5Hz),6.71(1H,d,J 3.5Hz),4.75(2H,s)和1.67(9H,s).
7-溴-5-溴甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.57(1H,s),7.56-7.52(2H,m),6.54(1H,d,J 3.5Hz),4.56(2H,s)和1.66(9H,s).
5-溴甲基-6-氯吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)8.23(1H,brs),7.60(1H,s),7.58(1H,d,J 3.5Hz),6.51(1H,d,J 4.5Hz),4.71(2H,s)和1.67(9H,s).
5-溴甲基-6-氟吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.88(1H,brd,J 11.0Hz),7.57(1H,d,J 4.0Hz),7.54(1H,d,J 7.0Hz),6.52(1H,d,J 4.5Hz),4.64(2H,s)和1.67(9H,s).
2-溴甲基-5-氟吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)8.12(1H,dd,J 9.0,4.5Hz),7.15(1H,dd,J 8.5,2.5Hz),7.04(1H,dt,J 9.0,2.5Hz),6.66(1H,s),4.90(2H,s)和1.72(9H,s).
5-溴甲基-7-氯吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.56(1H,d,J 4.0Hz),7.49(1H,d,J 2.0Hz),7.37(1H,s),6.54(1H,d,J 3.5Hz),4.56(2H,s)和1.65(9H,s).
2-(1-溴丙基)-5,6-二甲基吡啶NMR δH(400MHz,CDCl3)7.39(1H,d,J 8.0Hz),7.18(1H,d,J 8.0Hz),4.93(1H,t,J7.5Hz),2.49(3H,s),2.27(3H,s),2.29-2.24(2H,m)和1.02(3H,t,J 7.0Hz);M/Z 228(M+H)+.
通过使用方法AC将2-(1-甲氧基丙基)-6-甲基吡啶溴化,合成了下列新化合物。
2-溴-1-(6-甲基吡啶-2-基)丙酮NMR δH(400MHz,CDCl3)7.91(1H,d,J 7.5Hz),7.74(1H,t,J 7.5Hz),7.35(1H,d,J7.5Hz),6.13(1H,q,J 7.0Hz),2.62(3H,s)和1.89(3H,d,J 7.0Hz).
方法AD
7-甲基吲哚-1-甲酸叔丁酯
将7-甲基吲哚(1.18g,9mmol)在无水THE(50mL)中的搅拌溶液用NaH(360mg,60%油悬浮液,9mmol)处理,搅拌10分钟,用二碳酸二叔丁酯(2.3mL,9.3mmol)处理,搅拌1小时,用4-(N,N-二甲基氨基)吡啶(催化量)处理,并搅拌1小时。将该混合物在EtOAc(50mL)与饱和NH4Cl溶液(30mL)之间分配,将有机相干燥(MgSO4),真空浓缩,并通过色谱法纯化[SiO2;异己烷∶EtOAc(5∶1)],获得了本标题化合物(2.35g,100%),为橙色油状物;
NMR δH(400MHz,CDCl3)7.51(1H,d,J 4.0Hz),7.37(1H,d,J 7.5Hz),7.13(1H,t,J 7.5Hz),7.08(1H,d,7.5Hz),6.51(1H,d,J 4.0Hz),2.64(3H,s)和1.63(9H,s).
使用方法AD由合适的吲哚化合物合成了下列新化合物。
5-氯-7-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.52(1H,d,J 4.0Hz),7.35(1H,d,J 2.0Hz),7.07(1H,d,J1.5Hz),6.46(1H,d,J 3.5Hz),2.61(3H,s),和1.63(9H,s).
5,7-二甲基吲哚-1-甲酸叔丁酯NMR δH(CDCl3)7.48(1H,d,J 4.0Hz)7.16(1H,s),6.92(1H,s),6.44(1H,d,J 4.0Hz),2.60(3H,s)2.38(3H,s)和1.62(9H,s).
7-氟-5-甲基吲哚-1-甲酸叔丁酯NMR δH(CDCl3)7.59(1H,d,J 4.0Hz),7.10(1H,s),6.84(1H,d,J 13.5Hz),6.50-6.47(1H,m),2.40(3H, s)和1.64(9H,s).
4-氯-5-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.92(1H,d,J 8.0Hz),7.57(1H,d,J 3.5Hz),7.15(1H,d,J8.5Hz),6.66(1H,d,J 3.5Hz),2.46(3H,s)和1.66(9H,s).
7-溴-5-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.47(1H,d,J 3.5Hz),7.35(1H,s),7.26(1H,s),6.44(1H,d,J 4.0Hz),2.38(3H,s)和1.64(9H,s).
6-氯-5-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)8.17(1H,brs),7.53(1H,d,J 3.5Hz),7.38(1H,s),6.46(1H,d,J 3.0Hz),2.44(3H,s),1.67(9H,s).
6-氟-5-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.79(1H,brd,J 10.5Hz),7.51(1H,d,J 3.5Hz),7.30(1H,d,J 7.5Hz),6.46(1H,d,J 3.5Hz),2.34(3H,s)和1.66(9H,s).
5-氟-2-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)8.04(1H,dd,J 9.0,4.5Hz),7.07(1H,dd J 9.0,2.5Hz),6.92(1H,dt,J 9.5,3.0Hz),6.27(1H,s),2.58(3H,d,J 1.5Hz)和1.67(9H,s).
7-氯-5-甲基吲哚-1-甲酸叔丁酯NMR δH(400MHz,CDCl3)7.50(1H,d,J 3.5Hz),7.22(1H,s),7.14(1H,s),6.46(1H,d,J 4.0Hz),2.38(3H,s)和1.64(9H,s).
使用方法AD由2,6-二氟-4-羟基苄基醇合成了下述新化合物。(3,5-二氟-4-羟基甲基苯基)碳酸叔丁酯IRνmax(DR)/cm-1 3388,2983,1775,1605,1446,1396,1373,1289,1146,1072,967和882;NMR δH(400MHz,CDCl3)6.79(2H,m),4.75(2H,d,J 6.5Hz),1.84(1H,t,J 6.5Hz)和1.56(9H,s).
方法AE
2,6-二氟-4-羟基苄基醇
将3,5-二氟苯酚(25g,0.19mol)和KOH(85%,12.7g,0.19mol)的混合物用滴加水(50mL)处理,在60℃搅拌1小时,通过滴加甲醛溶液(37%,15.6mL,0.19mol)和水(50mL)来进行处理,在40℃搅拌过夜。将该混合物冷却,用6-M HCl酸化,过滤,用水洗涤所得固体,干燥,获得了本标题化合物(15g,49%),为白色固体:NMR δH(400MHz,DMSO)10.28(1H,s),6.43(2H,m),4.99(1H,t,J 5.6Hz)和4.37(2H,d,J 5.6Hz).
方法AF
7-(2-呋喃基)-3-(6-吲哚基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例152)
将6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯(135mg,4.08mmol)和NaOMe(22mg,4.08mmol)在MeOH(10mL)中的混合物回流1小时,用NaOMe(110mg,20.4mmol)处理,再回流4小时,然后在室温搅拌17小时。将该混合物真空浓缩至一半体积,过滤所得沉淀,用水洗涤,获得了本标题化合物(90mg,96%),为膏状固体。
方法AG
3-(2,6-二氟-4-甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例156)
在0℃,将3-(2,6-二氟-4-羟基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐(130mg,0.34mmol)在DMF(5mL)中的溶液用CsCO3(223mg,0.68mmol)处理,搅拌10分钟,用碘甲烷(21μL,0.34mmol)处理,并在室温搅拌30分钟。将该反应混合物用水(10mL)稀释,过滤,获得了本标题化合物(122mg,100%),为白色固体。
方法AH
2-氟-5-碘苄基醇
将2-氟-5-碘苯甲醛(1.173g,4.692mmol)在异丙醇(25mL)中的溶液用硼氢化钠(0.379g,10.02mmol)处理,在室温搅拌18小时,倒入水(125mL)内,并用异丙基醚(2×25mL)萃取。将合并的有机相干燥(Na2SO4),并真空浓缩,获得了本标题化合物(1.187g,99%),为浅黄色固体。
NMR δH(400MHz,CDCl3)7.77(1H,m),7.57(1H,m),6.82(1H,t,J 8.8Hz),4.73(2H,d,J 6.1Hz),和1.79(1H,t,J 6.1Hz).
方法AI
3-(叔丁氧基羰基氧基)-4-硝基苯甲酸
将3-羟基-4-硝基苯甲酸(1.83g,10mmol)在THF(10mL)中的溶液用Et3N(3.4mL,24mmol)和二碳酸二叔丁酯(2.40mL,11mmol)处理,并在室温搅拌16小时。将该反应混合物倒入10%柠檬酸溶液(20mL)内,用EtOAc(2×10mL)萃取,干燥(MgSO4)并真空浓缩,获得了本标题化合物(2.36g,83%),为膏状固体;
IRνmax(Nujol)/cm-12985,1772,1717 and 1592;NMR δH(400MHz,DMSO)13.85(1H,s),8.26(1H,d,J 8.5Hz),8.04(1H,dd,J 8.5,2.0Hz),7.98(1H,d,J 2.0Hz)和1.49(9H,s).
方法AJ
(5-溴甲基-2-硝基苯基)碳酸叔丁酯
在0℃,将3-(叔丁氧基羰基氧基)-4-硝基苯甲酸(2.26g,8mmol)和N-甲基吗啉(1.85mL,16.8mmol)在THF(20mL)中的溶液用氯甲酸异丁酯(1.09mL,8.4mmol)处理,并搅拌1小时。将该反应混合物加到NaBH4(605mg,16mmol)在MeOH(16mL)内的冷(-78℃)溶液中,并在室温搅拌1小时。将该反应混合物用EtOAc(20mL)稀释,用饱和碳酸氢钠(10mL)和10%柠檬酸溶液(10mL)洗涤,干燥(MgSO4)并真空浓缩,获得了(5-羟基甲基-2-硝基苯基)碳酸叔丁酯(1.36g,86%),为膏状固体。使用方法AB将该产物直接溴化,获得了本标题化合物(961mg,58%),为黄色油状物:
NMR δH(400MHz,CDCl3)8.09(1H,d,J 8.4Hz),7.41(1H,dd,J 8.4,2.0Hz),7.34(1H,d,J 2.0Hz),4.47(2H,s)和1.58(gH,s).
方法AK
3-(3-硝基苄基)-7-(1H-吡唑-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐(实施例266)
将7-氯-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(306mg,1mmol)、1-(2-(三甲基甲硅烷基)乙氧基甲基)-1H-吡唑-5-基硼酸(2mmol)、Pd(PPh3)4(100mg)和饱和碳酸氢钠(5mL)在THF(20mL)中的溶液回流2小时,用水(20mL)稀释,用EtOAc(2×20mL)萃取,干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;CH2Cl2∶EtOAc(6∶1)],获得了3-(3-硝基苄基)-7-(1-(2-(三甲基甲硅烷基)乙氧基甲基)-1H-吡唑-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(156mg,34%),为浅黄色浆状物。
将3-(3-硝基苄基)-7-(1-(2-(三甲基甲硅烷基)乙氧基甲基)-1H-吡唑-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(156mg,0.34mmol)在MeOH(2mL)中的溶液用4-M HCl的二氧杂环己烷溶液(4mL)处理,在室温搅拌2小时,真空浓缩,用乙醚研制并过滤,获得了本标题化合物(110mg,97%),为黄色固体。
方法AL
3-(6-乙酰氨基甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例177)
将7-(2-呋喃基)-3-(6-邻苯二甲酰亚氨基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(210mg,0.465mmol)在EtOH(50mL)中的悬浮液用乙二胺(62μl,0.929mmol)处理,在90℃搅拌3小时,将所得澄清的溶液冷却至室温,,并真空浓缩,获得了3-(6-氨基甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺。在0℃,将该产物在吡啶(10mL)中的溶液用乙酰氯(109ml,1.53mmol)处理,搅拌10分钟,倒入水(70mL)内,用EtOAc(3×20mL)萃取,将合并的有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;EtOAc],获得了本标题化合物(110mg,65%),为米色固体。
方法AM
3-(6-烯丙氧基甲基-2-吡啶基甲基)-N,N-二烯丙基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例182)
在0℃,将7-(2-呋喃基)-3-(6-羟基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(120mg,0.377mmol)在DMF(5mL)中的溶液用氢化钠(30mg,0.743mmol)处理,搅拌15分钟,用烯丙基溴(96μl,1.11mmol)处理,在室温搅拌16小时,真空浓缩至约2mL,并通过色谱法纯化[SiO2;异己烷∶EtOAc(3∶1)],获得了本标题化合物(50mg,30%),为黄色固体。
方法AN
6-烯丙氧基甲基-2-吡啶甲醇
在0℃,将2,6-吡啶二甲醇(5.0g,35.9mmol)在DMF(30mL)中的溶液用氢化钠(1.44g,35.9mmol)处理,搅拌30分钟,用烯丙基溴(3.42ml,39.5mmol)处理,在室温搅拌16小时,倒入水(150mL)内,用EtOAc(3×30mL)萃取,并将合并的有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(3∶1-1∶1)],获得了本标题化合物(1.56g,24%),为无色油状物:
NMR δH(400MHz,CDCl3)7.69(1H,t,J 7.5Hz),7.37(1H,d,J 7.5Hz),7.13(1H,d,J 7.5Hz),6.04-5.93(1H,m),5.38-5.21(2H,m),4.74(2H,d,J 5.0Hz),4.65(2H,s),4.15-4.09(2H,m)和3.76(1H,t,J 5.0Hz).
通过方法AN由合适的醇合成了下列新化合物:
2-(1-甲氧基丙基)-6-甲基吡啶NMR δH(400MHz,CDCl3)7.58(1H,t,J 8.0Hz),7.18(1H,d,J 8.0Hz),7.04(1H,d,J8.0Hz),4.17(1H,dd,J 5.5,7.5Hz),3.30(3H,s),2.55(3H,s),1.84-1.69(2H,m)和0.93(3H,t,J 7.5Hz).
6-异丁氧基甲基吡啶-2-甲醇NMR δH(400MHz,CDCl3)7.69(1H,t,J 7.5Hz),7.37(1H,d,J 7.5Hz),7.13(1H,d,J7.5Hz),4.74(2H,s),4.63(2H,s),3.94(1H,brs),3.33(2H,d,J 6.5Hz),1.91-2.01(1H,m)和0.96(6H,d,J 6.5Hz).
6-异丙氧基甲基吡啶-2-甲醇NMR δH(400MHz,CDCl3)7.70-7.66(1H,m),7.39(1H,d,J 7.5Hz),7.11(1H,d,J 8.0Hz),4.74(2H,s),4.64(2H,s),3.75(1H,sept,J 6.0Hz)和1.25(6H,d,J 6.0Hz).
方法AO
3-异丙基-4-硝基苄基溴
在-70℃,通过向4-硝基苄基溴(432mg,2mmol)在THF(5mL)内的溶液中滴加异丙基氯化镁(1mL,2-M的Et2O溶液,2mmol)处理,搅拌1小时,用DDQ(499mg,2.2mmol)处理,并在室温搅拌16小时。将该反应混合物倒入水(10mL)中,用EtOAc(2×10mL)萃取,干燥(MgSO4),真空浓缩并过滤。通过色谱法纯化所得固体[SiO2;EtOAc∶庚烷(1∶4)],获得了本标题化合物(183mg,35%),为浅黄色固体,其不用进一步纯化直接用于下一反应。
使用方法AO由4-硝基苄基溴合成了下述新化合物:
3-乙基-4-硝基苄基溴NMR δH(400MHz,CDCl3)7.87(1H,d,J 8.3Hz),737(1H,s),7.35(1H,d,J 8.3Hz),4.47(2H,s),2.92(2H,q,J 7.5Hz)和1.30(3H,t,J 7.5Hz).
方法AP
2-(三甲基甲硅烷基)乙氧基甲基4-硝基-2-((2-三甲基甲硅烷基)乙氧基甲氧基)苯甲酸
将2-羟基-4-硝基苯甲酸(1.83g,10mmol)在THF(20mL)中的溶液用N,N-二异丙基乙基胺(3.92mL,22mmol)和2-(三甲基甲硅烷基)乙氧基甲基氯(3.46mL,20mmol)处理,搅拌16小时,然后通过色谱法直接纯化[SiO2;EtOAc∶庚烷(1∶4)],获得了本标题化合物(5.82mg,定量产率),为白色固体,其不用进一步纯化直接用于下一反应;
NMR δH(400MHz,CDCl3)8.09-8.07(1H,m),7.87-7.85(2H,m),5.50(2H,s),5.35(2H,s),3.78(4H,t,J 8.5Hz),1.00-0.88(4H,m),0.00(9H,s)和0.03(9H,s).
方法AQ
2-(2-三甲基甲硅烷基)乙氧基甲氧基-4-硝基苄基醇
在0℃,将2-(三甲基甲硅烷基)乙氧基甲基4-硝基-2-(2-(三甲基甲硅烷基)乙氧基甲氧基)苯甲酸(2.91mg,5mmol)在Et2O(10mL)中的溶液用LiAlH4(190mg,22mmol)处理,并搅拌30分钟。将该反应混合物倒入水(20mL)中,用EtOAc(2×10mL)萃取,干燥(MgSO4)并真空浓缩,获得了本标题化合物(1.35g,91%),为轻微不纯的无色油状物;
NMR δH(400MHz,CDCl3)7.96-7.99(1H,m),7.90(1H,dd,J 8.5,2.0Hz),7.55(1H,d,J 8.5Hz),5.35(2H,s),4.78(2H,s),3.80-3.74(2H,m),0.99-0.94(2H,m)和0.00(9H,s).
方法AR
4,6-二异丙基-2-吡啶甲醇
通过向2-吡啶甲醇(5.00g,45.8mmol)、浓硫酸(2.44ml,45.8mmol)、硫酸亚铁(II)七水合物(1.53g,5.50mmol)和异丙基碘(13.7ml,137mmol)在DMSO(150mL)内的溶液中滴加过氧化氢(27.5wt%水溶液,17.0mL,137mmol)来进行处理,用冰浴冷却以将内温保持在25-30℃。再加入一部分硫酸亚铁(II)七水合物(1.53g,5.50mmol),用1小时让该混合物冷却至室温,倒入水(500mL)中,用5-MNaOH碱化至pH 9,用二氯甲烷(3×100mL)萃取,将合并的有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(3∶2)],获得了4,6-二异丙基-2-吡啶甲醇(500mg,6%),为无色油状物;
NMR δH(400MHz,CDCl3)6.90(1H,s),6.85(1H,s),4.69(2H,brs),4.35(1H,brs),3.03(1H,sept,J 7.0Hz),2.87(1H,sept,J7.0Hz),130(6H,d,J 7.0Hz)和1.25(6H,d,J 7.0Hz),
和6-异丙基-2-吡啶甲醇(900mg,13%),为无色油状物。
通过方法AR由2-吡啶甲醇还合成了下述的新化合物:
6-正丙基-2-吡啶甲醇NMR δH(400MHz,CDCl3)7.58(1H,t,J 7.5Hz),7.03(2H,t,J 7.5Hz),4.72(2H,s),4.15(1H,brs),2.77(2H,t,J 7.5Hz),1.77(2H,sept,J 7.5Hz)和0.97(3H,t,J 7.5Hz).
方法AS
5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-甲酸叔丁酯(实施例203)
在0℃,将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(300mg,1.49mmol)在DMF(5mL)中的溶液用60%氢化钠的矿物油分散液(60mg,1.49mmol)处理,搅拌30分钟,用4-(溴甲基)苯基碳酸叔丁酯(471mg,1.64mmol)处理,在室温搅拌16小时,并通过色谱法纯化[SiO2;EtOAc∶庚烷(1∶2)],获得了本标题化合物(55mg,12%),为米色固体。
方法AT
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-苯基乙酮(实施例211)
将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(101mg,0.5mmol)在DMF(2mL)中的溶液用2-溴苯乙酮(100mg,0.5mmol)和三乙胺(105μL,0.75mmol)处理,在室温搅拌3天,用水(100mL)稀释并过滤。通过色谱法纯化所得固体[SiO2;己烷∶EtOAc,(3∶1-1∶1)],获得了本标题化合物(20mg,13%),为黄色固体。
方法AU
7-(2-呋喃基)-3-(6-羟基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐(实施例213)
将6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吡啶-2-甲醛(62mg,0.193mmol)在MeOH(20mL)中的溶液用乙酸(5mL)、二甲胺(2-M的MeOH溶液,1.93mL,3.86mmol)和氰基硼氢化钠(242mg,3.86mmol)处理,搅拌16小时并真空浓缩。用饱和碳酸氢钠溶液(20mL)处理残余物,用EtOAc(3×10mL)萃取,并将合并的有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;EtOAc],获得了游离碱,为黄色固体。将所得固体悬浮在MeOH(1mL)中,用HCl(4-M的二氧杂环己烷溶液,0.25mL)处理,搅拌10分钟,真空浓缩,用乙醚研制,获得了本标题化合物(22mg,29%),为黄色固体。
方法AV
3-(6-氰基甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例220)
将3-(6-溴甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(200mg,0.517mmol)和氰化钠(51mg,1.03mmol)在DMF(5mL)中的溶液于60℃搅拌16小时,倒入水(40mL)中,用EtOAc(3×8mL)萃取,将合并的有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(1∶1)],获得了本标题化合物(50mg,26%),为黄色固体。
方法AW
3-(4-羟基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例221)
在0℃,将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(400mg,1.98mmol)在DMF(3mL)中的溶液用60%氢化钠的矿物油分散液(80mg,1.98mmol)处理,搅拌30分钟,用4-(2-(三甲基甲硅烷基)乙氧基甲氧基)苄基溴(1.23g,3.96mmol)处理,在室温搅拌48小时,并通过色谱法纯化[SiO2;EtOAc∶庚烷(1∶2)]。将所得黄色固体溶解在MeOH∶DMF(1∶2)中,通过离子交换柱(Isolute SPE SCX-2),真空浓缩,用水和乙醚洗涤,获得了本标题化合物(41mg,7%),为浅黄色固体。
方法AX
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)丙磺酰胺(实施例224)
在0℃,将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(153mg,0.5mmol)在吡啶(2mL)中的溶液用丙磺酰氯(62μL,0.55mmol)处理,并在室温振摇16小时。将该混合物倒入水(50mL)中,用EtOAc(2×10mL)萃取,用10%柠檬酸(10mL)洗涤,并将合并的有机相干燥(MgSO4),真空浓缩,获得了本标题化合物(111mg,54%),为膏状固体。
方法AY
7-(2-呋喃基)-3-(6-(N-甲基氨基)甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例226)
在0℃,将N-甲基-2,2,2-三氟乙酰胺(197mg,1.55mmol)在DMF(5mL)中的溶液用氢化钠(60%矿物油分散液;62mg,1.55mmol)处理,搅拌15分钟,用3-(6-溴甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(120mg,0.310mmol)处理,在50℃搅拌1小时,冷却至室温,倒入水(20mL)中,用EtOAc(3×10mL)萃取,并将合并的有机相干燥(MgSO4),真空浓缩,获得了N-(6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-吡啶基甲基)-N-甲基三氟乙酰胺。将该产物在MeOH(20mL)中的溶液用钠(71mg,3.10mmol)在MeOH(10mL)中的溶液处理,搅拌16小时,真空浓缩,用EtOAc(20mL)处理,经由硅藻土过滤,并真空浓缩。将所得固体悬浮在MeOH(2 mL)中,用HCl(4-M的二氧杂环己烷溶液,1.0mL)处理,搅拌10分钟,真空浓缩,用乙醚研制,获得了本标题化合物(80mg,58%),为黄色固体。
方法AZ
3-(1H-苯并三唑-5-基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例158)
将5-甲基-1H-苯并三唑(666mg,5mmol)在THF(20mL)中的混合物用NaH(60%分散液,200mg,5mmol)处理,在室温搅拌10分钟,用二碳酸二叔丁酯(115mg,5mmol)处理,并搅拌过夜。将该混合物用饱和碳酸氢钠溶液(10mL)处理,用EtOAc(2×10mL)萃取,干燥(MgSO4),经由二氧化硅塞过滤,真空浓缩,获得了5-甲基苯并三唑-1-甲酸叔丁酯(是与6-甲基区域异构体的混合物)(1.08g,92%),为无色油状物。
将5-甲基-1H-苯并三唑-1-甲酸叔丁酯(是与6-甲基区域异构体的混合物)(1.08g,4.63mmol)、过氧化苯甲酰(112mg,0.46mmol)和N-溴琥珀酰亚胺(0.76g,4.63mmol)在CCl4(25mL)中的溶液回流过夜,冷却,过滤,真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(10∶1)],获得了5-(溴甲基)-1H-苯并三唑-1-甲酸叔丁酯(666mg,46%)(是与6-溴甲基区域异构体的混合物),为无色油状物。
将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(404mg,2mmol)在DMP(4mL)中的溶液用NaH(60%分散液,80mg,2mmol)处理,在室温搅拌10分钟,用5-(溴甲基)-1H-苯并三唑-1-甲酸叔丁酯(是与6-溴甲基区域异构体的混合物)(624mg,2mmol)在DMF(2mL)中的溶液处理,并搅拌过夜。将该混合物真空浓缩并通过色谱法纯化[SiO2,异己烷∶EtOAc(2∶1)],获得了5-(5-氨基-7-(2-呋喃基)-3H-三唑并[4,5-d]嘧啶-3-基)甲基-1H-苯并三唑-1-甲酸叔丁酯(135mg,24%)(是与6-取代的区域异构体的混合物),为白色固体。
将5-(5-氨基-7-(2-呋喃基)-3H-三唑并[4,5-d]嘧啶-3-基)甲基-1H-苯并三唑-1-甲酸叔丁酯(是与6-取代的区域异构体的混合物)(135mg,0.31mmol)在MeOH(5mL)和THF(5mL)中的溶液用40%二甲胺水溶液(0.176mL,1.56mmol)处理,回流25分钟,真空浓缩,用乙醚研制所得固体,过滤,用MeOH研制,过滤并干燥,获得了本标题化合物(31mg,30%),为黄色固体。
方法BA
4-((5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)甲基)-2-甲基苯基氨基甲酸乙酯(实施例274)
在室温,通过向3-(4-氨基-3-甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(260mg,0.812mmol)在吡啶(5mL)内的悬浮液中滴加氯甲酸乙酯(0.155mL,1.62mmol)来进行处理,搅拌30分钟,倒入水(30mL)中,用EtOAc(2×10mL)萃取,并将合并的有机相干燥(MgSO4),真空浓缩,获得了本标题化合物(318mg,100%),为米色固体。
方法BB
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-甲基苯基)甲酰胺(实施例244)
将4-((5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)甲基)-2-甲基苯基氨基甲酸乙酯(318mg,0.81mmol)和LiAlH4(62mg,1.62mmol)在无水THF(30mL)中的混合物回流过夜,冷却至室温,用13%NaOH水溶液(0.1mL)处理,然后用水(0.3mL)处理,搅拌30分钟,经由硅藻土过滤,并真空浓缩。用THF研制所得固体,过滤,获得了本标题化合物(20mg,7%),为黄色固体。
方法BC
7-氟-5-甲基吲哚
将水合氯醛(7.3g,44mmol)、硫酸钠十水合物(52g,160mmol)和水(100mL)的溶液缓慢地加到2-氟-4-甲基苯胺(5.0g,40mmol)、羟基胺盐酸盐(11.1g,160mmol)和浓盐酸(3mL)在H2O(50mL)内的搅拌溶液中。将该反应混合物回流1小时,在室温搅拌5小时,过滤,并将所得固体从MeOH/H2O中结晶,获得了棕色晶体(1.53g)。然后在搅拌下将于70℃将所得产物以少量多次的方式加到浓硫酸(20mL)中,搅拌1小时,然后在快速搅拌下缓慢地加到冰/H2O(200mL)中,用EtOAc(2×25mL)萃取两次,将合并的有机相干燥(MgSO4),并真空浓缩,获得了7-氟-5-甲基靛红(1.68g,24%),为深红色树胶状物。
将7-氟-5-甲基靛红(1.68g,9.43mmol)在无水THF(50mL)中的溶液缓慢地加到LiAlH4(1.18g,31mmol)在无水THF(50mL)内的冰冷的搅拌着的悬浮液中,回流2小时,冷却至室温,然后依次用水(1.2mL)、15%NaOH(1.2mL)和H2O(3mL)处理。将该溶液经由硅藻土垫过滤,用THF充分洗涤滤饼,将深蓝色滤液真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(9∶1)],获得了本标题化合物(480mg,41%),为浅蓝色油状物;
NMR δH(CDCl3)8.19(1H,brs),7.21-7.16(2H,m),6.74(1H,d,J 12.0Hz),6.51-6.46(1H,m)和2.42(3H,s).
方法BE
3-(7-氟-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例246)
将7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(303mg,1.5mmol)在DMF(2mL)中的搅拌悬浮液用NaH(60%油分散液,60mg,1.5mmol)处理,搅拌10分钟,缓慢地用5-溴甲基-7-氟吲哚-1-甲酸叔丁酯(460mg,1.5mmol)在DMF(1mL)中的溶液处理,搅拌2小时,然后通过色谱法直接纯化[SiO2;异己烷∶EtOAc(2∶1)],获得了BOC保护的产物(180mg,0.417mmol),为浅绿色固体。将该产物溶解在MeOH(5mL)中,用甲醇钠(113mg,2mmol)处理,回流4小时,冷却至室温,用水稀释,过滤,获得了本标题化合物(118mg,81%),为膏状固体。
方法BF
3-(3-(4-氟苄基氨基)苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(实施例252)
将3-(3-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺(200mg,0.65mmol)和4分子筛在THF(10mL)中的悬浮液用4-氟苯甲醛(0.04mL,0.37mmol)处理,在40℃加热3小时,冷却至室温,用三乙酰氧基硼氢化钠(400mg,1.89mmol)和乙酸(0.1mL)处理,并搅拌15分钟。通过加入饱和碳酸氢钠(5mL)来中止该反应,用EtOAc(2×5mL)萃取,将合并的有机相干燥(MgSO4),真空浓缩并通过色谱法纯化[(SiO2;EtOAc∶庚烷(1∶2)],获得了本标题化合物(60mg,44%),为白色固体。
方法BG
2-(2-甲氧基乙基)-6-(三苯基甲氧基)甲基吡啶
在0℃,将(甲氧基甲基)三苯基氯化鏻(2.79g,8.13mmol)在THF(50mL)中的搅拌溶液用滴加n-BuLi(1.6-M的己烷溶液,5.08mL,8.13mmol)处理,搅拌1小时,用6-(三苯基甲氧基)甲基吡啶-2-甲醛(1.54g,4.06mmol)在THF(15mL)中的溶液处理,让其温热至室温并保持过夜。用饱和NH4Cl溶液(5mL)处理该反应,用水(50mL)稀释,用EtOAc(2×50mL)萃取,将合并的有机相用异己烷(50mL)稀释,干燥(MgSO4),经由二氧化硅过滤并真空浓缩,获得了2-(2-甲氧基乙烯基)-6-(三苯基甲氧基)甲基吡啶(1.58g),为黄色油状物。将该烯烃粗产物和10%Pd/C(216mg,0.203mmol)在EtOAc(50mL)中的溶液于氢气氛下搅拌16小时,经由硅藻土过滤并真空浓缩,获得了本标题化合物(1.08g,65%),为黄色油状物;
NMR δH(400MHz,CDCl3)7.67-7.64(1H,m),7.52-7.49(6H,m),7.32-7.21(10H,m),7.09-7.07(1H,m),4.34(2H,s),3.69(2H,t,J 6.5Hz),3.32(3H,s)和2.98(2H,t,J 6.5Hz);M/Z 410(M+H)+.
方法BH
2-溴甲基-6-(2-甲氧基乙基)吡啶
将2-(2-甲氧基乙基)-6-(三苯基甲氧基)甲基吡啶(1.08g,2.64mmol)在4-M HCl的二氧杂环己烷溶液(10mL,40.0mmol)中的溶液搅拌4小时,并真空浓缩。将残余物在二氯甲烷(15mL)与饱和碳酸氢钠溶液(15mL)之间分配,用二氯甲烷(10mL)萃取水相,将合并的有机相干燥(MgSO4),真空浓缩,获得了6-(2-甲氧基乙基)吡啶-2-甲醇。在0℃,将该产物在二氯甲烷(40mL)中的溶液用三苯基膦(830mg,3.16mmol)处理,然后用四溴化碳(1.31g,3.96mmol)分批处理,搅拌1小时,真空浓缩并通过色谱法纯化[SiO2;异己烷∶EtOAc(4∶1)],获得了本标题化合物(303mg,50%),为黄色油状物;
NMR δH(400MHz,CDCl3)7.60(1H,t,J 7.5Hz),7.28(1H,d,J 7.5Hz),7.13(1H,d,J 7.5Hz),4.53(2H,s),3.76(2H,t,J 6.5Hz),3.35(3H,s)和3.05(2H,t,J 6.5Hz).
表2中提供了实施例1-274的实验数据。
使用下列条件进行HPLC:柱:Waters Xterra RP 18(50×4.6mm);粒径5μM;流动相:MeOH:10mM NH4OAc水溶液(pH7缓冲液);梯度:50∶50等度洗脱1分钟,然后50∶50至80∶20的线性梯度5分钟,之后是80∶20等度洗脱3分钟;流速:2.0mL/分钟;检测波长λ=230nM。表2提供了保留时间。
表2
实施例 | 方法 | 产率(%) | 物理数据 |
1 | A | 65 | IR νmax(Nujol)/cm-13403,3329,3134,2925,1656,1634,1582,1565,1463 and1377;NMR δH(400MHz,DMSO)6.83-6.87(1H,m),7.12(2H,s),7.89(1H,d,J 3.1Hz),8.09-8.10(1H,m),15.52(1H,s);M/Z 203(M+H)+. |
2 | B | 11 | IR νmax(Nujol)/cm-12924,2854,1612,1587,1526,1489,1456,1372,1221 and753;NMR δH(400MHz,DMSO)4.98(2H,s),5.14(2H,s),5.71(2H,s),6.85-6.87(1H,m),7.00-7.14(3H,m),7.14-7.46(9H,m),7.89(1H,d,J 3.5Hz),8.16(1H,d<J 1.0Hz);Anal.Calcd for C29H21F3N6O·0.25H2O:C,65.59;H,4.08;N,15.83.Found:C,65.46;H,4.03;N,15.76. |
3 | B | 22 | IR νmax(Nujol)/cm-13480,3312,3195,3118,2925,2854,1652,1609,1581,1487,1456,1436,1027 and 759;NMR δH(400MHz,DMSO)5.60(2H,s),6.84-6.86(1H,m),7.15-7.29(3H,m),7.32-7.43(3H,m),7.89(1H,d,J 2.9Hz),8.12(1H,s). |
4 | B | 9 | mp 221.0-221.1℃;IR νmax(Nujol)/cm-1 3470,3310,3191,3144,2924,2854,1642,1610,1521,1463 and 1354;NMR δH(400MHz,DMSO)5.85(2H,s),6.87(1H,s),7.37(2H,s),7.63-7.73(2H,m),7.91(1H,d,J 2.8Hz),8.13(1H,s),8.18(1H,s),8.20(1H,s).Anal.Calcd for C15H11N7O3:C,50.57;H,3.11;N,27.52.Found:C,50.99;H,3.23;N,27.21. |
5 | C | 92 | mp 259.8-259.9℃;IR νmax(Nujol)/cm-113452,3367,3318,3185,3142,2922,1651,1602,1514,1463 and 1377;NMR δH(400MHz,DMSO)5.09(2H,s),5.49(2H,s),6.35(1H,s),6.41(1H,d,J 7.5Hz),6.45(1H,d,J 8.0Hz),6.85-6.86(1H,m),6.96(1H,t,J 8.0Hz),7.30(2H,s),7.90(1H,d,J 3.5Hz),8.11(1H,s).Anal.Calcd for C15H13N7O:C,56.63;H,4.50;N,30.82.Found:C,56.82;H,4.25;N,30.57. |
6 | B | 21 | IR νmax(Nujol)/cm-13405,3328,3211,3155,2925,2854,1719,1603,1577,1463,1023 and 731;NMR δH(400MHz,DMSO)3.84(3H,s),5.76(2H,s),6.85-6.87(1H,m),7.33-7.38(2H,s),7.50-7.59(2H,m),7.89-7.92(3H,s),8.12-8.13(1H,m);Anal.Calcd for C17H14N6O3·0.25H2O:C,57.54;H,4.12;N,23.68.Found:C,57.42;H,3.75;N,23.37. |
7 | B | 27 | IR νmax(Nujol)/cm-13506,3309,3189,3131,2925,2854,1635,1606,1580,1502,1417,1204,1025 and 762;NMR δH(400MHz,DMSO)3.70(6H,s),5.58(2H,s),6.44(3H,s),6.84-6.87(1H,m),7.34(2H,s),7.90(1H,d,J 3.5Hz),8.11-8.12(1H,m);Anal.Calcd for C17H216N6O3·0.5H2O:C,56.50;H,4.74;N,23.26.Found:C,56.44;H,4.56;N,22.98. |
8 | B | 21 | IR νmax(Nujol)/cm-13488,3314,3146,2922,2853,1667,1608,1583,1463 and1378;NMR δH(400MHz,DMSO)5.79(2H,s),6.84-6.87(1H,m),7.01(1H,d,J 4.0Hz),7.05(1H,d,J 4.0Hz),7.38(2H,s),7.89(1H,d,J 3.5Hz),8.11-8.13(1H,m). |
9 | D | 14 | IR νmax(Nujol)/cm-13458,3299,3174,3111,2923,1625,1605,1463 and 1377;NMR δH(400MHz,DMSO)3.61(3H,s),5.58(2Hs),6.84-6.94(3H,m),7.06-7.11(1H,d,J 8.5Hz),7.19(1H,t,J 8.0Hz),7.34(2H,s),7.64-7.67(2H,m),7.91(1H,d,J 3.0Hz),8.12(1H,s),10.21(1H,s);Anal.Calcd for C29H21F3N6O·0.25H2O:C,65.59;H,4.08;N,15.83.Found:C,65.46;H,4.03;N,15.76. |
10 | E | 18 | IR νmax(Nujol)/cm-13404,3313,3202,3122,2923,2854,1724,1639,1609,1557,1456,1407 and 1379;NMR δH(400MHz,DMSO)4.60(2H,d,J 6.0Hz),6.86-6.89(1H,m),7.25-7.32(1H,m),7.33-7.44(4H,m),7.67(2H,s),7.91(1H,d,J 3.5Hz),8.14-8.16(1H,m),9.25(1H,t,J 6.0Hz). |
11 | B | 40 | IR νmax(Nujol)/cm-13327,3207,2924,2854,1650,1602,1583,1566,1513 and1487;NMR δH(400MHz,DMSO)3.72(3H,s),5.63(2H,s),6.80(1H,d,J 7.5Hz),6.85-6.89(3H,m),7.26(1H,t,J 7.5Hz),7.33(2H,s),7.90(1H,d,J 3.5Hz),8.11(1H,s);Anal.Calcd for C16H14N6O2·0.25H2O:C,58.80;H,4.47;N,25.71.Found:C,58.90,H,4.40;N,25.75. |
12 | B | 21 | IR ν max (Nujol)cm -1 3374,3311,3202,1636,1606,1586,1530,1511,1465, 1439,1377 and 1343;NMR δ H (400MHz,DMSO)6.03(2H,s),6.86-6.89(1H, m)6.98(1H,d,J 7.5Hz),7.36(2H,s),7.60-7.73(2H,m),7.92(1H,d,J 3.5 Hz),8.14(1H,s),8.2(1H,d,J 8.0Hz):Anal.Calcd for C 15 H 11 N 7 O 3 ·0.35H 2 O: C,52.43;H,3.43;N,28.54,Found;C,52.51;H,3.33;N,28.21. |
13 | C | 67 | IR ν max (Nujol)/cm -1 3489,3313,3191,1638,1603,1505,1460 and 1378;NMR H (400MHz,DMSO)5.27(2H,s),5.47(2H,s),6.50(1H,t,J 7.5Hz),6.67- 6.78(2H,m),6.86(1H,s),7.01(1H,t,J 7.0Hz),7.36 (2H,s),7.90(1H,d,J 3.0 Hz),8.12(1H,s). |
14 | F | 35 | IR νmax(Nujol)/cm-13447,3327,3205,2922,2853,1725,1652,1611 and 1458;NMR δH(400MHz,DMSO)8.13(1H,d,J 1.0Hz),7.90(1H,d,J 3.5Hz),7.38(2H,s),6.87-6.85(1H,m),5.40(2H,s),4.18(2H,q,J 7.0Hz)and 1.21(3H,t,J 7.0Hz);Anal.Calcd for C12H12N6O2+0.2H2O:C,49.38;H,4.28,N,28.79.Found:C,49.25;H,4.09;N,28.47. |
15 | B | 15 | IR νmsx(Nujol)/cm-13490,3307,3189,2230,1959,1728,1642,1611,1583,1565,1463,1377,1283,1234,1030 and 761;NMR δH(400MHz,DMSO)5.75(2H,s),6.82-6.89(1H,m),7.35(2H,s),7.57-7.59(2H,m),7.79-7.81(2H,m),7.91(1H,d,J 3.5Hz),8.12(1H,s). |
16 | B | 6 | IR νmax(Nujol)cm-13309,3184,2726,1639,1608,1585,1456,1377,1026,1002,953 and 750;NMR δH(400MHz,DMSO)2.22(2H,quin,J 7.0Hz),2.67(2H,t,J 7.0Hz),4.45(2H,t,J 7.0Hz),6.83-6.88(1H,m),7.23-7.35(3H,m),7.66(1H,dt,J 8.0,2.0Hz),7.89(1H,dd,J 3.5,1.0Hz),8.10-8.13(1H,m);Anal.calcd for C16H15N7O·0.6H2O:C,57.86;H,4.92;N,29.52.Found:C,57.58;H,4.53;N,29.66. |
17 | B | 7 | IR νmax(Nujol)/cm-13379,3336,3208,1655,1604,1513,1456,1325,11687,1124,1025 and 755;NMR δH(400MHz,DMSO)5.79(2H,s),6.83-6.88(1H,m),7.36(2H,s),7.53(1H,d,J 7.5Hz),7.60(1H,t,J 7.5Hz),7.67-7.76(2H,m),7.91(1H,d,J 3.5Hz),8.13(1H,s);Anal.Calcd.for C16H11F3N6O:C,53.34;H,3.08;N,23.31.Found:C,53.38;H,3.18;N,23.15. |
18 | G | 100 | IR νmax(Nujol)/cm-1 3451,3206,2361,2261,1655,1604,1459,1378,1195,1028 and 774;NMR δH(400MHz,DMSO)5.57(2H,s),6.57-6.63(1H,m),6.65-6.74(2H,m),6.83-6.88(1H,m),7.14(1H,t,J 7.5Hz),7.91(1H,d,J3.0Hz),8.12(1H,d,J 1.0Hz). |
19 | J | 77 | mp 291.8-292.0℃;IR νmax(DR)/cm-13436,3178,1651,1615,1398,1226,1029 and 977;NMR δH(400MHz,DMSO)15.5-15.3(1H,brs),7.84(1H,d,J3.5Hz),7.07(2H,brs),6.48(1H,dd,J 3.5,J 1.0Hz),2.44(3H,s). |
20 | B | 47 | mp 213.5.-213.7℃;IRνmax(DR)/cm-13300,3218,3098,2957,2927,2744,2368,1645,1602,1570,1537,1508,1490,1438,1328 and 1233;NMR δH(400MHz,DMSO)7.86(1H,d,J 3.0Hz),7.43-736(1H,m),7.31(2H,brs),7.28-7.15(3H,m),6.50(1H,dd,J 1.0,J 3.5Hz),5.68(2H,s)and 2.45(3H,s). |
21 | K | 99 | IR νmax (DR)/cm-13151,2360,1654,1182,998,824,681,and 572;NMR δH(400MHz,DMSO)10.28(1H,d,J 2.0Hz)and 9.73(1H,d,J 2.5Hz) |
22 | A | 8 | IR νmax(DR)/cm-13479,3289,3169,1597,1502,1226,1119,999,880 and 757;NMR δH(400MHz,DMSO)9.43(1H,s),9.25(1H,s),7.48-7.34(3H,m)7.30-7.22(2H,m),7.21-7.15(1H,m)and5.72(2H,s). |
23 | B | 20 | mp 187.3-187.7℃;IR νmax(DR)/cm-13993,3489,3319,3197,2951,2725,2353,1954,1719,1633,1604,1503,1420,1232,1032 and 740;NMR δH(400MHz,DMSO)2.27(3H,s)5.62(2H,s),6.82-6.88(1H,m),7.02-7.16(3H,m),7.24(1H,t,J 7.5Hz),7.33(2H,s),7.90(1H,d,J 3.5Hz)8.12(1H,s). |
24 | N | 46 | mp 196.9-197.1℃;IR νmax(DR)/cm-13448,3321,3200,1649,1616,1509,1488;NMR δH(400MHz,DMSO)8.49-8.47(1H,m),8.12-8.11(1H,m),7.91(1H,d,J 3.5Hz),7.81-7.77(1H, m),7.34-7.30(1H,m),7.27(2H,brs),7.24(1H,d,J 8.0Hz),6.86-6.85(1H,m),5.77(2H,s). |
25 | N | 50 | IR νmax(DR)/cm-13326,3211,2956,2856,1641,1612,1507,1491;NMR δH(400 MHz,CDCl3)8.77-8.76(1H,m),8.58-8.56(1H,m),8.08(1H,d,J 3.5Hz),7.78(1H,m),7.75-7.72(1H,m),7.29-7.25(1H,m),6.71-6.69(1 H,m),5.68(2H,s),5.37(2H,br s);Anal.Calcd for C14H11N7O·0.2 H2O·0.4 C4H8O2:C,56.41;H,4.43,N,29.52.Found:C,56.10;H,4.33;N,29.52. |
26 | O | 85 | mp 291.0-291.1℃;IR νmax(Nujol)/cm-13401,3317,3205,2995,1714,1646,1615,1587,1483 and 1247;NMR δH(400MHz,DMSO)13.58-13.31(1H,s),8.12(1H,s),7.91(1H,d,J 3.5Hz),7.36(2H,s),6.87-6.86(1H,m) and 5.29(2H,s);Anal.Calcd for C10H8N6O3·0.6H2O:C,44.32;H,3.42,N,3 1.01.Found:C,44.26;H,3.07;N,30.74. |
27 | B | 19 | mp 209.9-210.1℃;IR νmax(DR)/cm-13504,3312,3201,2948,1611,1503,1435,1279,1220,1025 and 755;NMR δH(400MHz,DMSO)5.69(2H,s),6.82-6.87(1H,m),7.19-7.25(1H,m),7.33(2H,s),7.37-7.40(3H,m),7.90(1H,d,J 3.5Hz),8.10-8.13(1H,m).Anal.Calcd for C15H11N6OCl·0.2H2O:C,54.54;H,3.48;N,25.44.Found:C,54.69;H,3.33;N,25.09. |
28 | K | 40 | IR νmax(DR)/cm-13282,2852,1630,1368,1120,871 and 618;NMR δH(400MHz,DMSO)7.94(1H,d,J 2.5Hz),7.45-7.36(2H,m),7.29-7.22(2H,m),7.21-7.16(1H,m)and 5.71(2H,s). |
29 | B | 8 | IR νmax(DR)/cm-13999,3483,3438,3310,3207,2950,2732,2452,1846,1657,1486,1312,1030 and 754;NMR δH(400MHz,DMSO)4.02(3H,s),6.81-6.88(1H,m),7.25(2H,s),7.88(1H,d,J 3.5Hz),8.09-8.11(1H,m). |
30 | P | 39 | IR νmax(Nujol)/cm-13500-3200,2946,2835,1700 and 1523;NMR δH(400MHz,DMSO)8.11(1H,s),7.S9(1H,d,J 3.5Hz),7.69(1H,s),7.34(1H,s),7.26(2H,s),6.87-6.84(1H,m)and 5.08(2H,8). |
31 | P | 48 | IR νmax(Nujol)/cm-13457,3313,1666,1617,1523 and 1442;NMR δH(400MHz,DMSO)10.68(1H,s),8.12(1H,s),7.91(1H,d,J 3.5Hz),7.75(1H,s),7.45(1H,d,J 8.0Hz),7.37(1H,t,J 8.0Hz),7.30(2H,s),7.15(1H,d,J 8.0Hz),6.88-6.84(1H,m and 5.39(2H,s);Anal.Calcd for C16H12N7O2Cl·0.8H2O:C,50.02;H,3.57,N,25.27.Found:C,50.15;H,3.48;N,25.12. |
32 | N | 76 | mp 191.4-192.0℃;IR νmax(DR)/cm-13511,3306,3194,2955,1638,1476;NMR δH(400MHz,DMSO)8.12-8.11(1H,m),7.91(1H,dd,J 3.5,1.0Hz),7.66(1H,dd,J 8.0,7.0Hz),7.27(2H,brs),6.87-6.85(1H,m),6.73-6.70(2H,m),5.69(2H,s),3.68(3H,s);Anal.Calcd for C15H13N7O2·0.2C4H8O2:C,55.66;H,4.32,N,28.76.Found:C,55.88;H,4.17;N,28.59. |
33 | B | 11 | mp 204.1-204.2℃;IR νmax(DR)/cm-13490,3321,3200,2923,2711,2490,1749,1605,1502,1376,1272,1034 and 761;NMR δH(400MHz,DMSO)5.83(2H,s),6.83-6.86(1H,m),7.01(1H,dd,J 5.0,3.5Hz),7.16(1H,dd,J 3.5,1.0Hz),7.34(2H,s),7.48(1H,dd,J5.0,1.5Hz),7.89(1H,d,J 3.5Hz),8.09-8.12(1H,m). |
34 | Q | 30 | mp 225-230℃;IR νmax(DR)/cm-13520,3344,1734,1611,1438,1240,996,833 and 761;NMR δH(400MHz,DMSO)8.26(1H,d,J 3.0Hz),8.15(1H,d,J3.0Hz),7.50-7.44(2H,brs),7.42-7.36(1H,m),7.29-7.21(1H.m),7.21-7.15(1H,m)and 5.73(2H,s). |
35 | H | 51 | mp 174.0-174.2℃;IR νmax(DR)/cm-13473,3317,3188,2740,1736,1648,1243,1004 and 752;NMR δH(400MHz,DMSO)8.68(1H,dd,J 4.0,1.5Hz),7.99(1H,dd,J 5.0,1.0Hz),7.43-7.35(2H,m),7.31-7.16(5H,m)and 5.71(2H,s). |
36 | C | 50 | mp 231.7-234.0℃;IR νmax(DR)/cm-13498,3404,3309,2931,1607,1539,1498,1317,1101 and 1027;NMR δH(400MHz,DMSO)7.86(1H,dd,J 0.5,3.5Hz),7.24(2H,brs,),6.96(1H,t,J 7.8Hz),6.50(1H,dd,J 1.0,3.5Hz),6.48-6.43(1H,m),6.43-6.38(1H,m),6.36(1H,t,J 1.7Hz),5.46 (2H,s),5.07(2H,brs)and 2.43(3H,s). |
37 | N | 60 | mp 200.8-218.9℃;NMR δH(400MHz,DMSO)8.12-8.11(1H,m),7.91(1H,d,J 3.5Hz),7.64(1H,t,J 7.5Hz),7.29(2H,brs),7.18(1H,d,J 7.5Hz),6.90(1H,d,J 7.5 Hz),6.86-6.85(1H,m),5.70(2H,s)and 2.42(3H,s). |
38 | Q | 35 | mp 242.0-242.1℃;IR νmax(DR)/cm-13513,3294,1570,1234,999 and 755;NMR δH(400MHz,DMSO)7.96(1H,s),7.46-7.34(3H,m),7.30-7:13(3H,m),5.72(2H,s)and 2.60(3H,s). |
39 | B | 26 | IR νmax(Nujol)/cm-13464,3340,3 189,2966,2748,1692,1643 and 1605;NMRδH(400MHz,DMSO)8.11-8.09(1H,m),7.90(1H,d,J 3.5Hz),7.33-7.24(4H,m),7.19-7.12(2H,m),7.09(1H,s),6.86-6.84(1H,m),5.64(2H,s),4.07(2H,d,J 6.0Hz)and 1.33(9H,s). |
40 | B | 12 | IR νmax(Nujol)/cm-13474,3323,3184,3006,2971,2941,2837,1648,1606 and1496;NMRδH(400MHz,DMSO)8.13-8.10(1H,m),7.90(1H,d,J 3.5Hz),7.32(2H,s),6.98(1H,d,J 9.0Hz),6.89-6.84(2H,m),6.48(1H,d,J 3.0Hz),5.57(2H,s),3.76(3H,s)and 3.62(3H,s). |
41 | B | 32 | mp 213.8-213.9℃;IR νmax(DR)/cm-13996,3654,3507,3320,2930,2562,2621,1944,1837,1676,1428,1230,1095,1026 and 797;NMR δH(400MHz,DMSO)5.65(2H,s),6.81-6.86(1H,m),7.16(2H,t,J 8.5Hz),7.31(2H,s),7.44-7.56(1H,m),7.86(1 H,dd,J 3.5,1.0Hz),8.07-8.13(1H,m).Anal.Calcd for C15H10N6OF2:C,54.88;H,3.07;N,25.59.Found:C,54.57;H,3.05;N,25.23. |
42 | Q | 29 | mp 265.7-26.2℃;IR νmax(DR)/cm-13491,3370,3120,1614,1232,972,753and 514;NMR δH(400MHz,DMSO)7.72(1H,s),7.51-7.43(2H,s),7.42-7.35(1H,m),7.30-7.14(3H,m),5.73(2H,s)and 2.55(3H,s). |
43 | H | 65 | mp 281.1-280.2℃;IR νmax(DR)/cm-13466,3326,1641,1503,1379,1240,1056,and 825;NMR δH(400MHz,DMSO)15.5(1H,brs),8.6(1H,dd,J 1.0,4.0Hz),7.96(1H,dd,J 1.0,5.0Hz),7.36(1H,dd,J 4.0,5.0Hz)and 7.0(2H,brs). |
44 | S/T | 28 | IR νmax(DR)/cm-13255,1686,1590,1458;NMR δH(400MHz,DMSO)11.24(1H,s),8.95-8.94(1H,m),8.37-8.35(1H, m),8.08-8.07(1H,m),7.96-7.95(1H,m),7.68(1H,d,J 8.0Hz),6.85-6.84(1H,m). |
45 | A | 59 | mp 190.4-190.8℃;IR νmax(DR)/cm-13322,3162,1665,1576,1351,1119,1000,809 and 604;NMR δH(400MHz,DMSO)9.44(1H,s),9.26(1H,s),8.24-8.16(2H,m),7.95(1H,s),7.74-7.63(2H,m),7.45(2H,brs)and 5.87(2H,s). |
46 | K | 99 | IR νmax(Nujol)/cm-12967,1651 and 1463;NMR δH(400MHz,DMSO)8.35-8.24(3H,s),8.14-8.11(1H,m),7.91(1H,d,J 3.5Hz),7.47-7.39(2H,m),7.36-7.31(2H,s),6.88-6.84(1H,m),5.67(2H,s)and 3.98(2H,q,J 5.5Hz);Anal.Calcd for C16H15N7O·2HCl·0.9H2O:C,46.82;H,4.62,N,23.89.Found: |
C,47.10;H,4.40;N,23.84. | |||
47 | B | 26 | IR νmax(Nujol)/cm-13375,3194,2929,2753,1732,1657,1515,1400 and 1334;NMR δH(400MHz,DMSO)8.14-8.11(1H,m),7.90(1H,d,J 3.0Hz),7.45-7.29(6H,m),6.88-6.84(1H,m),5.71(2H,s),2.95(3H,s)and 2.85(3H,s);Anal.Calcd for C18H17N7O2·0.5H2O:C,58.06;H,4.87,N,26.33.Found:C,58.16;H,4.65;N,26.06. |
48 | C | 49 | mp 265.9-266.0℃;IR νmax(DR)/cm-13448,3363,3316,3189,1645,1597,1511,1440 and 1103;NMR δH(400 MHz,DMSO)8.69(1H, dd,J 1.2,3.7Hz),7.95(1H,dd,J 1.2,5.0Hz),7.38(1H,dd,J 3.9,5.0Hz),7.26(2H,brs),6.97(1H,t,J 7.7Hz),6.48-6.45(1H,m),6.44-6.40(1H,m),6.36(1H,t,J 1.7Hz),5.5(2H,s)and 5.11(2H,brs). |
49 | B | 8 | IR νmax(Nujol)/cm-13488,33 19,2952,1641,1503 and 1420;NMR δH(400MHz,DMSO)8.49-8.42(1H,m),8.14(1H,d,J 1.0Hz),7.91(1H,d,J 3.5Hz),7.78-7.71(2H,m),7.48-7.32(4H,m),6.88-6.85(1H,m),5.72(2H,s)and2.75(3H,d,J 4.5Hz). |
50 | C | 60 | mp 228.2-228.3℃;IR νmax(DR)/cm-13441,3318,3197,1738,1648,1515,1122,1006,888 and 747;NMR δH(400MHz,DMSO)9.45(1H,s),9.27(1H,s),7.44(2H,brs),6.97(1H,t,J 8.0Hz),6.49-6.39(2H,m),6.35(1H,s),5.52(2H,s),and 5.13(2H,s). |
51 | N | 70 | mp 182.9-183.1℃;IR νmax(DR)/cm-13488,3311,3199,2943,1611,1504;NMR δH(400MHz,DMSO)8.10(1H,d,J 3.5Hz),7.78(1H,m),7.01(1H,t,J9.0Hz),6.79(1H,dt,J 9.0,3.5Hz),6.75-6.73(1H,m),6.71-6.70(1H,m),5.70(2H,s),5.38(2H,brs),3.71(3H,s);Anal.Calcd for C16H13N6O2F·0.1H2O:C,56.17;H,3.89,N,24.56.Found:C,56.27;H,3.85;N,24.22. |
52 | P | 70 | mp 263.8-264.0 ℃;IR νmax(Nujol)/cm-13305,3 192,1705,1635 and 1442;NMR δH(400MHz,DMSO)11.04(1H,s)8.37(1H,d,J 4.0Hz),8.15-8.11(1H,m),7.96(1H,d,J 7.0Hz),7.91(1H,d,J 3.0Hz),7.79(1H,dt,J7.5,2.0Hz),7.32(2H,s),7.18-7.11(1H,m),6.88-6.85(1H,m)and 5.46(2H,s). |
53 | P | 77 | mp 256.1-256.4℃;IR νmax(Nujol)/cm-13454,3311,2993,1664,1488 and1439;NMR δH(400MHz,DMSO)8.86(1H,t,J 6.0Hz),8.50(1H,d,J 4.5Hz),8.12(1H,s),7.90(1H,d,J 3.5Hz),7.79(1H,dt,J 7.5,1.5Hz),7.41-7.25(4H,m),6.88-6.84(1H,m)and 5.23(2H,s),4.41(2H,d,J 6.0Hz);Anal.Calcd forC16H14N8O2·0.25H2O:C,54.16;H, 4.12,N,31.58.Found:C,54.01;H,4.03;N, |
31.44. | |||
54 | P | 61 | mp 292.2-292.3℃;IR νmax(Nujol)/cm-13433,3323,2975,2941,1673 and1446;NMR δH(400MHz,DMSO)10.50(1H,s),8.13(1H,s),7.92(1H,d,J 3.0Hz),7.57(2H,d,J 7.5Hz),7.37-7.27(4H,m),7.08(1H,t,J 7.5Hz),6.89-6.84(1H,m)and5.38(2H,s). |
55 | B | 18 | mp 264.5-264.8℃;IR νmax(DR)/cm-14007,3489,3308,3190,1649,1552,1433,1349,1227,1082,1030 and 729;NMR δH(400MHz,DMSO)5.99(2H,s),6.84-6.89(1H,m),7.39(2H,s),7.91(1H,d,J 3.5Hz),8.11-8.15(1H,m),8.59(2H,d,J 2.0Hz),8.78(1H,t,J 2.0Hz). |
56 | B | 30 | IR νmax(DR)/cm-13508,3300,3181,1611,1572,1504,142D,1352,1225 and1030;NMR δH(400MHz,DMSO)8.22-8.16(2H,m),7.86(1H,d,J 3.2Hz),7.63-7.72(2H,m),7.35(2H,brs),6.50(1H,dd,J 1.0,3.5Hz),5.82(2H,s)and 2.45(3H,s). |
57 | B | mp 188.8-188.9℃;IR νmax(Nujol)/cm-13492,3302,3189,2951,1635 and1505;NMR δH(400MHz,DMSO)8.14-8.10(1H,m),7.90(1H,d,J 3.0Hz),7.47-7.32(3H,m),7.20(1H,q,J 7.0Hz),7.05(1H,t,J 7.0Hz),6.88-6.83(1H,m)and 5.75(2H,s). | |
58 | B | 15 | mp 207.0-207.4℃;IR νmax(Nujol)/cm-13496,3229,3201,3057,2965,2743,1785 and 1615;NMR δH(400MHz,DMSO)8.13-8.10(1H,m),7.89(1H,d,J3.5Hz),7.40-7.27(4H,m),7.08(1H,dt,J 8.5,3.0Hz),6.87-6.84(1H,m)and 5.66(2H,s). |
59 | B | 30 | mp 187.9-188.7℃IRνmax(DR)/cm-13338,3202,1659,1607,1567,1523,1457,1424,1321,1204 and 1025;NMR δH(400MHz,DMSO)7.88(1H,d,J3.5Hz),7.65(1H,t,J 7.5Hz),7.29(2H,brs),7.18(1H,d,J 7.5Hz),6.89(1H,d,J 8.0Hz),6.51(1H,d,J 3.0Hz),5.69(2H,s),2.46(3H,s)and 2.42(3H,s);Anal.Calcd for C16H15N7O·0.2H2O:C,59.14;H,4.78,N,30.17.Found:C,59.37;H,4.66;N,29.86. |
60 | B | 33 | mp 209.7-209.8℃;IR νmax(DR)/cm-13404,3330,3226,3109,2961,2926,2742,1637,1601,1508,and 1474;NMR δH(400MHz,DMSO)7.83(1H,dd,J0.5,3.2Hz),7.54-7.46(1H,m),7.3(2H,brs),7.16(2H,t,J 8.2Hz),6.49(1H,dd,J 1.0,3.5Hz),5.63(2H,s)and 2.44(3H,s). |
61 | B | 20 | mp 193.8-194.1℃;IR νmax(DR)/cm-13336,3218,2980,2753,2432,1734,1654,1611,1438,1381,1331 and 1224;NMR δH(400MHz,DMSO)7.86(1H,d,J 3.0Hz),7.49(1H,dd,J 1.5.5.0Hz),7.3(2H,brs),7.16(1H,dd,J 1.0,3.5Hz),7.0(1H,dd,J 3.5,5.0Hz),6.50(1H,dd,J 1.0,3.5Hz),5.82 (2H,s)and2.45(3H,s). |
62 | B | 40 | mp 210.4-210.5℃;IR νmax(DR)/cm-13511,3300,3179,2940,2740,2688,1986,1832,1734,1634,1500 and 1436;NMR δH(400MHz,DMSO)7.87(1H,d,J 3.5Hz),7.40-7.37(3H,m),7.30(2H,brs),7.23-7.18(1H,m),6.51(1H,dd,J 1.0,5.1Hz),5.68(2H,s)and 2.45(3H,s). |
63 | N | 41 | mp 201.1-201.2℃;IR νmax(DR)/cm-13453,3317,3195,1638,1599,1510,1434;NMR δH(400MHz,DMSO)8.28(1H,d,J 6.0Hz),8.12-8.11(1H,m),7.91(1H,d,J 3.5Hz),7.29(2H,brs),6.91(1H,dd,J 6.0,2.5Hz),6.87-6.85(2H,m),5.71(2H,s),3.81(3H,s). |
64 | B | 9 | mp 218.0-218.1℃;IR νmax(DR)/cm-13999,3376,3209,2916,2747,2326,1957,1782,1610,1515,1278,1023 and 763;NMR δH(400MHz,DMSO)2.42(3H,s),5.64(2H,s),6.86(1H,s),6.91(1H,d,J 7.5Hz),7.13(1H,t,J 7.0Hz),7.17-7.26(2H,m),7.32(2H,s),7.90(1H,d,J 3.5Hz),8.12(1H,s). |
65 | B | 25 | mp 208.1-208.2℃;IR νmax(Nujol)/cm-13347,3199,2981,2932,2764,2719,1660 and 1612;NMR δH(400MHz,DMSO)8.14-8.11(1H,m),7.90(1H,d,J3.5Hz),7.41-7.22(4H,m),7.15-7.09(1H,m),6.87-6.83(1H,m)and 5.69(2H,s);Anal.Calcd for C15H10F2N6O·0.5H2O:C,53.42;H,3.29,N,24.92.Found:C,53.72;H,3.06;N,24.77. |
66 | W | 25 | mp 243.4-243.9℃;IR νmax(Nujol)/cm-14008,3483,3316,3196,1734,1599and 1505;NMR δH(400MHz,DMSO)8.32(1H,dd,J 9.0,3.0Hz),8.21(1H,d,J 3.0Hz),8.12-8.10(1H,m),7.68(1H,d,J 3.5Hz),7.31(1H,d,J 9.0Hz),7.00(2H,s),6.85-6.82(1H,m),5.94(2H,s)and 3.93(3H,s);Anal.Calcd forC16H13N7O4:C,52.32;H,3.57,N,26.68.Found:C,52.16;H,3.56;N,26.67. |
67 | B | 32 | mp 252.9-253.0℃;IR νmax(DR)/cm-13511,33260,2945,1732,1626,1573,1499,1422,1327 and 1222;NMR δH(400MHz,DMSO)8.4(1H,d,J 4.5Hz),7.87(1H,d,J 3.0Hz),7.77-7.71(2H,m)7.47-7.38(2H,m),7.3(2H,brs),6.50(1H,dd,J 1.0,3.5Hz),5.70(2H,s),2.75(3H,d,J 4.5Hz)and 2.45(3H,s). |
68 | R | 58 | mp 228.1-229.3℃;IR νmax(Nujol)/cm-13508,3263,2990,2946,2837,1646and 1419;NMR δH(400MHz,DMSO)8.29(1H,t,J 6.0Hz),8.14-8.09(1H,m),7.90(1H,d,J 3.5Hz),7.33(2H,s),7.29(1H,t,J 7.5Hz),7.21-7.09(3H, |
m),6.88-6.83(1H,m),5.64(2H,s),4.20(1H,d,J 6.0Hz)and 1.83(3H,s);Anal.Calcd for C18H17N7O2·0.25H2O:C,58.77;H,4.79,N,26.65.Found:C,58.86;H,4.54;N,26.24. | |||
69 | X | 2 | NMR δH(400MHz,DMSO)8.53(1H,s),7.69(1H,s),7.58(2H,brs),7.45-7.36(1H,m),7.29-7.22(2H,m),7.21-7.15(1H,m)and 5.73(2H,s);保留时间1.14min. |
70 | N | 39 | NMR δH(400MHz,DMSO)8.45(1H,d,J 5.0,1.0Hz),8.13-8.12(1H,m),7.91(1H,dd,J 3.5,1.0Hz),7.51-7.48(2H,m),7.31(2H,br s),6.87-6.85(1H,m),5.80(2H,s);保留时间1.75min. |
71 | N | 65 | mp 228.7-228.9℃;IR νmax(DR)/cm-13408,3326,3210,1648,1614,1511;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),8.02-7.96(1H,m),7.92(1H,d,J 3.5Hz),7.33(2H,brs),7.20(1H,dd,J 7.5,2.0Hz),7.12(1H,dd,J 8.0,2.0Hz),6.87(1H,dd,J 3.5,1.0Hz),5.75(2H, s);Anal.Calcd for C14H11N7OF·0.2H2O·0.1C4H10O2:C,53.66;H,3.57,N,30.42.Found:C,53.68;H,3.44;N,30.24. |
72 | B | 28 | mp 195.4-196.5℃;IR νmax(DR)/cm-13328,3210,2956,2836,2740,1736,1648,1608,1438,1322 and 1250;NMR δH(400MHz,DMSO)7.87(1H,d,J3.5Hz),7.33-7.25(3H,m),7.05(1H,d,J 7.5Hz),6.88(1H,td,J 1.0,7.5Hz),6.87(1H,dd,J 2.0,7.5Hz),6.50(1H,dd,J 1.0,3.5Hz),5.58(2H,s),3.83(3H,s)and 2.45(3H,s). |
73 | B | 28 | mp 178.7-179.3℃;IR νmax(DR)/cm-13468,3346,3172,2988,2747,2130,1943,1696,1610,1418,1330,and 1177;NMR δH(400MHz,DMSO)7.86(1H,d,J 3.01Hz),7.34-7.26(4H,m),7.20-7.10(2H,m)7.09(1H,s),6.50(1H,dd,J 1.0,3.5Hz),5.63(2H,s),4.2(2H,d,J 6.0Hz),2.45(2H,s)and 1.34(9H,s). |
74 | C | 40 | mp 214.6-215.2℃;IR νmax(DR)/cm-12877,1653,1596,1523,1470,1355,1284,1241,1210 and 1109;NMR δH(400MHz,DMSO)7.87(1H,d,J 3.0Hz),7.16(1H,t,J 7.0Hz),7.0-6.75(3H,m),6.51(1H,d,J 3.0Hz),5.58(2H,s)and 2.45(3H,s). |
75 | C | 3 | NMR δ H (400MHz,DMSO)4.74(4H,s)5.33(2H,s),5.62 (2H,d,J 2.0Hz), 5.71(1H,t,J 2.0Hz),6.83-6.88(1H,m),7.29(2H,s),7.91(1H,dd,J 3.5,1.0 Hz),8.10-8.12(1H,m):保留时间2.95min. |
76 | K | 100 | IR νmax(DR)/cm-13011,1650,1525,1468,1351,1284 and 1210;NMR δH 400MHz,CD3OD)8.36(1H,d,J 3.5Hz),7.53-7.42(4H,m),6.72(1H,dd,J 1.0Hz,3.5Hz),5.76(2H,s),4.11(2H,s)and 2.61(3H,s). |
77 | W | 25 | mp 212.1-214.3℃:IR ν max (DR)/cm -1 4007,3474,3323,3199,2934,2747, 2105,1647,1603,1492,1245,1028 and 754;NMR δ H (400 MHz,DMSO)3.82 (3H,s),5.60(2H,s),6.78-6.93(3H,m),7.05(1H,d,J 8.5Hz),7.24-7.38 (3H,m),7.90(1H,d,J 3.0Hz),8.12(1H,s). |
78 | B | 21 | IR νmax(DR)/cm-14002,3482,3313,3201,2938,2739,2339,2107,1936,1731,1650,1436,1253,1082 and 751;NMR δH(400MHz,DMSO)5.82 (2H,s),6.84-6.88(1H,m),7.38(2H,s),7.58(1H,t,J 9.0Hz),7.90(1H,t,J 3.0Hz),8.12(1H,d,J 1.0Hz),8.23-8.28(1H,m),8.29-8.35(1H,m). |
79 | C | 64 | mp 308.2-308.3℃;IR νmax(DR)/cm-14013,3456,3322,3193,2958,2745,2103,1861,1653,1516,1237,1026 and 777;NMR δH(400MHz,DMSO)4.95(2H,s),5.56(2H,s),6.15-6.20(1H,m ),6.44-6.51(1H,m),6.84-6.93(2H,m),7.34(2H,s),7.91(1H,d,J 3.0Hz),8.12(1H,d,J 1.0 Hz). |
80 | Y | 10 | NMR δH(400MHz,DMSO)8.84(1H,brs),7.46-7.35(2H,m),7.32-7.14(4H,m)and 5.72(2H,s);保留时间0.84min. |
81 | B | 47 | mp 229.3-229.4℃;IR νmax (DR)/cm-13514,3292,3166,1614,1503;NMR δH(400MHz,DMSO)7.88-7.84(2H,m),7.47(1H,d,J 8.0Hz),7.31(2H,brs),7.22(1H,d,J 7.0 Hz),6.52-6.51(1 H,m),5.75(2H,s),2.46(3H,s);Anal.Calcd for C15H12N7OCl·0.1H2O:C,52.44;H,3.58,N,28.54.Found:C,52.62;H,3.59;N,28.20. |
82 | H | 36 | mp 205.0-205.3℃;NMR δH(400MHz,DMSO)7.97-7.85(5H,m),7.46-7.41(3H,m),7.32(2H,brs),7.13(1H,d,J 8.5Hz),6.53-6.52(1H,m),5.85(2H,s)2.46(3H,s). |
83 | C | 19 | mp 252.8-253.3℃;NMR δH(400MHz,MeOD)8.21(1H,d,J 3.0Hz),7.98(1H,d,3.5Hz),7.62-7.52(2H,m),7.37-7.31(2H,m)and 5.81(2H,s);保留时间0.83min. |
84 | C | 53 | mp 235.8-236.5℃;IR νmax(DR)/cm-13309,2836,2033,1823,1651,1505,1468,1354,1250 and 1209;NMR δH(400MHz,CD3OD)8.18(1H,d,J 4.0Hz),7.47-7.37(3H,m),6.61(1H,dd,J 1.0,3.5Hz),5.82(2H,s)and 2.57(3H,s). |
85 | R | 72 | mp 215.9-217.5℃;IR νmax(Nujol)/cm-13308,2955,2869,1634,1505 and1435;NMR δH(400MHz,DMSO)8.27(1H,t,J 5.5Hz),8.13(1H,d,J 1.0Hz),7.91(1H,d,J 3.5Hz),7.36(2H,s),7.31(1H,t,J 7.5Hz),7.17(2H,t,J 7.5Hz),7.09(1H,s),6.89-6.84(1H,m),5.64(2H,s),4.21(2H,d,J 6.0Hz),1.93(2H,s)and 0.79(6H,d,J 6.5Hz). |
86 | B | 51 | NMR δH(400MHz,DMSO)8.84(1H,d,J 5.5Hz),8.14(1H,d,J 2.0Hz),8.08(1H,dd,J 5.5,1.0Hz),7.89(1H,d,J 5.5Hz),7.34(2H,brs),6.53-6.52(1H,m),5.98(2H,s),2.46(3H,s);保留时间1.85min. |
87 | Z | 73 | NMR δH(400MHz,DMSO)9.10(1H,s),8.69(1H,s),8.05(1H,d,J 5.5Hz),7.89(1H,d,J 3.0Hz),732(2H,brs),6.59-6.57(1H,m),6.53-6.51(1H,m),6.37-6.36(1H,m),5.60(2H,s),2.46(3H,s);M/Z 339(M+H)+;保留时间0.79min. |
88 | B | 11 | mp 258.8-259.0℃;IR νmax(DR)/cm-14014,3316,3204,2966,2746,2561,2106,1962,1606,1526,1436,1351,1029 and 758;NMR δH(400MHz,DMSO)2.46(3H,s),5.79(2H,s),6.86-6.88(1H,m),7.23(1H,d,J 7.5Hz),7.30-7.50(3H,m),7.81(1H,d,J 8.0Hz),7.91(1H,d,J 3.5Hz),8.13-8.15(1H,m).Anal.Calcd for C16H13N7O3:C,54.70;H,3.73;N,27.89.Found:C,54.70;H,3.77;N,27.48. |
89 | C | 57 | mp 247.1-247.2℃;IR νmax(DR)/cm-13322,1740,1600,1240,1167,959 and770;NMR δH(400MHz,DMSO)2.10(3H,s),4.93(2H,s),5.56(2H,s),6.11(1H,d,J 6.5Hz),6.58(1H,d,J 8.0Hz),6.80(1H,t,J 7.5Hz),6.85-6.87(1H,m),7.35(2H,s),7.90(1H,d,J 3.5Hz),8.12-8.14(1H,m). |
90 | C | 38 | mp 268.5-269.1℃;IR νmax(DR)/cm-14010,3451,3317,3182,2957,2749,2104,1844,1652,1608,1487,1335,1025 and 764;NMR δH(400MHz,DMSO)1.99(3H,s),4.89(2H,s),5.47(2H,s),6.36-6.43(2H,m),6.84-6.89(2H,m),7.35(2H,s),7.91(1H,d,J 3.5Hz)8.12-8.14(1H,m). |
91 | B | 15 | mp 284.3-284.5℃;IR νmax(DR)/cm-13321,3216,1612,1031,765 and 552;NMRδH(400MHz,DMSO)8.12(1H,d,J 1.0Hz),7.88(1H,d,J 3.5Hz),7.35(2H,brs),6.85(1H,dd,J 3.5,1.5Hz),5.44(2H,s),2.52(3H,s)and 2.25(3H,s) |
92 | B | 8 | mp 267.9-268.5℃;NMR δH(400MHz,DMSO)2.32(3H,s),5.69(2H,s),6.85-6.89(1H,s),7.04-7.10(1H,m),7.33-7.54(4H,m),7.90(1H,d,J 3.5Hz),8.13-8.15(1H,m). |
93 | B | 4 | IR νmax(Nujol)/cm-13316,3193,2926,2851,1637,1508 and 1437;NMR δH(400MHz,DMSO)8.11-8.09(1H,m),7.89(1H,dd,J 3.5,1.0Hz),7.27(2H,s),6.86-6.83(1H,m),4.26(2H,d,J 7.5Hz),2.04-1.90(1H,m),1.72-1.50(5H,m)and 1.25-0.95(5H,m). |
94 | B | 15 | mp 237.8-238.0℃;NMR δH(400MHz,DMSO)2.49(3H,s),5.76(2H,s),6.84-6.88(1H,m),7.28(1H,dd,J 8.5,1.5Hz),7.30-7.42(3H,m),7.91(1H,d,J 3.5Hz),7.97(1H,d,J 8.5Hz),8.11-8.14(1H,m).Anal.CalcdforC16H13N7O3·0.1H2O:C,54.42;H,3.77;N,27.77.Found:C,54.73;H,3.78;N, |
27.40. | |||
95 | N | 32 | mp 249.8-250.0℃;IR νmax(DR)/cm-13437,3317,3210,2964,2865,1610,1508;NMR δH(400MHz,DMSO)8.19-8.17(1H,m),8.12(1H,m),7.92-7.91(1H,m),7.66-7.63(1H,m),7.24-7.20(3H,m),6.86(1H,dd;J 3.5,1.5Hz),5.80(2H,s),2.44(3H,s). |
96 | B | 4 | mp 226.6-226.9℃;NMR δH(400MHz,DMSO)2.32(3H,s),5.98(2H,s),6.84(1H,s),6.85-6.90(1H,m),7.35(2H,s),7.43(1H,d,J 7.5Hz),7.91(1H,d,J7.5Hz),8.07-8.15(2H,m). |
97 | C | 63 | mp 245.3-246.1℃;IR νmax(DR)/cm-14010,3406,3320,3198,2929,2746,1608,1507,1414,1285,1022 and 753;NMR δH(400MHz,DMSO)2.00(3H,s),4.86(2H,s),5.42(2H,s),6.54(1 H,d,J 8.0Hz),6.82-6.85(1H,m),6.90(1H,dd,J 8.0,2.0Hz),6.92-6.95(1H,m),7.29(2H, s),7.88(1H,d,J 3.5Hz),8.09-8.12(1H,m).Anal.Calcd for C16H15N7O·0.2H2O:C,59.14;H,4.78;N,30.17.Found:C,59.44;H,4.74;N,29.82. |
98 | O | 98 | IR νmax(Nujol)/cm-13324,3206,1698,1650 and 1611;NMR δH(400MHz,DMSO)13.56-12.46(1H,s),8.13-8.11(1H,s),7.92-7.84(3H,m),7.56-7.31(3H,m),6.87-6.85(1H,m)and7.74(2H,s). |
99 | P | 66 | IR νmax(Nujol)/cm-13324,1644,1491 and 1417;NMR δH(400MHz,DMSO)8.12(1H,s),7.98-7.93(1H,s),7.91(1H,d,J 3.0Hz),7.81(1H,d,J 6.5Hz),7.77(1H,s),7.47-7.29(5H,m),6.86(1H,s)and 5.77-5.68(2H,m). |
100 | B | 13 | mp 285.7-285.9℃;IR νmax(DR)/cm-13345,3197,1664,1613,1116,766 and600;NMR δH(400MHz,DMSO)8.13-8.02(1H,m)7.90(1H,d,J 3.5Hz),7.37-7.27(3H,m),6.86(1H,dd,J 3.5,2.0Hz),5.67(2H,s)and 2.52(3H,s). |
101 | AA | 32 | mp 279.9-280.3℃;NMR δH(400MHz,DMSO)8.33(3H,brs),7.93(1H,d,J2.0Hz),7.51-7.39(2H,m),7.39-7.31(3H,m),5.69(2H,s)and 3.98(2H,q,J5.5Hz). |
102 | P | 23 | IR νmax(Nujol)/cm-13480,3322,3202,283,1608 and 1506;NMR δH(400MHz,DMSO)8.12(1H,s),7.90(1H,d,J 3.5Hz),7.47-7.25(5H,m),6.87-6.84(1H,m),5.72(2H,s),3.77-3.61(1H,s),2.76(3H,s),1.10(3H,s)and 0.99(3H,s). |
103 | P | 58 | IR νmax(Nujol)/cm-13298,2972,1635 and 1418;NMR δH(400MHz,DMSO)8.21(1H,d,J 7.5Hz),8.12(1H,s),7.91(1H,d,J 3.0Hz),7.82-7.74(2H,m),7.48-7.29(4H,m),6.86(1H,s),5.71(2H,s),4.13-4.01(1H,m)and 1.13(6H,d,J 6.5Hz). |
104 | C | 10 | mp 249.9-250.5℃;NMR δH(400MHz,DMSO)2.07(3H,s),5.06(2H,s),5.43(2H,s),6.60-6.65(2H,m),6.81-6.89(2H,m),7.37(2H,s),7.90(1H,dd,J 3.5,1.0Hz),8.12(1H,d,J 1.0Hz).Anal.Calcd for C16H15N7O·0.2 H2O:C,59.14;H,4.78;N,30.17.Found:C,59.53;H,4.75;N,29.87. |
105 | B | 16 | mp 263.2-263.5℃;IR νmax(DR)/cm-13499,3307,3192,2958,2238,1610,1490;NMR δH(400MHz,DMSO)8.73(1H,d,J 5.0Hz),8.13-8.12(1H,m),7.92-7.90(1H,m),7.85-7.81(2H,m),7.30(2H,brs),6.87-6.86(1H,m),5.87(2H,s). |
106 | B | 16 | mp 288.1-288.2℃;IR νmax(DR)/cm-13324,3196,1609,1489,1166,1004,798and 550;NMR δH(400MHz,DMSO)8.59(1H,s),8.44(1H,s),8.12(1H,s),7.90(1H,d,J 3.5Hz),7.31(2H,brs),6.86(1H,dd,J 3.5,1.5Hz),5.81(2H,s)and 2.48(3H,s). |
107 | B | 22 | mp 276.4-277.4℃;IR νmax(DR)/cm-13443,3324,3202,1610,1324,1229,1030and 788;NMR δH(400MHz,DMSO)9.01(1H,dd,J 4.0,2.0Hz),8.45(1H,dd,J 8.5,2.0Hz),8.14-8.12(1H,m),7.97(1H,d,J 8.0Hz),7.93(1H,d,J 3.5Hz),7.64(1H,1H,dd,J 8.5,4.0Hz),7.52(1H,t,J 7.0Hz),7.31(2H,brs),7.15(1H,d,J7.5Hz),6.87(1H,dd,J 3.5,2.0Hz)and 6.31(2H,s). |
108 | B | 30 | mp 215.0-215.3℃;IR νmax(DR)/cm-13325,3198,1612,1246,1026,727 and567;NMR δH(400MHz,DMSO)8.14-8.12(1H,m),7.91(1H,dd,J 3.5,1.0Hz),7.90-7.85(2H,m),7.52(1H,s),7.51-7.46(3H,m),7.36(2H,brs),6.86(1H,dd,J 3.5,1.5Hz),and 5.81(2H,s). |
109 | Q | 23 | mp 289.8-289.9℃;IR νmax(DR)/cm-13350,2924,2863,1981,1723,1618,1351,1100,974,766 and 524;NMR δH(400MHz,DMSO)8.23-8.16(2H,m),7.77-7.62(3H,m),7.49(2H,brs),5.88(2H,s)and 2.56(3H,s). |
110 | B | 31 | mp247.4-247.5℃;IR νmax(DR)/cm-13999,3470,3316,3198,2929,2744,2345,2103,1924,1837,1773,1649,1435,1355,1237,1029 and 768;NMR δH(400MHz,DMSO)5.79(2H,s),6.85-6.87(1H,m),7.36(2H,s),7.56(1H,dd,J 8.5,2.0Hz),7.76(1H,d,J 8.0Hz),7.91(1H,dd,J 3.5,1.0Hz),8.04(1H,d,J2.0Hz),8.12-8.13(1H,m).Anal.Calcd for C15H10N7O3Cl:C,48.47;H,2.71;N,26.36.Found:C,48.63;H,2.80;N,26.22. |
111 | B | 14 | mp 244.1-244.6℃;NMR δH(400MHz,DMSO)5.84(2H,s),6.85-6.89(1H,m),7.37(2H,s),7.54(1H,dd,J 9.5,1.5Hz),7.84(1H,t,J 1.0 Hz),7.92(1H,d,J 3.5Hz),8.08(1H,dd,J 9.0,1.0Hz),8.12-8.15(1H,m).Anal.Calcdfor C15H10N8O2·0.75C3H7NO:C,53.25;H,3.95;N,31.50.Found:C,53.08;H,3.79;N,31.38. |
112 | B | 28 | mp 190.4-191.4℃;IR νmax(DR)/cm-13482,3308,3194,2940,2880,1610,1508;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.92(1H,d,J 3.5Hz),7.78(1H,t,J 8.0Hz),7.35-7.32(3H,m),7.04(1H,d,J 7.5Hz),6.86(1H,dd,J3.5,2.0Hz),5.75(2H,s),4.43(2H,s),3.33(3H,s). |
113 | B | 39 | IR νmax(Nujol)/cm-13499,3316,3193,2946,1651 and 1509;NMR δH(400MHz,DMSO)8.13-8.10(1H,m),7.90(1H,d,J 3.5Hz),7.39-7.26(7H,m),6.87-6.84(1H,m)and 5.67(2H,s);Anal.Calcd for C15H12N6O·0.75H2O:C,58.91;H,4.45,N,27.48.Found:C,58.84;H,4.10;N,27.32. |
114 | C | 67 | mp 256.7-257.1℃;IR νmax(DR)/cm-14003,3452,3324,3203,2950,2746,2102,1733,1654,1516,1420,1305,1221,1106,1024 and 761;NMRδH(400MHz,DMSO)5.38(2H,s),5.51(2H,s),6.46(1H,dd,J 8.5,2.5Hz),6.58(1H,d,J 2.0Hz),6.84-6.87(1H,m),7.15(1H,d,J 8.0Hz),7.32(2H,s),7.91(1H,dd,J 3.5,1.0Hz),8.11-8.13(1H,m).Anal.Calcd for C15H12N7OCl·0.3H2O:C,51.90;H,3.66;N,28.24.Found:C,52.12;H,3.48;N,27.86. |
115 | B | 12 | NMR δH(400MHz,DMSO)8.84(1H,d,J5.5Hz),8.15-8.12(2H,m),8.08-8.06(1H,m),7.92-7.91(1H,m),7.32(2H,brs),6.87(1H,dd,J 3.5,1.5Hz),5.99(2H,s);保留时间1.28min. |
116 | Z | 87 | NMR δH(400 MHz,DMSO)9.08(1H,brs),8.66(1H,brs),8.13-8.12(1H,m),8.06-8.04(1H,m),7.93-7.91(1H,m),7.32(2H,brs),6.87-6.86(1H,m),6.60-6.58(1H,m),6.38-6.37(1H,m),5.61(2H,s);M/Z 325(M+H)+. |
117 | B | 9 | IR νmax(DR)/cm-13491,3310,3198,2976,1612;NMR δH(400MHz,DMSO)8.14-8.13(1H,m),7.99-7.98(1H,m),7.93-7.91(1H,m),7.80-7.79(1H,m),7.34(2H,brs),6.88-6.86(1H,m),5.90(2H,s),2.57(3H,s). |
118 | Z | 91 | NMR δH(400 MHz,DMSO)13.45(1H,brs),9.50(1H,brs),8.15-8.14(1H,m),7.92(1H,d,J 3.5Hz),7.39(2H,brs),6.87-6.86(1H,m),6.56(1H,brs),6.15(1H,brs),5.67(2H,s),2.39(3H,s);M/Z 339(M+H)+. |
119 | B | 15 | mp>230℃;IR νmax(DR)/cm-13993,3509,3314,3195,2997,2950,2682,2561,2101,1943,1780,1613,1501,1433,1345,1100,1027,889 and 780;NMR δH(400MHz,DMSO)6.00(2H,s),6.85-6.90(1H,m),7.05(1H,d,J 8.5 |
Hz),7.37(2H,s),7.78(1H,dd,J 8.5,2.0Hz),7.91(1H,d,J 3.5Hz),8.14(1H,d,J 1.0Hz),8.27(1H,d,J 2.5Hz).Anal.Calcd for C15H10N7O3Cl.0.3H2O:C,47.77;H,2.83;N,26.00.Found:C,47.65;H,2.71;N,25.85. | |||
120 | C | 19 | mp 211.4-211.6℃;IRνmax(DR)/cm-14015,3325,3218,2969,2878,2101,1653,1508,1423,1275,1023,834 and 761;NMR δH(400MHz,DMSO)5.45(2H,s),5.60(2H,s),6.51(1H,dd,J 8.0,2.0Hz),6.70-6.79(2H,m),6.83-6.89(1H,m),7.38(2H,s),7.90(1H,d,J 3.5Hz),8.12(1H,s). |
121 | B | 13 | mp 292.3-292.4℃;IR νmax(DR)/cm-13324,3207,2098,1602,1527,1352,1024and 813;NMRδH(400MHz,CDCl3)8.10(1H,d,J 3.0Hz),7.79(1H,d,J 1.5Hz),7.64(2H,d,J 8.5Hz),7.49(2H,d,J 8.5Hz),6.71(1H,dd,J 3.5,1.5Hz),5.71(2H,s)and 5.38(2H,brs). |
122 | A | 50 | mp 227.5-228.5℃;IR νmax(DR)/cm-1,3265,1701,1521,1480,1413,1355,1309,1204 and 1147;NMR δH(400MHz,DMSO)8.11(1H,d,J 1.0Hz),7.9(1H,d,J 3.5Hz),7.3(2H,brs),7.04(1H,d,J 2.0Hz),6.90(1H,d,J 8.0Hz),6.85(1H,dd,J 1.5,3.5Hz),6.79(1H,dd,J 2.0,8.0Hz),5.57(2H,s),3.71(3H,s,)and 3.72(3H,s). |
123 | B | 35 | mp 214.6-216.2℃;IR νmax(DR)/cm-13512,3295,3173,2988,2736,2415,1636,1437,1340 and 1228;NMR δH(400MHz,DMSO)7.97(1H,d,J 8.5Hz),7.87(1H,d,J 3.0Hz),7.40(1H,d,J 1.0Hz),7.31(2H,brs),7.27(1H,dd,J 1.5,8.0Hz),6.51(1H,dd,J 1.0,3.5Hz),5.74(2H,s),2.48(3H,s)and 2.46(3H,s). |
124 | C | 65 | mp 215.7-216.7℃;IR νmax(DR)/cm-13328,2928,2424,2345,1609 and 1263;NMRδH(400MHz,DMSO)7.85(1H,d,J3.5Hz),7.26(2H,brs),6.93(1H,d,J 1.5Hz),6.89(1H,dd,J 2.0,8.0Hz),6.54(1H,d,J 8.0Hz),6.49(1H,J 1.0,3.5Hz),5.40(2H,s),4.89(2H,brs),2.45(3H,s)and 2.27(3H,s). |
125 | B | 29 | mp 221.5-221.6℃;IR νmax(DR)/cm-13506,3294,3178,2683,1613,1315,1027 and 697;NMR δH(400 MHz,DMSO)8.13-8.11(1H,m),7.90(1H,d,J4.5Hz),7.38(2H,brs),6.86(1H, dd,J 3.5,1.5Hz),6.18-6.16(1H,m),5.70(2H,s)and 2.36(3H,s). |
126 | N | 26 | mp 229.6-230.3℃;IR νmax(DR)/cm-13317,3198,1602,1499;NMR δH(400MHz,DMSO)8.44-8.43(1H,m),8.31(1H,d,J 5.0Hz),8.14-8.13(1H,m),7.92(1H,d,J 3.0Hz),7.35(2H,brs),6.88-6.86(1H,m),6.70(1H,d,J 5.0Hz),5.71(2H,s),2.39(3H,s), |
127 | B | 13 | mp 275.0-273.3℃;IR νmax(DR)/cm-13449,3310,3202,1605,1487,1420,1023,836,760 and 551;NMR δH(400MHz,DMSO)8.15-8.11(1H,m),8.07(1H,d,J 9.0Hz),7.91(1H,d,J 3.5Hz),7.68(1H,dd,J 9.0,6.5Hz),7.38-7.29 |
(3H,m),6.86(1H,dd,J 3.5,1.5Hz)and 6.15(2H,s). | |||
128 | B | 16 | mp 129.1-131.0℃;IR νmax(DR)/cm-13993,3470,3310,3197,1610,1508,1420,1239,1002 and 796;NMR δH(400MHz,DMSO)8.74(1 H,d,J 1.5Hz),8.61(1H,d,J 2.5Hz),8.57-8.54(1H,m),8.13-8.11(1H,m),7.91(1H,d,J3.5Hz),7.31 (2H,brs),6.86(1H,dd,J 3.5,2.0Hz)and 5.88(2H,s). |
129 | B | 20 | mp 266.5-266.7℃;IR νmax(DR)/cm-14018,3487,3310,3193,2744,1636,1585,1539,1507,1437,1347,1266,1238 and 1196;NMR δH(400MHz,DMSO)8.15(1H,dd,J 2.5,7.5Hz),8.12(1H,d,J 1.0Hz),7.90(1H,d,J 3.5Hz),7.73-7.68(1H,m),7.58(1H,dd,J 11.3,8.8Hz),7.36(2H,brs),6.88(1H,dd,J 1.5,3.5Hz)and 5.78(2H,s). |
130 | H | 32 | mp 149.0-149.6℃;IR νmax(DR)/cm-14072,3332,3198,1654,1604,1348,1237,1111,1012,775,691 and 570;NMR δH(400MHz,DMSO)8.79-8.70(2H,m),8.25-8.14(2H,m),7.77-7.58(5H,m),7.38(2H,brs)and 5.87(2H,s). |
131 | B | 22 | mp 225.7-225.8℃;NMR δH(400MHz,DMSO)8.33(1H,d,J 4.5Hz),8.13-8.12(1H,m),7.92-7.91(1H,m),7.30(2H,brs),7.15(1H,d,J 5.0Hz),7.07-7.06(1H,m),6.86(1H,dd,J 1.5,3.5Hz),5.72(2H,s),2.28(3H,s);Anal. Calcdfor C15H13N7O·0.7 H2O:C,56.31;H,4.54,N,30.65.Found:C,56.57;H,4.24;N,30.33. |
132 | N | 10 | IR νmax(DR)/cm-13332,2977,1694,1608;NMR δH(400 MHz,DMSO)8.41(1H,d,J 4.5Hz),8.14-8.13(1H,m),7.92(1H,d,J 3.5Hz),7.43(1H,t,J 6.0Hz),7.33(2H,brs),7.16(1H,d,J 4.5Hz),6.97-6.96(1H,m),6.87(1H,dd,J2.0,3.5Hz),5.76(2H,s),4.10(2H,d,J 6.0Hz),131(9H,s). |
133 | B | 14 | mp 209.7-209.9℃;IR νmax(Nujol)/cm-13506,3311,3196,2996,2951,1637,1518 and 1283;NMR δH(400MHz,DMSO)8.15-8.12(1H,m),7.91(1H,dd,J 3.5,1.0Hz),7.84(1H,d,J 8.0Hz),7.43(1H,d,J 1.5Hz),7.42-7.35(2H,s),6.88-6.82(2H,m),5.77(2H,s)and 3.91(3H,s). |
134 | B | 14 | mp 240.9-241.1℃.IR νmax(DR)/cm-14010,3629,3499,3313,3196,2946,2733,2447,1943,1638,1528,1420,1351,1222,1025 and 960.NMR δH(400MHz,DMSO)5.85(2H,s),6.84-6.89(1H,m),7.36(2H,s),7.50(2H,dt,J 8.5,2.0Hz),7.92(1H,dd,J 3.5,1.0Hz),8.12-8.14(1H,m),8.22(2H,dt,J 9.0,2.0Hz).Anal.Calcd for C15H11N7O3·0.6H2O:C,51.75;H,3.53;N,28.17.Found:C,5208;H,3.22;N,27.96. |
135 | B | 18 | mp 208.6-208.8℃;IR νmax(DR)/cm-13432,3304,3191,2961,1616,1500,1434;NMR δH(400MHz,DMSO)8.14-8.13(1H,m),7.93-7.91(1H,m),7.67(1H,t,J 7.5Hz),7.35(2H,brs),7.19(1H,d,J 7.5Hz),6.90-6.86(2H,m),5.73(2H,s),2.68(2H,q,J 7.5Hz),1.14(3H,t,J 7.5Hz). |
136 | B | 18 | mp 172.7-173.2℃;NMR δH(400 MHz,DMSO)8.42(1H,d,J 5.5Hz),8.14(1H,m),7.92(1H,d,J 3.5Hz),7.39(2H,brs),7.11-7.10(1H,m),6.97(1H,d,J 5.5Hz),6.87(1H,dd,J 2.0,3.5Hz),5.70(2H,s),2.71(2H,q,J 7.5Hz),1.18(3H,t,J 7.5Hz). |
137 | B | 13 | mp 176.3-176.5℃;IR νmax(DR)/cm-13452,3326,3209,2973,1734,1611,1328,1026 and 774;NMR δH(400MHz,DMSO)8.13(1H,d,J 2.5Hz),7.90(1H,d,J 3.5Hz),7.72(1H,d,J 3.5Hz),7.61(1H,d,J 8.5Hz),7.34(2H,brs),7.19(1H,t,J 8.0Hz),6.86(1H,dd,J 3.5,2.0Hz),6.77(1H,d,J 4.0Hz),6.75.(1H,d,J 7.5Hz),6.07(2H,s)and 1.54(9H,s). |
138 | B | 26 | mp 58.5-62.6℃;IR νmax(DR)/cm-13430,33 15,3210,3973,1718,1165,834and 772;NMR δH(400MHz,DMSO)8.13-8.11(1H,m),8.03(1H,d,J 8.0Hz),7.89(1H,d,J 3.5Hz),7.73(1H,d,J 4.0Hz),7.39(2H,brs),7.30(1H,t,J8.5Hz),7.08(1H,d,J 7.0Hz),6.91(1H,d,J4.5Hz),6.86(1H,dd,J 3.5,1.5Hz),5.90(2H,s)and 1.62(9H,s). |
139 | K | 85 | mp 192.3-193.5℃;NMR δH(400MHz,DMSO)11.27(1H,brs),8.12(1H,d,J 2.5Hz),7.90(1 H,d,J 3.5Hz),7.39-7.33(2H,m),7.04(1H,t,J 8.0Hz),6.87-6.83(2H,m),6.56-6.52(1H,m)and 5.86(2H,s). |
140 | B | 20 | mp 184.0-185.2℃;IR νmax(DR)/cm-13638,3462,3331,3184,2976,1686,1174,1026 and 756;NMR δH(400MHz,DMSO)8.1 3(1H,d,J 1.0Hz),7.90(1H,d,J 3.5Hz),7.45-7.31(3H,m),7.27-7.17(4H,m),6.86(1H,dd,J 3.5,2.0 Hz),5.64(2H,s),4.08(2H,d,J 6.0Hz)and 1.37(9H,s). |
141 | C | 45 | mp 240.3-240.4℃.IR νmax(DR)/cm-13320,3198,2929,1610,1505,1438,1280,1233,1028,956 and 759;NMR δH(400MHz,DMSO)5.85(2H,s),6.84-6.89(1H,m),7.36(2H,s),7.50(2H,dt,J 8.5,2.0Hz),7.92(1H,dd,J 3.5,1.0Hz),8.12-8.14(1H,m),8.22(2H,dt,J 9.0Hz). |
142 | B | 14 | mp 189.0-189.1℃;IR νmax(DR)/cm-13506,3304,3180,1735,1609,1167,1029 and 766;NMR δH(400MHz,DMSO)8.15-8.1 1(1H,m),8.02(1H,d,J8.5Hz),7.91(1H,d,J 3.5Hz),7.68(1H,d,J 3.5Hz),7.53(1H,s),7.37(2H,brs),7.29(1H,dd,J 8.5,1.5Hz),6.86(1H,dd,J 3.5,2.0Hz),6.70(1H,d,J 3.5Hz),5.75(2H,s)and 1.61(9H,s). |
143 | B | 18 | mp 167.0-167.3℃;IR νmax(DR)/cm-13650,3485,3320,3194,2978,1726,1168,953 and 756;NMR δH(400MHz,DMSO)9.00(1H,brs),8.13(1H,s),7.91(1H,d,J 3.5Hz),7.57(1H,t,J 8.0Hz),7.39(2H,brs),7.16(1H,d,J 11.5Hz),7.04(1H,d,J 8.5Hz),6.86(1H,dd,J 3.5,2.0Hz),5.64(2H, brs)and 1.44(9H,s). |
144 | K | 56 | mp>300℃ dec;IR νmax(DR)/cm-12903,2030,1606,1464,1033,779 and 589;NMR δH(400MHz,DMSO)8.30(2H,brs),8.14(1H,s),7.92(1H,d,J 3.5Hz),7.46(2H,d,J 8.0Hz),7.32(2H,d,J 8.0Hz),6.92-6.84(1H,m),5.69(2H,s)and 4.04-3.96(2H,m). |
145 | H | 30 | IR νmax(DR)/cm-13511,3292,3164,2971,1609,1525,1437,1354 and 1239;NMR δH(400MHz,DMSO)8.19(2H,m),7.90(1H,d,J 3.5Hz),7.72-7.64(2H,m),7.36(2H,brs),6.53(1H,d,J 3.5Hz),5.83(2H,s),2.80(2H,q,J 7.5Hz)and 1.27(3H,t,J 7.5Hz). |
146 | B | 35 | mp 180.0-180.5℃;IR νmax(DR)/cm-13325,3206,2976,1734,1604,1341,1024 and 768;NMR δH(400MHz,DMSO)7.92(1H,d,J 3.0Hz),7.84(1H,s),7.67(1H,d,J 4.0Hz),7.62(1H,d,J 8.0Hz),7.37(2H,brs),7.26(1H,d,J 8.0Hz),6.87(1H,dd,J 3.5,1.5Hz),6.70(1H,d,J 3.5Hz),5.80(2H,s)and 1.51(9H,s). |
147 | K | 57 | mp>200℃ dec;IR νmax(DR)/cm-12816,2004,1660,1507,1427,1277,1030,746 and 524;NMRδH(400MHz,DMSO)8.15-8.12(1H,m),7.91(1H,d,J 3.5Hz),7.14(1H,d,J 12.0Hz),7.06-6.94(2H,m),6.86(1H,dd,J 3.5,2.0Hz)and5.57(2H,s). |
148 | B | 43 | Mp 259.8-259.9℃.IR νmax(DR)/cm-13382,3214,2986,2731,2090,1767,1730,1606,1487,1372,1275,1137,1029,873 and 771;NMR δH(400MHz,DMSO)1.49(9H,s),5.63(2H,s),6.85-6.86(1H,m),7.20-7.27(2H,m),7.40(2H,s),7.87(1H,d,J 3.0Hz),8.11-8.14(1H,m). |
149 | K | 96 | IRνmax(Nujol)/cm-13375,3061,1653,1509 and 1474;NMR δH(400MHz,DMSO)11.15-10.13(1H,s),8.43-7.36(3H,s),8.14-8.12(1H,m),7.89(1H,dd,J 3.5,1.0Hz),6.87-6.84(1H,m),6.59-6.51(2H,m)and 5.51(2H,s). |
150 | C | 37 | IR νmax(DR)/cm-14043,3461,3312,3198,2970,2748,2438,1923,1650,1514,1497 and 1324;NMR δH(400MHz,DMSO)7.9(1H,d, J 3.5Hz),7.31(2H,brs),6.97(1H,t,J 8.0 Hz),6.53(1H,d,J 3.5Hz),6.45(1H,dd,J 1.5,8.0Hz),6.40(1H,d,J 7.5 Hz),6.34(1H,t,J 1.7Hz),5.48(2H,s),5.12(2H,s),2.80(2H,q,J 7.5Hz)and 1.27(3H,t,J 7.5Hz). |
151 | C | 48 | mp 251.2-251.5℃;IR νmax(DR)/cm-13449,3365,3314,3196,2954,2742,1731,1642,1598,1556,1463 and 1407;NMR δH(400MHz,DMSO)8.76-8.72(2H,m),7.67-7.62(3H,m),7.36(2H,brs),6.97(1H,t,J 8.0Hz),6.46(1H,dd,J 1.5,8.0Hz),6.43(1H,d,J 7.5Hz),6.36(1H,t,J 1.7Hz),5.52(2H,s)and 5.13(2H,s). |
152 | AF | 86 | mp 298.9-299.0℃;IR νmax(DR)/cm-13422,3321,3105,3942,1601,1351,1219,1019 and 762;NMR δH(400MHz,DMSO)11.09(1H,brs),8.13(1H,s),7.91(1H,d,J 3.0Hz),7.51(1H,d,J 8.5 Hz),7.43-7.31(3H,m),7.28(1H,s),7.00(1H,d,J 8.0Hz),6.89-6.83(1H,m),6.39(1H,s)and 5.73(2H,brs). |
153 | AF | 75 | mp 226.8-227.4℃;IR νmax(DR)/cm-13475,3320,2739,1645,1506,1223,1008 and778;NMRδH(400MHz,DMSO)11.14(1H,brs),8.14-8.10(1H,m),7.90(1H,d,J 3.5Hz),7.50(1H,s),7.40-7.31(4H,m),7.09(1H,dd,J 8.0,1.5Hz),6.85(1H,dd,J 3.5,1.5Hz),6.43-6.38(1H,m)and 5.70(2H,s). |
154 | AF | 77 | mp 295.3-295.5℃;IR νmax(DR)/cm-13215,1610,1005,758,650 and 565;NMR δH(400MHz,DMSO)11.36(1H,brs),8.15-8.11(1H,m),7.91(1H,d,J3.5Hz),7.51(1H,d,J 8.0Hz),7.46(1H,t,J 2.5Hz),7.43(2H,brs),6.92(1H,t,J 7.5Hz),6.86(1H,dd,J 3.5,2.0Hz),6.71(1H,d,J 7.0Hz),6.53-6.49(1H,m)and 5.93(2H,s). |
155 | B | 35 | mp 258.6-258.7℃;IR νmax(Nujol)/cm-13386,3206,1646,1607 and 1481;NMR δH(400MHz,DMSO)8.33(1H,dd,J 9.0,4.5Hz),8.15(1H,s),7.92(1H,d,J 3.5Hz),7.55-7.47(1H,m),7.47-7.35(2H,s),6.93-6.85(2H,m)and6.03(2H,s). |
156 | AG | 99 | mp 274.2-27.43℃;IR νmax(Nujol)/cm-13482,330S,3197,2963,1606,1499and 1420;NMR δH(400MHz,DMSO)8.12(1H,s),7.87(1H,d,J 3.0Hz),7.37(2H,s),6.86-6.77(3H,m),5.55(2H,s)and 3.79(3H,s);Anal.Calcd forC16H12N6O2F2.0.5H2O:C,52.32;H,3.57,N,22.88.Found:C,52.62;H,3.31;N,22.72. |
157 | B | 24 | mp 204.2-204.4℃;NMR δH(400 MHz,DMSO)1.41(9H,s),4.37,(2H,d,J6.0Hz),5.72(2H,s),6.83(1H,d,J 6.0Hz),6.85-6.88(1H,d,J 7.5Hz),7.14-7.22(1H,m),7.30(2H,d,J 4.0Hz),7.36(2H,s),7.48(1H,t,J 6.0Hz),7.91(1H,d,J 3.5Hz),8.12-8.14(1H,m).Anal.Calcd for C21H23N7O3:C,59.85;H,5.50;N,23.25.Found:C,59.69;H,5.54;N,22.74. |
158 | AZ | mp>300℃ dec;IR νmax(DR)/cm-13212,1607,1438,1212,1029 and 770;NMR δH(400MHz,DMSO)15.74(1H,brs),8.13(1H,s),7.91(1H,d,J 3.5Hz),7.80(2H,brs),7.54-7.30(3H,s),6.86(1H,dd,J 4.0,2.0Hz)and 5.85 |
(2H,s). | |||
159 | B | 16 | Mp 235.9-237.8℃;NMR δH(400MHz,DMSO)8.15-8.13(1H,m),7.93-7.91(1H,d,J 3.5Hz),7.84-7.82(1H,d,J 2.5Hz),7.80-7.76(1H,dd,J 2.5,8.5Hz),7.43-7.37(2H,s)7.04-7.00(1H,d,J 8.5Hz),6.89-6.86(1H,dd,J2.0,3.5Hz),5.71-5.69(2H s),and 3.99-3.97(3H s). |
160 | B | 28 | mp 277.4-277.9℃;NMR δH(400MHz,DMSO)9.93(1H,s),8.15-8.12(1H,m),7.92(1H,d,J 3.5Hz),7.55(1H,d,J 8.0Hz),7.38(2H,s),7.34(1H,s),7.27(1H,t,J 8.0Hz),6.96(1H,d,J 7.5Hz),6.88-6.85(1H,m),5.63(2H,s)and1.99(3H,s). |
161 | K | 100 | mp>250℃ dec;IR νmax(DR)/cm-13035,1968,1654,1464,1354,1247,1032and 746;NMR δH(400MHz,DMSO)4.39(2H,q,J 5.5Hz),5.81(2H,s),6.84-6.89(1H,m),7.13(1H,d,J 7.5Hz),7.31-7.46(3H,m),7.55(1H,d,J 7.5Hz),7.90(1H,d,J 3.5Hz),8.12-8.16(1H,m),8.44(3H,s).Anal.Calcd forC16H15N7O·2HCl·1.5H2O:C,45.62;H,4.79;N,23.27.Found:C,45.63;H,4.71;N,23.14. |
162 | B | 14 | mp 195.1-195.2℃;IR νmax(DR)/cm-13490,3375,3310,3199,2895,1734,1609,1507,1421,1228,1026,1001 and 760;NMR δH(400MHz,DMSO)2.86(6H,s),5.58(2H,s),6.48(1H, d,J 7.5Hz),6.64(1H,dd,J 8.0,2.0Hz),6.72-6.75(1H,m),6.84-6.87(1H,m),7.12(1H,t,J 7.5Hz),7.35(2H,s),7.90(1H,d,J 3.5Hz)and 8.10-8.14(1H,m). |
163 | B | 20 | IR νmax(DR)/cm-13489,3324,3199,2560,1605,1235,1121,1048 and 762;NMRδH(400MHz,DMSO)8.12(1H,d,J 2.5Hz),7.90(1H,d,J 3.5Hz),7.44-7.32(4H,m),7.16(2H,J 9.0Hz),6.86(1H,dd,J 3.5,1.5Hz)and 5.67(2H,s). |
164 | B | 16 | mp 120.1-121.0℃;IR νmax(DR)/cm-13318,1772,1709,1607,1462,1395;NMRδH(400MHz,DMSO)8.15-8.14(1H,m),7.81(1H,d,J 3.5Hz),7.77(1H,t,8.0Hz),7.71-7.65(4H,m),7.33(1H,d,J 8.0Hz),7.21(2H,brs),7.12(1H, d,J 8.0Hz),6.88(1H,dd,J 1.5,3.5Hz),5.68(2H,s),4.80(2H,s). |
165 | C | 60 | mp 259.7-259.8℃;IR νmax(DR)/cm-13457,3315,3183,2959,2747,1734,1653,1608,1518,1441,1420 and 1386;NMR δH(400MHz,DMSO)8.12(1H,d,J 1.0Hz),7.90(1H,d,J 3.5Hz),7.35(2H,brs),6.93(1H,dd,J 8.0,11.5Hz),6.86(1H,dd,1.5,J 3.5Hz),6.58(1H,dd,J 2.0,J 8.5Hz)6.47-6.39(1H,m),5.49(2H,s)and 5.19(2H,s). |
166 | B | 10 | mp 210.3-211.2℃;NMR δH(400MHz,DMSO)8.15-8.10(1H,m),7.89(1H,d,J 4.5Hz),7.35(2H,brs),7.18(1H,s),7.08(1H,d,J 8.0Hz),6.85(1H,dd,J3.5,1.5Hz),6.72(1H d,J 8.0Hz),5.55(1H,s)4.49(2H,t,J 8.5Hz)and 3.13(2H,t,J 8.5Hz). |
167 | B | 11 | IR νmax(Nujol)/cm-13486,3319,and 1606;NMR δH(400MHz,DMSO)8.15-8.10(1H,m),7.92-7.87(1H,d,J 3.5Hz),7.64-7.56(1H,m),7.54-7.47(1H,m),7.46-7.35(2H,s),7.32-7.22(1H,t,J 9.5Hz),6.88-6.84(1H,dd,J 2.0,3.5Hz),and 5.71-5.65(2H s);Anal.Calcd for C15H10N6OFBr·0.5H2O:C,45.25;H,2.78;N,21.11.Found:C,45.10;H,2.48;N,20.69. |
168 | B | 12 | Mp 204.0-204.2℃;IR νmax(Nujol)/cm-13343 and 3208;NMR δH(400MHz,DMSO)8.14-8.12(1H,m),7.91-7.89(1H,dd,J 1.0,3.5Hz),7.62-7.53(1H,m),7.45-7.37(2H,s),7.05-6.97(1H,m),6.88-6.85(1H,dd,J 2.0,3.5Hz),and 5.76-5.74(2H,s). |
169 | B | 11 | IR νmax(Nujol)/cm-13490 and 3321;NMR δH(400MHz,DMSO)8.15-8.13(1H,m),7.91-7.89(1H, d,J 3.5Hz),7.78-7.72(1H,m),7.67-7.63(1H,dd,J2.0,7.0Hz),7.46-7.38(2H,s),7.15-7.08(1H,dd,J 9.0,10.0Hz)6.88-6.85(1H,dd,J 2.0,3.5Hz),and 5.67-5.64(2H,s). |
170 | B | 18 | IR νmax(Nujol)/cm-13495 and 3304;NMR δH(400MHz,DMSO)8.14-8.12(1H,m),7.90-7.88(1H,dd,J 1.0,3.5Hz),7.64-7.62(1H,dd,J 1.0,2.0Hz),7.43-7.37(2H,s),6.87-6.84(1H,dd,J 1.5,3.5Hz),6.51-6.48(1H,dd,J 1.0,3.5Hz),6.46-6.44(1H,dd,J2.0,3.5Hz)and 5.67-5.65(2H,s). |
171 | C | 59 | mp 219.3℃;IR νmax(Nujol)/cm-13508,3421,3307,3190,2949,1609 and 1506;NMR δH(400MHz,DMSO)8.14(1H,s),7.91(1H,d,J 3.5Hz),7.43(2H,s),6.92-6.85(2H,m),6.72(1H,dd,J 8.5,5.0Hz),6.52(1H,dd,J 9.5,3.0Hz),5.47(2H,s)and 5.19(2H,s). |
172 | B | 18 | IR νmax(Nujol)/m-13490,3304,3182,2986,1779,1762,1603,1345 and 1231;NMR δH(400MHz,DMSO)8.16(1H,d,J 8.5Hz),8.15-8.13(1H,m),7.92(1H,d,J 3.5Hz),7.46(1H,d,J 2.0Hz),7.45-7.36(2H,s),7.2(1H,dd,J 8.5,1.5Hz),6.88-6.86(1H,m),5.84(2H,s)and 1.47(9H,s). |
173 | C | 78 | mp 239.6-239.8℃;IR νmax(Nujol)/cm-13323,2936,2733,1772,1734,1609,1508 and 1282;NMR δH(400MHz,DMSO)9.07(1H,s),8.13-8.11(1H,m),7.89(1H,d,J 3.5Hz),7.34(2H,s),6.87-6.84(1H,m),6.59-6.50(3H,m),5.41(2H,s)and 4.57(2H,s). |
174 | K | 81 | mp>200℃ dec;IR νmax(DR)/cm-13144,2570,2004,1654,1458,1369,1280,1037 and 760;NMR δH(400MHz,DMSO)7.87(1H,d,J 3.5Hz),7.13(1H,d,J11.5Hz),7.05-6.91(2H,m),6.51(1H,dd,J 3.5,1.0Hz),5.55(2H,s)and 2.45(3H,s). |
175 | C | 17 | mp 279.3-281.3℃;IR νmax(DR)/cm-13462,3202,2952,1653,1510,1462,1416,1342,1293 and 1261;NMR δH(400MHz,DMSO)13.52(1H,brs),7.97(1H,brs),7.31(1H,s),7.25(2H,brs),6.96(1H,t,J 7.5Hz),6.46(1H,dd,J1.0,8.0Hz),6.42(1H,d,J7.0),6.34(1H,s),5.50(2H,s)and 5.13(2H,s). |
176 | K | 51 | IR νmax(Nujol)/cm-13651,3488,3317,1637,1507 and 1331;NMR δH(400MHz,DMSO)11.04(1H,s),8.15-8.13(1H,m),7.92(1H,dd,J 3.5,1.0Hz),7.87(1H,d,J 8.5Hz),7.41(2H,s),6.88-6.86(1H,m),6.85-6.81(2H,m)and5.72(2H,s);Anal.Calcd for C15H11N7O4·1.0H2O:C,48.52;H,3.53,N,26.24.Found:C,48.68;H,3.20;N,26.24. |
177 | AL | 65 | mp 245.9-247.0℃;IR νmax(DR)/cm-13284,3194,1654,1609,1523;NMR δH(400MHz,DMSO)8.41(1H,t,J 6.0Hz),8.14-8.13(1H,m),7.92(1H,dd,J1.0,3.5Hz),7.73(1H,t,J 7.5Hz),7.37(2H,brs),7.21(1H,d,J 7.5Hz),6.93(1H,d,J 7.5Hz),6.88-6.86(1H,m),5.74(2H,s),4.28(2H,d,J 6.0Hz),1.88(3H,s);Anal.Calcd for C17H16N8O2·0.5H2O·0.1C3H7NO:C,54.58;H,4.69,N,29.80.Found:C,54.90;H,4.43;N,29.46. |
178 | R | 20 | mp 216.7-218.4℃;IR νmax(DR)/cm-13854,3143,2569,2004,1654,1518,1437,1279,1207,1037 and 868;NMR δH(400MHz,DMSO)1.90 (3H,s),4.48(2H,d, J 6.0Hz),5.73(2H,s),6.82-6.89(2H,m),7.15-7.23(1H,m),7.25-7.46(4H,m),7.91(1H,d,J 3.5Hz),8.12-8.15(1H,m),8.39(1H,t,J 5.5Hz). |
179 | B | 11 | Mp 215.8-216.9℃;IR νmax(Nujol)/cm-13482 and 3305;NMR δH(400MHz,DMSO)8.13-8.11(1H,m),7.91-7.89(1H,d,J 3.5Hz),7.55-7.52(1H,dd,J3.0,5.0Hz),7.42-7.40(1H,m),7.39-7.34(2H,s),7.11-7.08(1H,dd,J 1.5,5.0Hz),6.87-6.85(1H,dd J 1.5,3.5Hz)and 5.66-5.64(2H,s);Anal.Calcdfor C13H10N6OS:C,52.34;H,3.38,N,28.16.Found:C,52.53;H,3.57;N,28.22. |
180 | C | 25 | mp 278.4-279.9℃;IR νmax(DR)/cm-13468,3184,2967,1735,1604,1436,1322,1234 and 1204;NMR δH(400MHz,DMSO)7.87(1H,d,J 3.0Hz),7.30(2H,brs),6.80(1H,t,J 8.0Hz),6.58(1H,dd,J 1.0,8.0Hz),6.51(1H,dd,J 3.0,1.0Hz),6.11(1H,d,J 7.0Hz),5.54(2H,s),4.93(2H,brs),2.45(3H,s)and 2.1(3H,s). |
181 | B | 12 | IR νmax(Nujol)/cm-13501 and 3316;NMR δH(400MHz,DMSO)8.13-8.11(1H,m),7.90-7.87(1H,dd,J 1.0,3.5Hz),7.43-7.32(2H,s),7.40-7.37(1H,d,J 5.0Hz),6.90-6.87(1H,d,J 5.0Hz),6.86-6.84(1H,dd,J 2.0,3.5Hz),5.73-5.72(2H,s),and 2.37-2.35(3H,s). |
182 | AM | 30 | mp 92.3-92.7℃;IR νmax(DR)/cm-13124,3073,2926,1609,1520,1411;NMRδH(400MHz,DMSO)8.18-8.17(1H,m),7.93(1H,d,J 3.0Hz),7.80(1H,t,J7.5Hz),7.37(1H,d,J 7.5Hz),7.19(1H,d,J 7.5Hz),6.87(1H,dd,J 1.5,3.5Hz),5.94-5.75(3H,m),5.78(2H,s),5.28-5.07(6H,m),4.48(2H,s),4.43-4.12(4H,m),4.02-3.99(2H,m);Anal.Calcd for C24H25N7O2:C,65.00;H,5.68,N,22.10.Found:C,65.23;H,5.80;N,21.60. |
183 | B | 27 | mp 152.0-153.5℃;IR νmax(DR)/cm-13515,3300,3183,2934,2822,1631,1450,1434;NMR δH(400MHz,DMSO)7.89(1H,d,J 3.0Hz),7.79(1H,t,J7.5Hz),7.33(2H,brs),7.34(1H,d,J 7.5Hz),7.02(1H,d,J 7.5Hz),6.53-6.51(1H,m),5.74(2H,s),4.43(2H,s),2.46(3H,s),3.33(3H,s);Anal.Calcd forC17H17N7O2:C,58.11;H,4.88,N,27.89.Found:C,57.75;H,4.85;N,27.59. |
184 | C | 76 | mp 219.7-220.4℃IR νmax(DR)/cm-13450,3312,2920,2728,1737,1638,1438,1354,1326,1291 and 1234;NMR δH(400MHz,DMSO)7.85(1H,d,J 3.0Hz),7.30(2H,brs),7.01(2H,d,J 8.5Hz),6.52-6.47(3H,m),5.41(2H,s),5.12(2H,s)and 2.44(3H,s). |
185 | B | 15 | mp 155.6-157.1℃;IR νamx(DR)/cm-13332,3197,2857,1655,1605,1525,1420;NMR δH(400MHz,DMSO)8.14-8.13(1H,m),7.92(1H,d,J 3.5Hz),7.79(1H,t,J 7.5Hz),7.37(1H,d,J 7.5Hz),7.36(2H,brs),7.05(1H,d,J 7.5Hz),6.88-6.86(1H,m),5.98-5.86(1H,m),5.76(2H,s),5.29-5.24(1H,m),5.17-5.13(1H,m),4.48(2H,s),4.06-4.00(2H,m)Anal.CalcdforC18H17N7O2:C,59.50;H,4.72,N,26.97.Found:C,59.39;H,4.70;N,26.99. |
186 | B | 23 | mp 149.0-149.3℃;IR νmax(DR)/cm-13514,3295,3168,2861,1634,1502,1435;NMR δH(400MHz,DMSO)7.88(1H,d,J 3.5Hz),7.79(1H,t,J 7.5Hz),7.37(1H,d,J 7.5Hz),7.33(2H,brs),7.04(1H,d,J 7.5Hz),6.52-6.51(1H,m),5.96-5.86(1H,m),5.74(2H,s),5.30-5.24(1H,m),5.17-5.13(1H,m),4.49(2H,s),4.06-4.00(2H,m),2.46(3H,s);Anal.Calcd for C19H19N7O2·0.2H2O:C,59.90;H,5.13,N,25.73.Found:C,59.71;H,5.02;N,25.64. |
187 | B | 20 | mp 191.7-191.9℃;IR νmax(Nujol)/cm-13501,3307,3189,2974,1611,1527and 1338;NMR δH(400MHz,DMSO)8.12-8.15(1H,m),7.91(1H,d,J 3.5Hz),7.76(1H,d,J 8.5Hz),7.67(1H,d,J 2.0Hz),7.44-7.36(2H,s),7.16(1H,dd,J 8.5,2.0Hz),6.87-6.85(1H,m),5.78(2H,s),3.22(1H,quin,J 6.5Hz) |
and 1.22(6H,d,J 6.5Hz). | |||
188 | B | 32 | mp 228.9-229.9℃;IR νmax(DR)/cm-13461,3317,3195,1606,1504,1320,1026 and 818;NMR δH(400MHz,DMSO)8.16-8.14(1H,m),7.98(1H,d,J 8.0Hz),7.94(1H,d,J 3.5,1.0Hz),7.91(1H,d,J 8.0Hz),7.78-7.73(1H,m),7.64-7.58(1H,m),7.36(1H,d,J8.5Hz),7.36(2H,brs),6.88(1H,dd,J 3.5,1.5Hz)and 5.98(2H,s). |
189 | K | 23 | NMR δH(400MHz,DMSO)8.14-8.12(1H,m),7.92-7.89(1H,dd,J 1.0,3.5Hz),7.35-7.31(2H,d,J 8.5Hz),7.28-7.16(2H,s),6.88-6.85(1H,dd,J 1.5,3.5Hz),5.66-5.64(2H,s),and 2.82-2.80(3H,s);M/Z 322(M+H)+. |
190 | B | 37 | mp 290.2-290.3℃;IR νmax(DR)/cm-13491,3338,3205,3128,2936,1710,1616,1490,1458;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.93(1H,t,J 7.5Hz),7.90(1H,dd,J 1.0,3.5Hz),7.84(1H,d,J 7.5Hz),7.56(1H,d,J 7.5Hz),7.34(2H,brs),6.86(1H,dd,J 2.0,3.5Hz),6.69(1H,q,J 7.5Hz),2.48(3H,s),1.98(3H,d,J 7.5Hz);Anal.Calcd for C17H15N7O2:C,58.45;H,4.33,N,28.05.Found:C,58.26;H,4.42;N,27.67. |
191 | C | 16 | mp 186.1-189.1℃;IR νmax(DR)/cm-13458,1598,1509,1460,1329,1267 and1220;NMR δH(400MHz,DMSO)11.73(1H,s),7.59(1H,s),7.17(1H,s),6.97(1H,t,J 7.8Hz),6.95-6.83(2H,brs),6.45(1H,dd,J1.5,J 8.0Hz),6.40(1H,d,J 8.0Hz),6.38-6.31(1H,m),5.47(2H,s)and 5.13(2H,s). |
192 | Q | 2 | NMR δH(400MHz,CD3OD)8.84(1H,d,J 4.5Hz),8.77(1H,d,J 8.0Hz),8.33(1H,t,J 1.7Hz),8.2(1H,dd,J 2.0,8.0Hz),8.06(1H,td,J 7.8,2.0Hz),7.81(1H,d,J 7.5Hz),7.65-7.58(2H,m)and 5.88(2H,s);M/Z 349 (M+H)+;保留时间1.77min. |
193 | B | 6 | mp 253.6-254.0℃;IR νmax(DR)/cm-13320,1611,1414,1315,1255,1026 and767;NMR δH(400MHz,DMSO)2.01(3H,s),5.59(2H;s),6.84-6.88(1H,m),7.22(2H,d,J 8.5Hz),7.36(2H,s),7.54(2H,d,J 8.5Hz)7.90(1H,d,J 3.5Hz),8.11-8.14(1H,m),9.97(1H,s). |
194 | B | 36 | mp 136.5-137.6℃;IR νmax(Nujol)/cm-13489,3311,3195,2954,1774 and1613;NMR δH(400MHz,DMSO)8.24(1H,s),8.04(1H,d,J 2.0Hz),8.00(1H,d,J 3.5Hz),7.96(1H,dd,J 8.5,2.0Hz),7.52-7.44(2H,s),7.40(1H,d,J8.5Hz),6.99-6.95(1H,m),5.83(2H,s),5.54(2H,s),3.66(2H,t,J 8.0Hz),0.93(2H,t,J 8.0Hz)and 0.00(9H,s);Anal.Calcd for C21H25N7O5Si·0.1H2O: |
C,51.97;H,5.23,N,20.20.Found:C,51.97;H,5.19;N,19.86. | |||
195 | B | 12 | IR νmax(Nujol)/cm-13652,3506,3307,3196,2990,2878,1633,1521 and 1344;NMR δH(400MHz,DMSO)8.14(1H,s),7.94-7.88(2H,m),7.46(1H,s),7.40(2H,s),7.23(1H,dd,J 8.5,2.0Hz),6.88-6.85(1H,m),5.78(2H,s),2.80(2H,q,7.5Hz)and 1.17(3H,t,J 7.5Hz);Anal.Calcd for C17H15N7O3·0.25H2O:C,55.21;H,4.22,N,26.51.Found:C,55.47;H,4.12;N,26.25. |
196 | B | 23 | mp 178.4-179.0℃;IR νmax(Nujol)/cm-13469 and 3311;NMR δH(400MHz,DMSO)8.13-8.11(1H,m),7.90-7.88(1H,dd,J 1.0,3.5Hz),7.37-7.32(2H,s),7.32-7.29(1H,dd,J 1.5,5.5Hz),6.92-6.89(1H,dd,J 3.5,5.5Hz),6.87-6.84(2H,m),4.70-4.64(2H,t,J 7.0Hz),and 3.53-3.48(2H,t,J 7.0Hz);Anal.Calcd for C14H12N6OS:C,53.84;H,3.87;N,26.89.Found:C,53.98;H,3.87;N,26.50. |
197 | B | 22 | mp 188.3-188.5℃;IR νmax(DR)/cm-13324,3189,2964,1649,1513;NMR δH(400MHz,DMSO)8.14-8.13(1H,m),7.93(1H,d,J 3.5Hz),7.67(1H,t,J 7.5Hz),7.34(2H,brs),7.20(1H,d,J 7.5Hz),6.89(1H,d,J 7.5Hz),6.87-6.86(1H,m),5.75(2H,s),2.93(1H,sept,J 7.0Hz),1.12(6H,d,J 7.0Hz);Anal.Calcd for C17H17N7O:C,60.88;H,5.11,N,29.22.Found:C,61.03;H,5.13;N,28.95. |
198 | B | 27 | IR νmax(DR)/cm-13466,3312,3187,2958,2850,1639,1511,1221,1047,756and 599;NMR δH(400MHz,DMSO)8.13(1H,s),8.09(1H,s),7.91(1H,d,J3.0Hz),7.72(1H,d,J 8.5Hz),7.68(1H,s),7.42(1H,d,J 8.5Hz),7.37(2H,brs),6.88-6.83(1H,m),5.82(1H,d,J 9.5Hz),5.77(2H,s),3.90-3.80(1H,m),3.77-3.64(1H,m),2.45-2.30(1H,m),2.10-1.88(2H,m),1.80-1.63(1H,m),1.62-1.49(2H,m). |
199 | B | 7 | mp 226.5-227.9℃;IR νmx(DR)/cm-13466,3316,3182,2962,1645,1606,1546,1514,1473;NMR δH(400MHz,DMSO)8.14-8.13(1H,m),7.92(1H,d,J 3.0Hz),7.33(2H,brs),7.07-7.06(1H,m),6.88-6.86(2H,m),5.71(2H,s),2.88(1H,sept,J 7.0Hz),2.82(1H,sept,J7.0Hz),1.14(6H, d,J 7.0Hz),1.09(6H,d,J 7.0Hz). |
200 | K | 99 | mp>300℃ dec;IR νmax(DR)/cm-13100,1662,1465,1281,1032,782 and 592;NMR δH(400MHz,DMSO)8.16-8.13(1H,m),8.07(1H,s),7.92(1H,d,J 3.5Hz),7.68(1H,s),7.54(1H,d,J 8.5Hz),7.35(1H,dd,8.5,1.5Hz),6.87(1H,dd,J3.5,2.0Hz)and 5.76(1H,s) |
201 | K | 99 | IR νmax(Nujol)/cm-12999,1656,1530 and 1461;NMR δH(400MHz,DMSO)11.10(1H,s),8.14(1H,d,J 1.0Hz),7.92(1H,d,J 3.5Hz),7.72(1H,d,J 2.5Hz),7.61(1H,dd,J 8.5,2.5Hz),7.0(1H,d,J 8.5Hz),6.86-6.88(1H,m),5.67(2H,s)and 5.11-5.16(3H,s). |
202 | B | 32 | mp 210.5-211.6℃;IR νmax(FILM)/cm-13352,3204,3001,1659,1569,1510,1440;NMR δH(400MHz,DMSO)8.14(1H,m),7.93(1H,d,J 3.5Hz),7.76(1H,t,J 7.5Hz),7.43(1H,d,J 7.5Hz),7.36(2H,brs),7.03(1H,d,J 7.5Hz),6.87(1H,dd,J 2.0,3.5Hz),6.75(1H,dd,J 10.5,17.5Hz),6.09(1H,dd,J 2.0,17.5Hz),5.78(2H,s),5.43(1H,dd,J 1.5,10.5Hz);Anal.Calcd for C16H13N7O:C,60.18;H,4.10,N,30.69.Found:C,60.14;H,4.20;N,30.39. |
203 | AS | 12 | IR νmax(Nujol)/cm-13514,3298 and 1761;NMR δH(400MHz,DMSO)8.16-8.15(1H,m),7.89-7.86(1H,dd,J 1.0,3.5Hz),7.80-7.40(2H,s),6.89-6.86(1H,dd,J 1.5,3.5Hz),and 1.66-1.64(9H,s). |
204 | B | 16 | mp143.6-144.5℃;IR νmax(DR)/cm-13644,3315,3195,2978,1743,1608,1163,1086 and 746;NMR δH(400MHz,DMSO)8.14-8.10(1H,m),8.05(1H,d,J 8.0Hz),7.88(1H,d,J 3.5Hz),7.81(1H,s),7.66(1H,d,J 7.5Hz),7.42(2H,brs),7.34(1H,t,J 8.0Hz),7.23(1H,t,J 8.0Hz),6.85(1H,dd,J 3.5,2.0Hz),5.78(2H,s)and 1.63(9H,s) |
205 | B | 19 | IR νmax(DR)/cm-13431,3325,3217,1646,1504,1431;NMR δH(400MHz,DMSO)9.87-9.86(1H,m),8.14(1H,m),8.05(1H,t,J 8.0Hz),7.94-7.92(1H,m),7.88(1H,d,J 8.0Hz),7.52(1H,d,J 8.0Hz),7.38(2H,brs),6.88-6.87(1H,m),5.91(2H,s);Anal.Calcd for C15H11N7O2·0.3H2O:C,55.15;H,3.58,N,30.01.Found:C,55.33;H,335;N,29.64. |
206 | B | 30 | IR νmax(film)/cm-13327,3209,2987,1730,1664,1390,1168,959,745 and 664;NMR δH(400MHz,DMSO)8.16(1H,s),8.09(1H,d,J 8.0Hz),7.97-7.92(2H,m),7.47(1H,d,J 7.5Hz),7.44-7.35(2H,brs)7.31(1H,t,J 7.5Hz),7.20(1H,t,J 7.0Hz),6.89(1H,dd,J 3.5,1.5Hz),6.03-5.96(3H,m)and 1.64(9H,s) |
207 | AF | 71 | mp 289.1-289.3℃;IR νmax(DR)/cm-13442,3317,3189,1649,1607,1519,1332,1118,1023 and 763 NMR δH(400MHz,DMSO)11.21(1H,brs),8.13(1H,s),7.91(1H,d,J 3.5Hz),7.46(1H,d,8.0Hz),7.38(2H,brs),7.33(1H,d,J 8.0Hz),7.06(1H,t,J 8.0Hz),6.96(1H,t,J 7.0Hz),6.86(1H,dd,J 3.5,1.5Hz),6.31(1H,s)and 5.79(2H,s) |
208 | B | 4 | NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.91-7.88(1H,dd,J 1.5,3.5Hz),7.46-7.36(2H,s),6.98-6.96(1H,d,J 3.5Hz),6.87-6.84(1H,dd,J 1.5,3.5Hz),6.72-6.69(1H,d,J 3.5Hz),5.76-5.74(2H,s),2.52-2.48(2H,h,J2.0,3.5Hz)and 1.20-1.14(3H,t,J 7.5Hz);M/Z 327(M+H)+. | |
209 | B | 17 | mp>250℃ dec;IR νmax(DR)/cm-13489,3316,2919,1610,1326,1037,862,760 and 593;NMR δH(400MHz,DMSO)8.13-8.11(1H,m),7.90(1H,d,J 2.5Hz),7.38(2H,brs),6.92(1H,d,J 2.0Hz),6.88(1H,d,J 8.0Hz),6.86(1H,dd,J 3.5,2.0Hz),6.79(1H,dd,J 8.0,1.5Hz),6.00(2H,s)and 5.56(2H,s). | |
210 | C | 36 | IR νmax(DR)/cm-13427,3318,3201,2966,1605,1503,1415,1281,1027 and762;NMR δH(400MHz,DMSO)1.08(3H,t,J 7.0Hz),2.39(2H,q,J 7.0Hz),4.91(2H,s),5.44(2H,s),6.54(1H,d,J 8.0Hz),6.80-9.62(2H,m),6.97(1H,s),7.34(2H,s),7.89(1H,s),8.12(1H,s).Anal.Calcd for C17H17N7O·0.6H2O:C,58.98;H,5.30;N,28.32.Found:C,59.37;H,5.02;N,28.05. | |
211 | AT | 13 | mp 257.1-257.3℃;IR νmax(DR)/cm-13491,3343,3205,3131,2971,1973,1691,1626,1499,1437,1239,1030 and 764;NMR δH(400MHz,DMSO)6.26(2H,s),6.86-6.91(1H,m),7.33(2H,s),7.63(2H,t,J 7.5Hz),7.77(1H,t,J7.5Hz),7.94(1H,d,J 3.0Hz),8.11-8.16(3H,m). | |
212 | R | 58 | IR ν max (DR)/cm -1 3321,1608,1438,1304,1025 and 757;NMR δ H (400MHz, DMSO)5.67(2H,s),6.86-6.88(1H,m),7.05(1H,d,J 7.5Hz),7.20(1H,dd,J 5.0,3.5Hz),7.35(1H,t,J 8.0Hz),7.39(2H,s),7.55-7.58(1H,m),7.72(1H, d,J 7.5Hz),7.85(1H,dd,J 5.0,1.0Hz),7.92(1H,d,J 3.5Hz),7.98(1H,dd,J 3.5,1.0Hz),8.12-8.15(1H,m),10.24(1H,s), | |
213 | AU | 29 | IR νmax(DR)/cm-13285,1975,1625,1461;NMR δH(400MHz,DMSO)8.14(1H,m),7.92(1H,d,J 3.0Hz),7.80(1H,t,J 7.5Hz),7.44(1H,d,J 7.5Hz),6.98(1H,d,J 7.5Hz),6.87(1H,dd,J 1.5,3.5Hz),5.75(2H, s),4.52(2H,s). | |
214 | R | 43 | IR νmax(DR)/cm-13321,2956,1610,1234,1027 and 757;NMR δH(400 MHz,DMSO)0.99(9H,s),2.14(2H,s),5.63(2H,s),6.85-6.89(1H,m),6.94(1H,d,J 8.0Hz),7.27(1H,t,J 7.5Hz),7.33-7.45(3H,m),7.59(1H,d,J 9.0Hz),7.92(1H,d,J 3.5Hz),8.12-8.15(1H,m). | |
215 | R | 52 | IR νmax(DR)/cm-13510,3278,1631,1425,1293,1217,1024 and 757;NMR δH(400MHz,DMSO)0.71-0.79(4H,m),1.72(1H,tt,J 5.5,7.0Hz),5.63(2H,s),6.85-6.89(1H,m),6.96(1H,d,J 8.0Hz),7.27(1H,t,J 7.5Hz),7.32-7.45(3H,m),7.55(1H,d,J 8.0Hz),7.92(1H,dd,J 3.5,1.0Hz),8.12-8.15(1H,m),10.19(1H,s).Anal.Calcd for C19H17N7O2·0.15H2O:C,60.36;H,4.61;N,25.93.Found:C,60.89;H,4.62;N,25.54. |
216 | B | 15 | mp 178.3-178.5℃;IR νmax(DR)/cm-13472,3324,3194,2964,1641,1598,1510;NMR δH(400MHz,DMSO)8.14(1H,m),7.92(1H,dd,J 1.0,3.5Hz),7.66(1H,t,J 8.0Hz),7.35(2H,brs),7.17(1H,d,J 8.0Hz),6.90(1H,d,J 8.0Hz),6.87(1H,dd,J 2.0,3.5Hz),5.73(2H,s),2.63(2H,t,J 7.5Hz),1.59(2H,sext,J 7.5Hz),0.83(3H,t,J 7.5Hz);Anal.Calcd for C17H17N7O·0.1C4H8O2:C,60.72;H,5.21,N,28.49.Found:C,60.85;H,5.22;N,28.29. |
217 | B | 16 | mp 146.7-149.3℃;IR νmax(DR)/cm-13518,3323,2955,1605,1511;NMR δH(400MHz,DMSO)8.14-8.13(1H,m),7.92(1H,d,J 3.5Hz),7.79(1H,t,J 7.5Hz),7.35(2H,brs),7.35(1H,d,J 7.5Hz),7.05(1H,d,J 7.5Hz),6.87(1H,dd,J 1.5,3.5Hz),5.75(2H,s),4.46(2H,s),3.22(2H,d,J 6.5Hz),1.77-1.87(1H,m),0.85(6H,d,J 6.5Hz);Anal.Calcd for C19H21N7O2·0.5H2O:C,58.75;H,5.71,N,25.24.Found:C,58.87;H,5.49;N,24.92. |
218 | B | 14 | mp 196.0-196.1℃;IR νmax(DR)/cm-13481,3325,3203,1646,1607,1518,1488;NMR δH(400MHz,DMSO)8.14(1H,m),7.92(1 H,d,J 3.5Hz),7.80(1H,t,J 7.5Hz),7.50(1H,d,J 7.5Hz),7.38(2H,brs),7.04(1H,d,J 7.5Hz),6.87(1H,dd,J 1.5,3.5Hz),5.77(2H,s),4.64(2H,s). |
219 | C | 37 | IR νmax(DR)/cm-13480,3379,3199,2958,2761,2104,1879,1776,1659,1516,1439,1334,1024,762 and 575;NMR δH(400MHz,DMSO)1.10(6H,d,J 7.0Hz),2.92(1H,sept,J 6.5Hz),4.93(2H,s),5.44(2H,s),6.54(1H,d,J 8.0Hz),6.80-6.88(2H,m),7.09(1H,d,J 2.0Hz),7.34(2H,s),7.88(1H,d,J 3.5Hz),8.10-8.13(1H,m).Anal.Calcd for C18H19N7O·0.3H2O:C,60.93;H,5.57;N,27.63.Found:C,60.77;H,5.50;N,27.42. |
220 | AV | 26 | mp 223.3-223.4℃;NMR δH(400MHz,DMSO)8.14(1H,m),7.92(1H,dd,J1.0,3.5Hz),7.82(1H,t,J 7.5Hz),7.37(1H,d,J 7.5Hz),7.36(2H,brs),7.07(1H,d,J 7.5Hz),6.87(1H,dd,J 1.5,3.5Hz),5.78(2H,s),4.18(2H,s). |
221 | AW | 7 | NMR δH(400MHz,DMSO)9.48-9.45(1H,s),8.12-8.10(1H,m),7.90-7.88(1H,dd,J 1.0,3.5Hz),7.36-7.30(2H,s),7.17-7.12(2H,dd,J 2.0,8.5Hz),6.86-6.84(1H,dd,J 2.0,3.5Hz),6.74-6.70(2H,dd,J 2.0,8.5Hz)and5.53-5.51(2H,s);M/Z 309(M+H)+. |
222 | B | 18 | IR νmax(DR)/cm-13483,3319,3200,2961,1953,1709,1612,1439,1343,1220,995 and 761;NMR δH(400MHz,DMSO)6.37(2H,s),6.86-6.91(1H,m),7.35(2H,s),7,94(1H,d,J 3.0Hz),8.15(1H,s),8.37(2H,d,J 8.5Hz),8.43(2H,d,J 8.5Hz).Anal.Calcd for C16H11N7O4·0.2H2O:C,52.09;H,3.11;N,26.58.Found:C,51.94;H,3.05;N,26.27. |
223 | B | 41 | IR νmax(DR)/cm-14013,3601,3456,3209,2959,2237,1938,1708,1625,1505,1171,1002,827 and 733;NMR δH(400MHz,DMSO)6.33(2H,s),6.84-6.91(1H,m),7.34(2H,s),7.94(1H,d,J 3.5Hz),8.09-8.18(3H,m),8.28(2H,d,J8.0Hz).Anal.Calcd for C17H11N7O2·0.7H2O:C,57.05;H,3.49;N,27.39.Found:C,56.97;H,3.12;N,27.37. |
224 | AX | 54 | IR νmax(DR)/cm-13423,3321,3212,1641,1511,1420,1316,1136 and 780;NMR δH(400MHz,DMSO)0.87(3H,t,J 7.5Hz),1.54-1.66(2H,m),2.96-3.04(2H,m),5.65(2H,s),6.85-6.88(1H,m),7.00-7.03(2H,m),7.10-7.16(1H,m),7.30(1H,t,J 7.5Hz),7.36(2H,s),7.91(1H,dd,J 3.5,1.0Hz),8.12-8.15(1H,m),9.79(1H,s).Anal.Calcd for C18H19N7O3S:C,52.29;H,4.63;N,23.70.Found:C,52.22;H,4.70;N,23.36. |
225 | AX | 47 | IR νmax(DR)/cm-13477,3319,3114,1609,1479,1414,1349,1162,956 and 763;NMR δH(400MHz,DMSO)5.63(2H,s),5.85-6.89(1H,m),6.92(1H,t,J 1.5Hz),7.02-7.11(3H,m),7.26-7.33(2H,m),7.37(2H,s),7.93(1H,dd,J 3.5,1.0Hz),8.12-8.15(1H,m),10.62(1H,s). |
226 | AY | 58 | mp 221.4-221.5℃;IR νmax(DR)/cm-13569,3134,2701,2421,1656,1460;NMR δH(400MHz,DMSO)8.14(1H,m),7.92(1H,dd,J 1.0,3.5Hz),7.88(1H,t,J 7.5Hz),7.48(1H,d,J 7.5Hz),7.16(1H,d,J 7.5Hz),6.88-6.87(1H,m),5.80(2H,s),4.27-4.24(2H,m),2.60-2.56(3H,m). |
227 | B | 24 | IR ν max (DR)/cm -1 4011,3491,3377,3210,3125,2975,2663,2106,1924,1740, 1618,1438,1201,1004,796 and 752:NMR δ H (400MHz,DMSO)1.14(6H,t,J 6.5Hz),3.46(4H, q,J 6.5Hz),6.00(2H,s),6.76(2H,d,J 9.0Hz),6.87(1H,s), 7.26(2H,s),7.85-7.97(3H,m),8 .13(1H,s),Anal.Calcd for C 20 H 21 N 7 O 2 ·0.6 H 2 O:C,59.72:H,5.56:N,24.38.Found:C,60.00:H.5.40:N.24.03. |
228 | B | 26 | mp 164.3-169.3℃;IRνmax(DR)/cm-13376,3199,2964,1659,1613,1516,1441;NMR δH(400MHz,DMSO)8.53(1H,d,J 2.0Hz),8.12-8.11(1H,m),7.89(1H,d,J 3.5Hz),7.62(1H,dd,J 2.5,8.0Hz),7.35(2H,brs),7.26(1H,d,J7.5Hz),6.85(1H,dd,J 1.5,3.5Hz),5.67(2H,s),2.99(1H,sept, J 7.0Hz),1.20(6H,d,J 7.0Hz);Anal.Calcd for C17H17N7O·0.5H2O:C,59.29;H,5.27,N,28.47.Found:C,59.28;H,5.16;N,28.23. |
229 | B | 40 | mp 258.2-258.4℃;IR νmax(DR)/cm-13367,3200,2932,1671,1243,1178,1033,797 and 610;NMR δH(400MHz,DMSO)8.12-8.07(3H,m),7.91(1H,d,J 3.5Hz),7.15-7.09(4H,m),6.85(1H,dd,J 3.5,1.5Hz),6.10(2H,s)and3.89(3H,s). |
230 | B | 25 | IR νmax(DR)/cm-13436,3320,3208,2977,1609,1370,1323,1155,1025,840and 768;NMRδH(400MHz,DMSO)8.12-8.10(1H,m),7.89(1 H,d,J 3.5Hz),7.78(1H, d,J 4.0Hz),7.73(1H,d,J 2.5Hz),7.33(2H,brs),6.88-6.84(2H,m),6.76(1H,d,J4.0Hz),6.07(2H,s)and 1.50(9H,s). |
231 | AF | 76 | mp 321.8-322.2℃;IR νmax(DR)/cm-13993,3233,1645,1515,1437,1336,1102,854 and 759;NMR δH(400MHz,DMSO)11.56(1H,brs),8.13-8.11(1H,m),7.91(1H,d,J 3.5Hz)7.58(1H,d,J 2.0Hz)7.55(1H,t,J 3.5Hz),7.42(2H,brs),6.86(1H,dd,J 3.5,2.0Hz),6.73(1H,d,J 2.0Hz),6.52(1H,dd,J 3.0,2.0Hz)and 5.94(2H,s). |
232 | AX | 20 | IR νmax(DR)/cm-13216,1713,1610,1505,1421,1185,1124,1026,886 and 763;NMR δH(400MHz,DMSO)2.13(3H,s),2.35(3H,s),5.62(2H,s),6.85-6.88(1H,m),6.90-6.94(1H,m),6.98-7.03(1H,m),7.11(1H,d,J 8.0Hz),7.30(1H,t,J 7.5Hz),7.31(2H,s),7.91(1H,d,J 3.5Hz),8.11-8.14(1H,m),10.46(1H,s). |
233 | AV | 40 | mp 219.7-222.3℃;IR νmax(DR)/cm-13326,3191,2821,2772,1595,1504,1432;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.91(1H,dd,J 1.0,3.5Hz),7.74(1H,t,J 7.5Hz),7.35(1H,d,J 7.5Hz),7.31(2H,brs),6.98(1H,d,J7.5Hz),6.86(1H,dd,J 2.0,3.5 Hz),5.74(2H,s),3.46(2H,s),2.15(6H,s);Anal.Calcd for C17H18N8O:C,58.28;H,5.18,N,31.97.Found:C,57.94;H,5.17;N,31.70. |
234 | AV | 55 | mp 168.3-168.5℃;IR νmax(DR)/cm-13416,3322,3180,2911,1646,1612,1509,1436;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.91(1H,dd,J 1.0,3.5Hz),7.74(1H,t,J 7.5Hz),7.32(1H,d,J 7.5Hz),7.31(2H,brs),7.02(1H,d,J 7.5Hz),6.87-6.86(1H,m),5.75(2H,s),3.69(2H,s),1.92(3H,s);Anal.Calcd for C16H15N7OS·0.2H2O:C,53.83;H,4.35,N,27.46.Found:C,53.74;H,4.29;N,27.13. |
235 | B | 3 | mp 231.6-231.7℃;IR νmax(DR)/cm-13642,3320,3 198,1727,1533,1437,1223,1029,842 and 639;NMR δH(400MHz,DMSO)8.18(1H,d,J 7.5Hz),8.13(1H,s),8.00-7.93(2H,m),7.91(1H,d,J 3.5Hz),7.89-7.82(1H,m),7.34(2H,brs),6.87(1H,dd,J 3.5,1.5Hz)and 6.01(2H,s). |
236 | AX | 32 | NMR δH(400MHz,DMSO)2.19(3H,s),3.50(3H,s),5.58(2H,s),6.84-6.97(3H,m),7.08(1H,d,J 8.0Hz),7.20(1H,t,J 7.5Hz),7.35(2H,s),7.58(1H,s),7.91(1H,d,J 3.0Hz),8.13(1H,s)and 10.14(1H,s);保留时间0.97min. |
237 | AV | 40 | mp 259.3-259.4℃;IR νmax(DR)/cm-13323,3202,1607,1511;NMR δH(400MHz,DMSO)8.12-8.11(2H,m),7.91(2H,dd,J 1.0,3.5Hz),7.70-7.66(2H,m),7.30(4H,brs),7.10(4H,d,J 8.0Hz),6.85(2H,dd,J 1.5,3.5Hz),5.73(4H,s),4.23(4H,s),2.78(3H,s). | |
238 | AV | 17 | mp 238.2-238.6℃;IR νmax(DR)/cm-13189,2908,1653,1592,1470;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.91(1H,d,J 3.0Hz),7.85(1H,t,J 7.5Hz),7.43(1H,d,J 7.5Hz),7.30(2H,brs),7.23(1H,d,J 7.5Hz),6.87-6.85(1H,m),5.81(2H,s),4.56(2H,s),2.87(3H,s). | |
239 | AV | 71 | mp 205.8-206.0℃;IR νmax(Nujol)/cm-13502,3304,3185,2923,1628,1510;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.92(1H,d,J 3.0Hz),7.83(1H,t,J 8.0Hz),7.33(1H,d,J 8.0Hz),7.30(2H,brs),7.17(1H,d,J 8.0Hz),6.87-6.86(1H,m),5.79(2H,s),4.31(2H,s),2.84(3H,s),2.67(3H,s);Anal.Calcd for C17H18N8O3S:C,49.27;H,4.38,N,27.02.Found:C,49.14;H,4.49;N,26.74. | |
240 | C | 24 | mp 254.3-254.5.℃;IR νmax(DR)/cm-13443,3342,3187,1647,1593,1513,1414,1300,1268 and 1225;NMR δH(400MHz,DMSO)7.37(2H,s),6.96(1H,t,J 7.8Hz),6.46(1H,dd,J 1.0,J 8.0Hz),6.40(2H, d,J 7.5Hz),6.33(1H,s),5.56(2H,s),5.2(2H,s),2.5(3H,s)and 2.44(3H,s). | |
241 | C | 17 | NMR δH(400MHz,DMSO)8.11-8.09(1H,m),7.89-7.86(1H,dd,J 1.0,3.5Hz),7.32-7.27(2H,s),7.22-6.95(1H,t,J 9.0Hz),6.85-6.83(1H,dd,J 2.0,3.5Hz),6.35-6.29(2H,m),5.48-5.46(2H,s)and 5.46-5.44(2H,s);保留时间1.18min. | |
242 | B | 15 | IR νmax(DR)/cm-13850,3667,2923,1730,1601,1464,1023,751 and 593;NMRδH(400MHz,DMSO)3.68(1H,dd,J 16.0,5.5Hz),3.88(1H,dd,J 16.0,9.0Hz),6.05(1H,dd,J 8.5,5.5Hz),6.84-6.89(1H,m),7.29(2H,s),7.57(1H,t,J7.0Hz),7.72(1H,d,J 7.5Hz),7.78-7.87(2H,m),7.91(1H,d,J 3.5Hz),8.13(1H,s).Anal.Calcd for C17H12N6O2·0.2H2O:C,60.87;H,3.72;N,25.02.Found:C,60.89;H,3.68;N,24.85. | |
243 | AF | 53 | mp>300℃ dec;IR νmax(DR)/cm-13212,2923,1642,1605,1510,1461,1377,1023 and 757;NMR δH(400MHz,DMSO)11.16(1H,brs),8.12(1H,s),7.91(1H,d,J 3.5Hz),7.44-7.36(3H,m),7.29(1H,s),6.86(1H,dd,J 3.5,1.5Hz),6.58(1H,s),6.42-6.38(1H,m),5.87(2H,s)and 2.27(3H,s). | |
244 | BB | 7 | IR νmax(Nujol)/cm-13319,2924,1646,1606,1462;NMR δH(400MHz,DMSO)9.54(1H,s),8.27-8.26(1H,m),8.12-8.11(1H,m),7.90(1H,d,J3.5Hz),7.71(1H,d,J 8.0Hz),7.32(2H,brs),7.17-7.15(1H,m),7.11-7.09(1H,m), |
(1H,m)6.43-6.38(1H,m)and 5.76(2H,s) | |||
252 | BF | 44 | mp 200.2.-201.2℃ IR νmax(DR)/cm-13390,3205,2924,1725,1648,1603,1508,1423,1332,1277 and 1158;NMR δH(400MHz,DMSO)8.12(1H,s),7.90(1H,d,J 3.5Hz),7.35-7.25(4H,m),7.07-6.97(3H,m),6.86(1H,dd,J1.5,J 3.5Hz),6.45(2H,t,J 7.5Hz),6.37(1H,s),6.32(1H,t,J 6.0Hz),5.49(2H,s)and 4.16(2H,s,J 6.0Hz). |
253 | B | 18 | mp 181.8-182.1℃;IR νmax(DR)cm-13362,3208,2988,1654,1601,1513;NMR δH(400MHz,DMSO)8.13-8.12(1H,m),7.91(1H,d,J 3.5Hz),7.68(1H,m),7.29(2H,brs),6.87-6.85(1H,m),6.74(1H,d,J 7.5Hz),6.68(1H,d,J 8.0Hz),5.69(2H,s),4.07(2H,q,J 7.0Hz),1.12(3H,t,J 7.0Hz). |
254 | B | 14 | mp 190.8-190.9℃;IR νmax(DR)/cm-13514,3292,3158,2984,1615,1500;NMR δH(400MHz,DMSO)7.88(1H,d,J 3.5Hz),7.65(1H,dd,J 7.0,8.0Hz),7.25(2H,brs),6.72(1H,d,J 7.0Hz),6.68(1H,d,J 8.0Hz),6.52-6.50(1H,m),5.67(2H,s),4.08(2H,q,J 7.0Hz),2.46(3H,s),1.12(3H,t,J 7.0Hz). |
255 | BF | 20 | mp 184.5-184.6℃;IR νmax(DR)/cm-13202,1649,1601,1509,1436,1331,1277 and 1221;NMR δH(400MHz,DMSO)8.43(1H,d,J 4.89Hz),8.12(1H,dd,J 0.8,3.5Hz),7.91(1H,dd,J 0.9,3.5Hz),7.65(1H,td,J 1.7,7.7Hz),7.30(2H,brs),7.25(1H,d,J 7.9Hz),7.15(1H,dd,J 4.9,7.5Hz),7.0(1H,t,J 7.8Hz),6.86(1H,dd,J 1.7,3.5Hz),6.48-6.36(4H,m),5.49(2H,s),4.27(2H,s);Anal.Calcd for C21H18N8O·0.3H2O:C,62.46;H,4.64,N,27.75.Found:C,62.66;H,4.57;N,27.36. |
256 | B | 6 | Mp 167.6-168.1℃.IRνmax(DR)/cm-13509,3304,3178,1609,1494,1421,1325,1127,839 and 752.NMR δH(400MHz,DMSO)2.05(3H,d,J 7.0Hz),6.14(1H,q,J 7.0Hz),6.84-6.88(1H,m),7.30(2H,s),7.52(2H,d,J 8.5Hz),7.73(2H,d,J 8.0Hz),7.91(1H,dd,J 3.5,1.0Hz),8.11-8.13(1H,m).Anal.Calcd for C17H13N6F3O:C,54.55;H,3.50;N,22.44.Found:C,54.52;H,3.65;N,22.06. |
257 | BE | 75 | IRνmax(DR)/cm-13459,3348,3187,2960,1648,1513,1351,1244,1011,837and 759;NMR δH(400MHz,DMSO)11.18(1H,brs),8.11(1H,s),7.89(1H,d,J 3.0Hz),7.42(1H,d,J 7.5Hz),7.37-7.26(3H,m),7.21(1H,d,J 11.0Hz),6.89-6.81(1H,m),6.43-6.37(1H,s)and 5.72(2H,s). |
266 | AK | 99 | NMRδH(400MHz,DMSO)8.22-8.17(2H,m),7.94(1H,d,J 2.01Hz),7.73-7.63(2H,m),7.37(1H,d,J 2.5Hz)and 5.86(2H,s);M/Z 338(M+H)+;保留时间1.74min. |
267 | B | 58 | mp 255.6-255.7℃;IR νmax(DR)/cm-13512,3294,3179,2960,2692,1745,1638,1432 and 1371;NMR δH(400MHz,DMSO)7.88(1H,d,J 3.51Hz),7.81(1H,dd,J 1.0,J 8.0Hz),7.46-7.29(2H,brs),7.40(1H,t,J 7.8Hz),7.23(1H,d,J 8.0Hz),6.51(1H,dd,J 1.0,3.5Hz),5.78(2H,s)and 2.46(6H,s). |
268 | B | 40 | mp 248.1-249.0℃ IR νmax(DR)/cm-113507,3308,3190,2952,1626,1571,1519,1434,1348 and 1291;NMR δH(400 MHz,DMSO)8.22(2H,d,J 8.5Hz),7.89(1H,d,J 3.5Hz),7.49(2H,d,J 9.0Hz),7.36(2H,brs),6.52(1H,dd,J 1.0,3.5Hz),5.83(2H, s)and 2.46(3H,s). |
269 | B | 18 | NMR δH(400MH,DMSO)8.14-8.12(1H,m),7.92-7.90(1H,dd,J 1.0,3.5Hz),7.42-7.34(2H,s),7.26-7.25(4H,s),6.87-6.85(1H,dd,J 1.5,3.5Hz),5.66-5.64(2H,s),3.15-3.13(3H,s)and 1.38-1.36(9H,s). |
270 | H | 46 | NMR δH(400MHz,DMSO)8.22-8.13(2H,m),7.75-7.65(3H,m),7.59(1H,dd,J J.5,J 3.0Hz),7.34(2H,brs),6.96(1H,dd,J 1.5,J 3.5Hz),6.45(1H,t,J3.2Hz),5.85(2H,s)and 1.22(9H,s);M/Z 437(M+H)+;保留时间4.36min. |
271 | Q | 40 | NMR δH(400MHz,DMSO)8.21-8.17(2H,m),7.71-7.63(2H,m),7.48(2H,brs),5.87(2H,s),2.50(3H,s)and 2.44(3H,s);M/Z 383(M+H)+;保留时间3.69min.. |
272 | B | NMR δH(400MHz,DMSO)8.18(1H,dd,J 9.6,2.0Hz),8.13(1H,d,J 1.6Hz),8.05(1H,dd,J 8.4,2.4Hz),7.90(1H,d,J 3.2Hz),7.45(1H,t,J 8.0Hz),7.38(2H,brs),6.86(1H,dd,J 3.6,2.0Hz)and 5.84(2H,s). | |
273 | B | NMR δH(400MHz,DMSO)8.13-8.09(1H,m),7.89(1H,d,J3.5Hz),7.66(1H,d,J 3.5Hz),7.39(1H,s),7.29(2H,brs),6.85(1H,dd,J 3.5,2.0Hz),6.68(1H,d,J 3.5Hz),6.65(1H,s),2.27(3H,s)and 1.52(9H,s). | |
274 | BA | 99 | IR νmax(Nujol)/cm-13313,2923,1693,1603;NMR δH(400MHz,DMSO)8.78(1H,brs),8.12-8.11(1H,m),7.90(1H,d,J 3.5Hz),7.34-7.31(3H,m),7.13-7.12(1H,m),7.08-7.05(1H,m),6.86-6.85(1H,m),5.58(2H,s),4.08(2H,q,J 7.0Hz),2.16(3H,s),1.21(3H,t,J 7.0Hz). |
腺苷受体结合
在hA2A受体的结合亲和力
在使用标准技术,通过确定腺苷A2A受体选择性放射配体[3H]-CGS21680置换来测定体外结合人腺苷A2A受体的分析中测试本发明化合物。结果总结在表3中。
表3
实施例 | Ki(nM) |
实施例3 | 3 |
实施例4 | 4 |
实施例5 | 3 |
实施例8 | 3 |
实施例11 | 2 |
实施例12 | 7 |
实施例13 | 2 |
实施例15 | 4 |
实施例41 | 2 |
实施例57 | 2 |
实施例78 | 3 |
实施例92 | 2 |
实施例107 | 2 |
实施例120 | 1 |
实施例149 | 1 |
实施例156 | 2 |
实施例169 | 2 |
实施例188 | 1 |
实施例202 | 1 |
实施例209 | 1 |
实施例221 | 2 |
实施例233 | 4 |
实施例255 | 4 |
体内评价可能的抗帕金森氏病活性
氟哌啶醇引起的低运动模型
以前已经证实,腺苷拮抗剂例如茶碱可逆转多巴胺拮抗剂例如氟哌啶醇在啮齿动物中的行为抑制作用(Mandhane S.N.等人,腺苷A2受体调节氟哌啶醇在大鼠中引起的僵住症.Eur.J.Pharmacol.1997,328,135-141)。该方法还被认为是筛选可能具有抗帕金森氏病作用的药物的有效方法。因此,新的腺苷拮抗剂阻断氟哌啶醇在小鼠中引起的运动活动不足的能力可用于评价体内和可能的抗帕金森氏病效力。
方法
使用得自TUCK,UK的雌性TO小鼠(25-30g)进行所有实验。将动物分组(每组8只)[笼子大小-40(宽)×40(长)×20(高)cm]在12小时/黑暗周期(在早晨8点开始光照)中于温度(20±2℃)和湿度(55±15%)控制的环境下饲养。让动物能自由获得食物和水,并在开始实验使用之前让它们熟悉环境至少7天。
药物
使用盐水将液体可注射的氟哌啶醇(得自Baker Norton,Harlow,Essex的1ml氟哌啶醇安瓿,分别含有氟哌啶醇BP 5mg,批号P424)稀释至0.02mg/ml的终浓度。测试化合物一般是作为在8%吐温中的水悬浮液制得的。将所有化合物以10ml/kg的体积腹膜内给药。
操作
在测试之前1.5小时,给小鼠施用0.2mg/kg氟哌啶醇—将基准运动活动减小至少50%的剂量。测试物质一般是在测试之前施用5-60分钟。然后将动物单独置于干净、透明的聚碳酸酯笼子[20(宽)×40(长)×20(高)cm,具有平坦的有孔的有机玻璃盖]。通过将笼子置于包含3×6光电池阵列的框架上来测定水平运动活动,其中所述光电池与将光束中断制成列表的计算机相连。让小鼠保持不受干扰以探测1小时,并且将在该期间的光束中断数目记录为运动活动,将其与对照动物的数据比较以确定统计学显著差异。
6-OHDA动物
帕金森氏病是进行性神经变性疾病,其特征是肌肉僵硬、震颤运动缺乏(运动机能减退)和姿势不稳定。以前已经确定,PD的初期不足是发射到皮层上的黑质中多巴胺能神经元损失所致,并且实际上在观察到症状之前有相当一部分纹状体多巴胺已丧失了(约80-85%)。纹状体多巴胺的丧失导致基底神经节—调节平滑肌以及协调运动的一系列神经核的异常活动(Blandini F.等人,谷氨酸和帕金森氏病。Mol.Neurobiol.1996,12,73-94)。在帕金森氏病中的神经化学缺陷可通过将多巴胺能神经毒素6-羟基多巴胺局部注射到包含细胞体或黑质纹状体神经元轴索纤维的脑区域内来再现。
通过仅在脑的一侧来单侧损伤黑质纹状体途径,可观察到运动抑制的行为不对称。虽然单侧损伤的动物仍然是活动的并且能够自己维持,但是在受损一侧上,余下的多巴胺敏感性神经元变得对刺激超级敏感。这可通过观察到的下述现象来证实:全身施用多巴胺激动剂例如阿朴吗啡之后,动物在与损伤一侧相对的方向上表现出显著转动。化合物在6-OHDA损伤的大鼠中引起对侧转动的能力已被证实是预测药物具有治疗帕金森氏病效力的敏感模型。
动物
使用得自Charles River的雄性Sprague-Dawley大鼠来进行所有实验。将动物分组(每组5只)在12小时光照/黑暗周期(在早晨8点开始光照)中于温度(20±2℃)和湿度(55±15%)控制的环境下饲养。让动物能自由获得食物和水,并在传递后开始实验使用之前让它们熟悉环境至少7天。
药物
抗坏血酸、去郁敏、6-OHDA和阿朴吗啡(Sigma-Aldrich,Poole,UK)。在手术之前,将6-OHDA新制成在0.2%抗坏血酸盐中的浓度为4mg/mL的溶液。将去郁敏溶解在温热的盐水中,并以1ml/kg的体积给药。将阿朴吗啡溶解在0.02%抗坏血酸盐中,并以2mL/kg的体积给药。将测试化合物悬浮在8%吐温中,并以2mL/kg的体积注射。
手术
手术之前15分钟,给动物腹膜内注射去甲肾上腺素能摄取抑制剂去郁敏(25mg/kg)以防止破坏发多巴胺神经元。然后将动物置于麻醉室中,并用氧气与异氟烷的混合物麻醉。一旦无意识,即将动物转移到立体定位框架上,在框架上通过口罩保持麻醉。将动物头部的顶端剃光,并用碘溶液灭菌。一旦变干,即沿着头皮的中线制做2cm长的切口,皮肤缩回并将其夹住以暴露出头颅。然后在注射点上面通过熟练技术钻一个小孔。为了损伤黑质纹状体途径,将注射套管缓慢地降至在右内侧前脑束上面距离前囟前后-3.2mm、内侧-1.5mm的位置,并到达硬脑膜下7.2mm深度处。降低套管2分钟之后,用4分钟以0.5μL/分钟的速度输注2μL 6-OHDA,最终的剂量为8μg。将套管保留5分钟以促进扩散,之后将其缓慢地抽出。用Ethicon W501 Mersilk将皮肤缝合,将动物从立体定位框架上取下来,并放回其饲养笼子中。在进行行为测试之前,让大鼠用2周的时间从手术中恢复。
装置
使用由Med Associates,San Diego,USA提供的八站转子流速计系统测定转动行为。每个站由不锈钢滚球(45cm直径×15cm高)构成,不锈钢滚球封闭在透明的有机玻璃盖中,有机玻璃盖沿着滚球的边缘延伸,并延伸至29cm的高度。为了评价转动,将大鼠置于连接在弹簧系绳上的布夹套中,所述弹簧系绳与在滚球上面的光学转子流速计连接,光学转子流速计评价作为部分(45°)或完全(360°)转动的向左或向右的运动。所有8个站都与将数据列表的计算机相连。
操作
为了降低药物测试期间的紧张,首先在连续4天的时间内让大鼠熟悉装置15分钟。在测试的当天,在测试之前30分钟,给大鼠腹膜内注射测试化合物。就在测定之前给大鼠皮下注射阈下剂量的阿朴吗啡,然后置于挽具上,并在1个小时的时间内记录转动次数。在这1个小时测试期间内完全对侧转动的总次数用作抗帕金森氏病药物效力的指标。
Claims (64)
1.式(I)化合物或其可药用盐或其前药在制备用于治疗或预防其中阻断嘌呤受体可对其有益的病症的药物中的应用:
其中R1选自H、烷基、芳基、烷氧基、芳氧基、烷硫基、芳硫基、卤素、CN、NR5R6、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7;R2选自经由不饱和碳连接的芳基;R3选自H、烷基、COR5、CO2R7、CONR5R6、CONR4NR5R6和SO2R7;R4、R5和R6独立地选自H、烷基和芳基,或者当R5和R6在NR5R6基团中时,R5和R6可连接以形成杂环基,或者当R4、R5和R6在(CONR4NR5R6)基团中时,R4和R5可连接以形成杂环基;且R7选自烷基和芳基。
2.权利要求1的应用,其中R1选自烷基、芳基、烷氧基、芳氧基、烷硫基、芳硫基、卤素、CN、NR5R6、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7。
3.权利要求1的应用,其中R1选自烷基、烷氧基、烷硫基、NR5R6、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7。
4.权利要求1的应用,其中R1选自NR5R6、NR4COR5、NR4CONR5R6、NR4CO2R7和NR4SO2R7。
5.权利要求1的应用,其中R1选自NR5R6。
6.权利要求1的应用,其中R1是NH2。
7.权利要求1的应用,其中R1选自卤代烷基和芳基烷基。
8.前述权利要求任一项的应用,其中R2不是邻位,邻位-二取代的。
9.前述权利要求任一项的应用,其中R2没有在任一邻位上被取代。
10.前述权利要求任一项的应用,其中R2是杂芳基。
11.权利要求10的应用,其中R2是连接在式(I)嘧啶环上的杂芳基,这样杂原子与连接在所述嘧啶环上的不饱和碳原子相邻。
12.权利要求10或11的应用,其中R2是含有N、O或S的杂芳基。
13.权利要求10-12中任一项的应用,其中R2选自呋喃基、噻吩基、吡啶基、噻唑基、吡唑基、三唑基、吡咯基和噁唑基。
14.权利要求10-12中任一项的应用,其中R2选自2-呋喃基、2-噻吩基、2-噻唑基、2-吡啶基、3-吡唑基、2-吡咯基、4-三唑基和5-噁唑基。
15.权利要求10-12中任一项的应用,其中R2选自呋喃基、噻吩基、吡啶基、噻唑基和吡唑基。
16.权利要求10-12中任一项的应用,其中R2选自2-呋喃基、2-噻吩基、2-噻唑基、2-吡啶基和3-吡唑基。
17.权利要求10-12任一项的应用,其中R2是2-呋喃基。
18.权利要求1-9任一项的应用,其中R2是苯基。
19.前述权利要求任一项的应用,其中R3选自H和取代的烷基。
20.权利要求19的应用,其中R3选自被下列基团取代的烷基:芳基、环烷基、非芳族杂环基、CN、CO2R5、CONR5R6、CONR4NR5R6或C(=NR4)NR5R6。
21.权利要求19的应用,其中R3选自被芳基取代的烷基。
22.权利要求21的应用,其中R3选自(CR9R10)nR11,其中n是1-6,R9和R10独立地选自H、烷基和芳基,且R11选自取代的芳基(包括杂芳基)。
23.权利要求22的应用,其中R11选自式Ar(R12)a(R13)b(R14)c所代表的一-、二-或三-取代的芳基,其中Ar是芳基;其中R12、R13和R14是相同或不同的取代基;且其中a、b和c是0或1,条件是a+b+c≥1。
24.权利要求22或23的应用,其中n是1-3。
25.权利要求22或23的应用,其中n是1。
26.权利要求22-25任一项的应用,其中每个R9和R10选自H和烷基。
27.权利要求22-25任一项的应用,其中R9和R10当中至少有一个或者每个R9和R10是H。
28.权利要求22-25任一项的应用,其中R9和R10都是或者每个R9和R10是H。
29.权利要求23-28任一项的应用,其中R12、R13和R14独立地选自NR5R6、烷基、烷氧基、卤素、NO2、CN、羟基、NHOH、CHO、CONR5R6、CO2R5、NR4COR5、NR4CO2R7、NR4SO2R7、OCO2R7和芳基。
30.权利要求23-28任一项的应用,其中R12、R13和R14独立地选自NR5R6、烷基和卤素。
31.权利要求29或30的应用,其中R12、R13和R14独立地选自烷基,并且所述烷基是取代的烷基,且选自烷氧基烷基、羟基烷基、氨基烷基和卤代烷基。
32.权利要求29或30的应用,其中R12、R13和R14独立地选自未取代的烷基、NH2和氟。
33.权利要求22-32任一项的应用,其中所述取代的芳基R11或Ar选自苯基、吡啶基、吲哚基、呋喃基、噻吩基、异吲哚基、二氢吲哚基、异噁唑基、噁唑基、噻唑基、吡嗪基、嘧啶基、喹啉基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、吲唑基、苯并间二氧杂环戊烯基和二氢苯并呋喃基。
34.权利要求22-32任一项的应用,其中所述取代的芳基R11或Ar选自苯基、吡啶基、吲哚基、呋喃基和噻吩基。
35.权利要求34的应用,其中所述取代的芳基R11或Ar选自苯基、噻吩基、呋喃基和吡啶基。
36.权利要求34的应用,其中所述取代的芳基R11或Ar选自苯基、2-噻吩基、2-呋喃基和2-吡啶基。
37.权利要求1-18任一项的应用,其中R3选自(CR9R10)nR8,其中n是1-6,R9和R10独立地选自H、烷基和芳基,且R8选自环烷基、非芳族杂环基、CN、CO2R5、CONR5R6、CONR4NR5R6和C(=NR4)NR5R6。
38.权利要求37的应用,其中n、R9和R10如权利要求24-28任一项所定义。
39.权利要求37的应用,其中R8选自CONR5R6,R5是氢,且R6选自未取代的烷基和芳基烷基。
40.权利要求1-18任一项的应用,其中R3选自CONR5R6,R5是H,且R6选自芳基烷基,优选芳基甲基。
41.权利要求1的应用,其中所述化合物选自:
7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,N,N-二-(2-氟苄基)-3-(2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)甲基苯甲酸甲酯,
3-(3,5-二甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氯-2-噻吩基)甲基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)甲基)苯基-(1-甲基-1H-咪唑-4-基)磺酰胺,
5-氨基-N-苄基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基羧酰胺,
7-(2-呋喃基)-3-(3-甲氧基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基乙酸乙酯,
3-(3-氰基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-(3-吡啶基)丙基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-三氟甲基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-羟基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-甲基-2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(1H-吡唑-3-基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(5-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-甲基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)乙酸,
3-(3-氯苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(1H-吡唑-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-甲基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)乙酰胺,
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-N-(3-氯苯基)乙酰胺,
7-(2-呋喃基)-3-(6-甲氧基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-噻吩基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(2-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(2-噻吩基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(5-甲基-2-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)氨基甲酸叔丁酯,
3-(2,5-二甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,6-二氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(4-甲基-2-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-噻吩基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
6-氯-N-(7-(2-呋喃基)-1H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)吡啶-3-羧酰胺,
3-(3-硝基苄基)-7-(5-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-N,N-二甲基苯甲酰胺,
3-(3-氨基苄基)-7-(2-噻吩基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-N-甲基苯甲酰胺,
3-(3-氨基苄基)-7-(5-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟-5-甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-N-(2-吡啶基)乙酰胺,
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-N-(2-吡啶基甲基)乙酰胺,
(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-N-苯基乙酰胺,
3-(3,5-二硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-甲基-2-呋喃基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,3-二氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,4-二氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-甲基-2-呋喃基)-3-(6-甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,6-二氟苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-甲基-2-呋喃基)-3-(2-噻吩基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氯苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-甲氧基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-甲基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,5-二氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-甲氧基-5-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-N-甲基苯甲酰胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)乙酰胺,
3-(2-氟苄基)-7-(5-噁唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氯-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-氟-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-甲氧基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(3-(5-氨基-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)氨基甲酸叔丁酯,
3-(2-氨基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐,
3-(3,5-二氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基甲基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐,
7-(2-呋喃基)-3-(2-甲氧基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟-5-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟苄基)-7-(1H-三唑-4-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-氯-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-甲基-2-呋喃基)-3-(6-苯基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基苄基)-7-(2-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-2-氟苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)-3-甲基丁酰胺,
7-(5-甲基-2-呋喃基)-3-(4-硝基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-羟基氨基-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-甲基-3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基-2-甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基-4-甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3,5-二甲基异噁唑-4-基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-甲基-2-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-环己基甲基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-甲基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(5-甲基-2-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-3-甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯甲酸,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯甲酰胺,
7-(2-呋喃基)-3-(2-甲基噻唑-4-基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基甲基苄基)-7-(1H-吡唑-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-N-异丙基-N-甲基苯甲酰胺,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-N-异丙基苯甲酰胺,
3-(2-氨基-5-甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氰基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(5-甲基-2-吡嗪基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(8-喹啉基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-苯基噻唑-4-基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(4-甲基-2-噻唑基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氯-3-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(1,2,5-苯并噁二唑-5-基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-甲氧基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-苄基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基-4-氯苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-硝基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-羟基氨基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-甲基-4-硝基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-羟基氨基-6-甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氯-2-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氨基-4-氯苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氰基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3,4-二甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺三氟乙酸盐,
7-(5-甲基-2-呋喃基)-3-(3-甲基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-3-甲基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(5-甲基-3-噁唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-甲基-4-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(1,2,5-苯并噻二唑-4-基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-吡嗪基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氟-3-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-硝基苄基)-7-苯基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-4-吡啶基甲基)氨基甲酸叔丁酯,
7-(2-呋喃基)-3-(3-甲氧基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-乙基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-乙基-4-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯,
4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯,
7-(2-呋喃基)-3-(4-吲哚基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)氨基甲酸叔丁酯,
3-(4-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
5-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯,
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-氟苯基)氨基甲酸叔丁酯,
3-(4-氨基甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-乙基-2-呋喃基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯,
3-(4-氨基-3-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-3,5-二氟苯基)碳酸叔丁酯,
3-(2,6-二氟-4-羟基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基苄基)-7-(5-乙基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基苄基)-7-苯基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-吲哚基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(5-吲哚基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(7-吲哚基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氟-2-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,6-二氟-4-甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)氨基甲酸叔丁酯,
3-(1H-苯并三唑-5-基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-甲氧基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基乙酰胺,
3-(2-氨基甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-(N,N-二甲基氨基)苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-二氟甲氧基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-邻苯二甲酰亚氨基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基-4-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2,3-二氢苯并呋喃-5-基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-溴-2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2,3,5-三氟苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟-5-碘苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-呋喃基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氨基-5-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
(5-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-硝基苯基)碳酸叔丁酯,
3-(4-氨基-3-羟基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-3-氟苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基苄基)-7-(1H-吡唑-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-羟基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-吡啶基甲基)乙酰胺,
N-(2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苄基)乙酰胺,
7-(2-呋喃基)-3-(3-噻吩基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-氨基-2-甲基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-甲基-2-噻吩基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-烯丙氧基甲基-2-吡啶基甲基)-N,N-二烯丙基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-甲氧基甲基-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基苄基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-烯丙氧基甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-烯丙氧基甲基-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3-异丙基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(喹啉-2-基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(4-(N-甲基氨基)苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-(6-甲基-2-吡啶基)丙酮,
3-(3-氨基苄基)-7-(1H-吡咯-2-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-硝基苄基)-7-(2-吡啶基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)乙酰胺,
7-(2-呋喃基)-3-(4-硝基-2-(2-三甲基甲硅烷基乙氧基)甲氧基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-乙基-4-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-(2-噻吩基乙基))-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-异丙基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(1-(2 H-四氢吡喃-2-基)吲唑-5-基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4,6-二异丙基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(5-吲唑基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(2-羟基-4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-乙烯基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-甲酸叔丁酯,
3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯,
6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吡啶-2-甲醛(carboxaldehyde),
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)吲哚-1-甲酸叔丁酯,
3-(2-吲哚基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-乙基-2-噻吩基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(3,4-亚甲基二氧基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-3-乙基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-苯基乙酮,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-甲基)苯基)噻吩-2-羧酰胺,
7-(2-呋喃基)-3-(6-羟基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-甲基)苯基)-3,3-二甲基丁酰胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-甲基)苯基)环丙烷羧酰胺,
7-(2-呋喃基)-3-(6-正丙基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-异丁氧基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-溴甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-3-异丙基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-氰基甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-羟基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-(4-硝基苯基)乙酮,
4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基乙酰基)-苄腈,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)丙磺酰胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)-5-氯-2-噻吩磺酰胺,
7-(2-呋喃基)-3-(6-(N-甲基氨基)甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-(4-(N,N-二乙基氨基)苯基)乙酮,
7-(2-呋喃基)-3-(6-异丙基-3-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-(4-甲氧基苯基)乙酮,
7-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-5-氯吲哚-1-甲酸叔丁酯,
3-(5-氯-7-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)-3,5-二甲基异噁唑-4-基磺酰胺,
3-(6-(N,N-二甲基氨基)甲基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-甲硫基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-(2-硝基苯基)乙酮,
N-(3-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)-1,2-二甲基-1H-咪唑-4-基磺酰胺,
N,N-二(6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-吡啶基甲基)甲磺酰胺,
7-(2-呋喃基)-3-(6-甲基磺酰基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(6-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-吡啶基甲基)-N-甲基甲磺酰胺,
3-(3-氨基苄基)-7-(4,5-二甲基-2-噻唑基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-二氢茚酮,
7-(2-呋喃基)-3-(5-甲基-7-吲哚基甲基)-3-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-2-甲基苯基)甲酰胺,
2-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-1-苯基丙酮,
3-(7-氟-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-异丙氧基甲基-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-乙基-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氯-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(7-溴-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-氯-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-(4-氟苄基氨基)苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-乙氧基-2-吡啶基甲基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-乙氧基-2-吡啶基甲基)-7-(5-甲基-2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-(2-吡啶基甲基氨基)苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(1-(4-三氟甲基苯基)乙基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(6-氟-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(5-氟-2-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3,5-二甲基-4-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(1-(3-氟苯基)乙基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(7-氯-5-吲哚基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(4-氨基-3,5-二甲基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(1-(3-氨基苯基)乙基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(6-(2-甲氧基乙基)-2-吡啶基甲基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(2-呋喃基)-3-(1-(5,6-二甲基-2-吡啶基)丙基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(3-硝基苄基)-7-(1H-吡唑-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺盐酸盐,
7-(5-甲基-2-呋喃基)-3-(2-甲基-3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-甲基-2-呋喃基)-3-(4-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)苯基)-N-甲基氨基甲酸叔丁酯,
2-(5-氨基-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)吡咯-1-甲酸叔丁酯,
7-(4,5-二甲基噻唑-2-基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
3-(2-氟-4-硝基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺,
7-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基甲基)-5-甲基吲哚-1-甲酸叔丁酯,
N-(4-(5-氨基-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)甲基)-2-甲基苯基)氨基甲酸乙酯。
42.权利要求1的应用,其中所述化合物选自:
3-(2-氟苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;
7-(2-呋喃基)-3-(3-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;
3-(3-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;
3-(3-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;
7-(2-呋喃基)-3-(3-甲氧基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;
7-(2-呋喃基)-3-(2-硝基苄基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;
3-(2-氨基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺;和
3-(3-氰基苄基)-7-(2-呋喃基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-胺。
43.一种治疗或预防其中阻断嘌呤受体可对其有益的病症的方法,该方法包括给需要这样的治疗的个体施用有效剂量的如权利要求1-42任一项中所述的化合物或其可药用盐。
44.前述权利要求任一项的应用或方法,其中所述病症是由于嘌呤受体机能亢进引起的。
45.前述权利要求任一项的应用或方法,其中所述嘌呤受体是腺苷受体。
46.权利要求45的应用或方法,其中所述腺苷受体是A2A受体。
47.前述权利要求任一项的应用或方法,其中所述病症是运动病症。
48.权利要求47的应用或方法,其中所述运动病症是帕金森氏病。
49.权利要求4 8的应用或方法,其中所述应用或方法是用于治疗药物引起的帕金森神经功能障碍、脑炎后帕金森神经功能障碍、中毒引起的帕金森神经功能障碍或创伤后帕金森氏病。
50.权利要求47的应用或方法,其中所述运动病症是进行性核上麻痹、亨廷顿氏舞蹈病、多发性全身萎缩、皮质基底变性、Wilsons病、Hallerrorden-Spatz病、进行性苍白球萎缩、多巴反应性张力障碍帕金森神经功能障碍、痉挛状态或导致运动障碍的其它基底神经节病症。
51.权利要求47-50任一项的应用或方法,其中式(I)化合物与用于治疗运动病症的一种或多种其它药物联合使用,这些组分在相同制剂中或者在单独的制剂中用于同时或依次给药。
52.权利要求51的应用或方法,其中所述用于治疗运动病症的其它药物是可用于治疗帕金森氏病的药物。
53.权利要求51或52的应用或方法,其中所述其它药物或者其中一种其它药物是L-DOPA或多巴胺激动剂。
54.权利要求1-46任一项的应用或方法,其中所述病症是抑郁症、认知或记忆减损、急性或慢性疼痛、ADHD或嗜眠症。
55.权利要求54的应用或方法,其中所述认知或记忆减损病症是阿尔茨海默氏病。
56.如权利要求1-42任一项所述的化合物或其可药用盐在制备用于个体中神经保护的药物中的应用。
57.一种神经保护的方法,该方法包括给需要这样的治疗的个体施用有效剂量的如权利要求1-42任一项所述的化合物或其可药用盐。
58.权利要求56或57的应用或方法,其中所述药物或所述方法是用于在患有神经变性病症或有患神经变性病症危险的个体中进行神经保护。
59.权利要求58的应用或方法,其中所述神经变性病症是运动病症。
60.权利要求59的应用或方法,其中所述运动病症是如在权利要求48、49或50中所述的病症。
61.权利要求1-60任一项的应用或方法,其中所述个体是人。
62.用于治疗的如在权利要求1-42任一项中所述的化合物或其可药用盐或其前药。
63.如在权利要求1-42任一项中所述的化合物自身,所述化合物不包括其中R1是H,且R3是甲基的化合物。
64.权利要求63的化合物,所述化合物不包括其中R3是甲基的化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0100624.6 | 2001-01-10 | ||
GBGB0100624.6A GB0100624D0 (en) | 2001-01-10 | 2001-01-10 | Chemical compounds VII |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200910164664A Division CN101691370A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
CNA2008100024015A Division CN101214248A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1496262A true CN1496262A (zh) | 2004-05-12 |
Family
ID=9906571
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA028063031A Pending CN1496262A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
CNA2008100024015A Pending CN101214248A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
CN200910164664A Pending CN101691370A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2008100024015A Pending CN101214248A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
CN200910164664A Pending CN101691370A (zh) | 2001-01-10 | 2002-01-10 | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 |
Country Status (27)
Country | Link |
---|---|
US (3) | US7141575B2 (zh) |
EP (1) | EP1392312B1 (zh) |
JP (2) | JP4287146B2 (zh) |
KR (1) | KR100913845B1 (zh) |
CN (3) | CN1496262A (zh) |
AT (1) | ATE424207T1 (zh) |
AU (1) | AU2002219355B2 (zh) |
BR (1) | BR0206559A (zh) |
CA (1) | CA2433453C (zh) |
CZ (1) | CZ301916B6 (zh) |
DE (1) | DE60231394D1 (zh) |
DK (1) | DK1392312T3 (zh) |
ES (1) | ES2323301T3 (zh) |
GB (1) | GB0100624D0 (zh) |
HK (1) | HK1061206A1 (zh) |
HR (1) | HRP20030533A2 (zh) |
HU (1) | HUP0401047A3 (zh) |
IL (2) | IL156713A0 (zh) |
MX (1) | MXPA03006165A (zh) |
NO (1) | NO328475B1 (zh) |
NZ (1) | NZ527248A (zh) |
PL (1) | PL363101A1 (zh) |
PT (1) | PT1392312E (zh) |
RS (1) | RS51121B (zh) |
RU (1) | RU2317084C2 (zh) |
WO (1) | WO2002055083A1 (zh) |
ZA (1) | ZA200305087B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100398542C (zh) * | 2005-03-18 | 2008-07-02 | 北京大学 | 具有抗hiv活性的取代1,2,3-三唑并嘧啶新化合物,制备方法及用途 |
CN106883191A (zh) * | 2017-01-19 | 2017-06-23 | 华侨大学 | 一种n‑取代苯并三氮唑衍生物的制备方法 |
Families Citing this family (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2842424A1 (fr) * | 2002-07-22 | 2004-01-23 | Univ Paris 7 Denis Diderot | Utilisation du nad ou de l'un de ses analogues, substrat des mono-adp-ribosyl tranferases, pour la preparation d'un medicament destine au traitement des pathologies liees aux recepteurs purinergiques |
JP2006514697A (ja) | 2002-12-19 | 2006-05-11 | シェーリング コーポレイション | アデノシンA2aレセプターアンタゴニストの使用 |
DK1622912T3 (da) | 2003-04-23 | 2009-09-07 | Schering Corp | 2-alkynyl- og 2-alkenyl-pyrazolo-[4,3-E]-1,2,4-triazolo-[1,5-C]-pyrimidinadenosin-A2A-receptorantagonister |
MXPA06002997A (es) * | 2003-09-18 | 2007-02-08 | Conforma Therapeutics Corp | Novedosos compuestos heterociclicos como inhibidores- hsp90. |
TW200538118A (en) | 2004-04-21 | 2005-12-01 | Schering Corp | Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists |
WO2006032273A1 (en) | 2004-09-22 | 2006-03-30 | H. Lundbeck A/S | 2-acylaminothiazole derivatives |
AU2006230447A1 (en) * | 2005-03-30 | 2006-10-05 | Conforma Therapeutics Corporation | Alkynyl pyrrolopyrimidines and related analogs as HSP90-inhibitors |
US7674912B2 (en) | 2005-04-25 | 2010-03-09 | H. Lundbeck A/S | Pro-drugs of N-thiazol-2-yl-benzamide derivatives |
ES2385702T3 (es) * | 2005-06-07 | 2012-07-30 | Kyowa Hakko Kirin Co., Ltd. | Antagonistas de A2A para uso en el tratamiento de trastornos de la motricidad |
CA2617817C (en) * | 2005-08-02 | 2014-05-27 | Kyowa Hakko Kogyo Co., Ltd. | Thiazole derivatives for treating or preventing sleep disorders |
JP2009508871A (ja) | 2005-09-19 | 2009-03-05 | シェーリング コーポレイション | アデノシンA2a受容体アンタゴニストとしての2−ヘテロアリール−ピラゾロ−[4,3−e]−1,2,4−トリアゾロ−[1,5−c]−ピリミジン |
WO2007035963A2 (en) * | 2005-09-23 | 2007-03-29 | Conforma Therapeutics Corporation | Anti-tumor methods using multi drug resistance independent synthetic hsp90 inhibitors |
PE20070521A1 (es) | 2005-09-23 | 2007-07-13 | Schering Corp | 7-[2-[4-(6-FLUORO-3-METIL-1,2-BENCISOXAZOL-5-IL)-1-PIPERAZINIL]ETIL]-2-(1-PROPINIL)-7H-PIRAZOL-[4,3-E]-[1,2,4]-TRIAZOL-[1,5-C]-PIRIMIDIN-5-AMINA COMO ANTAGONISTA DEL RECEPTOR DE ADENOSINA A2a |
DE102005049954A1 (de) * | 2005-10-19 | 2007-05-31 | Sanofi-Aventis Deutschland Gmbh | Triazolopyridin-derivate als Inhibitoren von Lipasen und Phospholipasen |
US20080027079A1 (en) * | 2006-06-22 | 2008-01-31 | Board Of Regents, University Of Texas System | Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activity |
JP2010515690A (ja) * | 2007-01-05 | 2010-05-13 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | 医薬品の多形及び溶媒和物、並びに製造方法 |
WO2008088927A1 (en) * | 2007-01-12 | 2008-07-24 | Biogen Idec Ma Inc. | Pharmaceuticals, compositions and methods of making and using the same |
FR2915199B1 (fr) * | 2007-04-18 | 2010-01-22 | Sanofi Aventis | Derives de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur preparation et leur application en therapeutique. |
FR2915197B1 (fr) | 2007-04-18 | 2009-06-12 | Sanofi Aventis Sa | Derives de triazolopyridine-carboxamides, leur preparation et leur application therapeutique. |
FR2915198B1 (fr) * | 2007-04-18 | 2009-12-18 | Sanofi Aventis | Derives de triazolopyridine-carboxamides et triazolopyridine -carboxamides, leur preparation et leur application en therapeutique. |
EP2262811B1 (en) | 2008-03-04 | 2016-04-27 | Merck Sharp & Dohme Corp. | 1,2,4-triazolo[4,3-c]pyrimidin-3-one and pyrazolo [4,3-e]-1,2,4-triazolo [4,3-c]pyrimidin-3-one compounds for use as adenosine a2a receptor antagonists |
JP2011514350A (ja) | 2008-03-04 | 2011-05-06 | シェーリング コーポレイション | アデノシンA2a受容体アンタゴニストとして使用するためのアミノ−キノキサリンおよびアミノ−キノリン化合物 |
TWI473614B (zh) | 2008-05-29 | 2015-02-21 | Kyowa Hakko Kirin Co Ltd | Anti-analgesic inhibitors |
WO2009152521A2 (en) * | 2008-06-13 | 2009-12-17 | Parkinson's Institute | Diagnosis of neurodegenerative disorders |
GB0906579D0 (en) * | 2009-04-16 | 2009-05-20 | Vernalis R&D Ltd | Pharmaceuticals, compositions and methods of making and using the same |
AU2009274876C1 (en) * | 2008-07-23 | 2016-08-18 | Kyowa Kirin Co., Ltd. | Therapeutic agent for migraine |
TWI469979B (zh) * | 2008-12-24 | 2015-01-21 | Bial Portela & Ca Sa | 脂肪酸醯胺水解酶(faah)抑制劑、以及其藥學組成物與用途 |
AU2010222289B2 (en) | 2009-03-13 | 2013-07-11 | Advinus Therapeutics Private Limited | Substituted fused pyrimidine compounds |
WO2011050160A1 (en) * | 2009-10-22 | 2011-04-28 | Biogen Idec Ma Inc. | Pharmaceuticals, compositions and methods of making and using the same |
US8796290B2 (en) | 2009-11-09 | 2014-08-05 | Advinus Therapeutics Limited | Substituted fused pyrimidine compounds, its preparation and uses thereof |
US8435994B2 (en) | 2009-11-16 | 2013-05-07 | Merck Sharp & Dohme Corp. | Substituted [1,2,4]triazolo[4,3-alpha]quinoxalines as adenosine A2a receptor antagonists |
AU2011212430B2 (en) | 2010-02-05 | 2014-05-29 | Nxera Pharma Uk Limited | 1,2,4-triazine-4-amine derivatives |
WO2012066330A1 (en) | 2010-11-17 | 2012-05-24 | Heptares Therapeutics Limited | Compounds useful as a2a receptor inhibitors |
WO2014101120A1 (en) * | 2012-12-28 | 2014-07-03 | Merck Sharp & Dohme Corp. | Heterobicyclo-substituted-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds with a2a antagonist properties |
WO2016126570A1 (en) | 2015-02-06 | 2016-08-11 | Merck Sharp & Dohme Corp. | Aminoquinazoline compounds as a2a antagonist |
JP6847958B2 (ja) | 2015-12-24 | 2021-03-24 | コーバス・ファーマシューティカルズ・インコーポレイテッド | がんの治療方法 |
CN107021963A (zh) * | 2016-01-29 | 2017-08-08 | 北京诺诚健华医药科技有限公司 | 吡唑稠环类衍生物、其制备方法及其在治疗癌症、炎症和免疫性疾病上的应用 |
WO2018102786A1 (en) | 2016-12-03 | 2018-06-07 | Juno Therapeutics, Inc. | Methods for modulation of car-t cells |
MX2019006286A (es) | 2016-12-03 | 2020-02-07 | Juno Therapeutics Inc | Metodos para determinar la dosificacion en la terapia celular. |
US11066413B2 (en) * | 2017-03-07 | 2021-07-20 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aminopyrimidine five-membered heterocyclic compound, and intermediate, preparation method, pharmaceutical composition and application thereof |
WO2018183965A1 (en) * | 2017-03-30 | 2018-10-04 | Corvus Pharmaceuticals, Inc. | Processes for making triazolo[4,5d] pyramidine derivatives and intermediates thereof |
WO2018187484A1 (en) | 2017-04-04 | 2018-10-11 | Corvus Pharmaceuticals, Inc. | Methods of treating cancer |
CN110730908A (zh) | 2017-04-07 | 2020-01-24 | 朱诺治疗学股份有限公司 | 表达前列腺特异性膜抗原(psma)或其修饰形式的工程化细胞及相关方法 |
BR112019025403A2 (pt) | 2017-06-02 | 2020-08-18 | Juno Therapeutics Inc | artigos de fabricação e métodos para tratamento usando terapia celular adotiva |
JP2020526194A (ja) | 2017-06-29 | 2020-08-31 | ジュノー セラピューティクス インコーポレイテッド | 免疫療法薬と関連する毒性を評価するためのマウスモデル |
BR112020008323A2 (pt) | 2017-11-01 | 2020-11-03 | Juno Therapeutics Inc | anticorpos e receptores de antígenos quiméricos específicos para antígeno de maturação de células b |
EP3703750A1 (en) | 2017-11-01 | 2020-09-09 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for b-cell maturation antigen and encoding polynucleotides |
WO2019089858A2 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Methods of assessing or monitoring a response to a cell therapy |
US20210198372A1 (en) | 2017-12-01 | 2021-07-01 | Juno Therapeutics, Inc. | Methods for dosing and for modulation of genetically engineered cells |
MA51184A (fr) | 2017-12-15 | 2020-10-21 | Juno Therapeutics Inc | Molécules de liaison à l'anti-cct5 et procédés d'utilisation associés |
US20200316077A1 (en) | 2017-12-19 | 2020-10-08 | Impetis Biosciences Ltd. | Pharmaceutical composition for the treatment of cancer |
EP3735413B1 (en) | 2018-01-04 | 2022-07-06 | Impetis Biosciences Ltd. | Tricyclic compounds, compositions and medicinal applications thereof |
FI3814357T3 (fi) * | 2018-06-27 | 2024-07-26 | Ptc Therapeutics Inc | Heterosykliset ja heteroaryliyhdisteet huntingtonin taudin hoitoon |
WO2020068583A1 (en) * | 2018-09-27 | 2020-04-02 | Corvus Pharmaceuticals, Inc. | Processes for making triazolo [4,5d] pyramidine derivatives and intermediates thereof |
EP3873937A2 (en) | 2018-11-01 | 2021-09-08 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for g protein-coupled receptor class c group 5 member d (gprc5d) |
EP3873943A2 (en) | 2018-11-01 | 2021-09-08 | Juno Therapeutics, Inc. | Methods for treatment using chimeric antigen receptors specific for b-cell maturation antigen |
EP3880238A1 (en) | 2018-11-16 | 2021-09-22 | Juno Therapeutics, Inc. | Methods of dosing engineered t cells for the treatment of b cell malignancies |
EP3886875B1 (en) | 2018-11-30 | 2024-05-08 | Juno Therapeutics, Inc. | Methods for treatment using adoptive cell therapy |
CA3123303A1 (en) | 2019-01-29 | 2020-08-06 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1) |
CN110251518A (zh) * | 2019-06-28 | 2019-09-20 | 青岛科技大学 | 1,2,4-三氮唑类杂环化合物在制备预防或治疗与中枢系统相关疾病药物中的应用 |
CN112592354B (zh) | 2019-07-30 | 2022-05-27 | 厦门宝太生物科技股份有限公司 | 一种异噁唑并嘧啶类杂环化合物的制备方法 |
CN112608316B (zh) | 2019-07-30 | 2022-10-21 | 厦门宝太生物科技股份有限公司 | 一种吡唑并三嗪类腺苷受体拮抗剂 |
WO2021050688A1 (en) * | 2019-09-10 | 2021-03-18 | X-Chem, Inc. | Compounds and uses thereof |
CA3158511A1 (en) * | 2019-10-22 | 2021-04-29 | Alphala Co., Ltd. | Pyrimidine amide compounds and use thereof |
US20230149462A1 (en) | 2020-04-10 | 2023-05-18 | Juno Therapeutics, Inc. | Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen |
CN111333655B (zh) * | 2020-04-13 | 2021-07-13 | 武汉工程大学 | 一种三唑并嘧啶类化合物及其制备方法和应用 |
WO2023250400A1 (en) | 2022-06-22 | 2023-12-28 | Juno Therapeutics, Inc. | Treatment methods for second line therapy of cd19-targeted car t cells |
WO2024031091A2 (en) | 2022-08-05 | 2024-02-08 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for gprc5d and bcma |
WO2024129778A2 (en) | 2022-12-13 | 2024-06-20 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for baff-r and cd19 and methods and uses thereof |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS56131587A (en) | 1980-03-18 | 1981-10-15 | Ss Pharmaceut Co Ltd | 7-substituted triazolopyrimidine derivative and its preparation |
JPS56131586A (en) | 1980-03-18 | 1981-10-15 | Ss Pharmaceut Co Ltd | Triazolopyrimidine derivative and its preparation |
JPS5962595A (ja) | 1982-09-30 | 1984-04-10 | Ss Pharmaceut Co Ltd | 3,5,7―トリ置換―トリアゾロピリミジン誘導体 |
DE3304330A1 (de) * | 1983-02-09 | 1984-08-09 | Basf Ag, 6700 Ludwigshafen | Neue 2h-v-triazolyl(4,5-d)-pyrimidine und deren verwendung |
JPS60140335A (ja) | 1983-12-28 | 1985-07-25 | Konishiroku Photo Ind Co Ltd | 熱現像カラ−感光材料 |
US5204353A (en) * | 1987-04-07 | 1993-04-20 | Ciba-Geigy Corporation | 3-benzyl-3H-1,2,3-triazolo[4,5-d]pyrimidines, compositions thereof, and method of treating epilepsy therewith |
US5194581A (en) | 1989-03-09 | 1993-03-16 | Leong Kam W | Biodegradable poly(phosphoesters) |
AU692484B2 (en) * | 1993-10-12 | 1998-06-11 | Du Pont Pharmaceuticals Company | 1N-alkyl-N-arylpyrimidinamines and derivatives thereof |
EE03616B1 (et) * | 1995-07-11 | 2002-02-15 | Astra Pharmaceuticals Limited | Uued vereliistakute agregatsiooni pärssivad ained |
ZA971896B (en) * | 1996-03-26 | 1998-09-07 | Du Pont Merck Pharma | Aryloxy-and arythio-fused pyridines and pyrimidines and derivatives |
PL332040A1 (en) * | 1996-08-28 | 1999-08-16 | Pfizer | Substitution 6,5-heterobicyclic derivatives |
ATE257156T1 (de) * | 1997-03-24 | 2004-01-15 | Kyowa Hakko Kogyo Kk | (1,2,4)triazolo(1,5-c)pyrimidin-derivate |
US5912225A (en) * | 1997-04-14 | 1999-06-15 | Johns Hopkins Univ. School Of Medicine | Biodegradable poly (phosphoester-co-desaminotyrosyl L-tyrosine ester) compounds, compositions, articles and methods for making and using the same |
IL132487A0 (en) * | 1997-04-30 | 2001-03-19 | Guilford Pharm Inc | Biodegradable compositions comprising poly (cycloaliphatic phosphoester) compounds articles and methods for using the same |
US6028163A (en) | 1997-06-27 | 2000-02-22 | Guilford Pharmaceuticals Inc. | Solution polymerization of high molecular weight poly(phosphoesters) in toluene |
CA2296014A1 (en) | 1997-07-03 | 1999-01-14 | Frank W. Hobbs | Aryl-and arylamino-substituted heterocycles as corticotropin releasing hormone antagonists |
US5939432A (en) * | 1997-10-29 | 1999-08-17 | Medco Research, Inc. | Thiophenes useful for modulating the adenosine receptor |
US6197788B1 (en) * | 1997-11-26 | 2001-03-06 | Vernalis Research Limited | (−)-mefloquine to block puringergic receptors and to treat movement or neurodegenerative disorders |
US6579868B1 (en) | 1998-01-05 | 2003-06-17 | Eisai Co., Ltd. | Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes |
GB9819384D0 (en) * | 1998-09-04 | 1998-10-28 | Cerebrus Ltd | Chemical compounds II |
GB9819382D0 (en) * | 1998-09-04 | 1998-10-28 | Cerebrus Ltd | Chemical compounds I |
GB9915437D0 (en) * | 1999-07-01 | 1999-09-01 | Cerebrus Ltd | Chemical compounds III |
AU778450B2 (en) | 1999-07-02 | 2004-12-09 | Eisai R&D Management Co., Ltd. | Fused imidazole compounds and remedies for diabetes mellitus |
-
2001
- 2001-01-10 GB GBGB0100624.6A patent/GB0100624D0/en not_active Ceased
-
2002
- 2002-01-10 MX MXPA03006165A patent/MXPA03006165A/es active IP Right Grant
- 2002-01-10 CN CNA028063031A patent/CN1496262A/zh active Pending
- 2002-01-10 AU AU2002219355A patent/AU2002219355B2/en not_active Ceased
- 2002-01-10 DE DE60231394T patent/DE60231394D1/de not_active Expired - Lifetime
- 2002-01-10 NZ NZ527248A patent/NZ527248A/en active IP Right Revival
- 2002-01-10 CN CNA2008100024015A patent/CN101214248A/zh active Pending
- 2002-01-10 HU HU0401047A patent/HUP0401047A3/hu unknown
- 2002-01-10 RS YUP-555/03A patent/RS51121B/sr unknown
- 2002-01-10 EP EP02729452A patent/EP1392312B1/en not_active Expired - Lifetime
- 2002-01-10 BR BR0206559-2A patent/BR0206559A/pt not_active Application Discontinuation
- 2002-01-10 AT AT02729452T patent/ATE424207T1/de active
- 2002-01-10 RU RU2003124651/04A patent/RU2317084C2/ru not_active IP Right Cessation
- 2002-01-10 JP JP2002555817A patent/JP4287146B2/ja not_active Expired - Lifetime
- 2002-01-10 CN CN200910164664A patent/CN101691370A/zh active Pending
- 2002-01-10 CZ CZ20031955A patent/CZ301916B6/cs not_active IP Right Cessation
- 2002-01-10 CA CA2433453A patent/CA2433453C/en not_active Expired - Lifetime
- 2002-01-10 KR KR1020037009240A patent/KR100913845B1/ko not_active IP Right Cessation
- 2002-01-10 ZA ZA200305087A patent/ZA200305087B/xx unknown
- 2002-01-10 PT PT02729452T patent/PT1392312E/pt unknown
- 2002-01-10 WO PCT/GB2002/000091 patent/WO2002055083A1/en active IP Right Grant
- 2002-01-10 DK DK02729452T patent/DK1392312T3/da active
- 2002-01-10 IL IL15671302A patent/IL156713A0/xx unknown
- 2002-01-10 ES ES02729452T patent/ES2323301T3/es not_active Expired - Lifetime
- 2002-01-10 US US10/250,942 patent/US7141575B2/en not_active Expired - Lifetime
- 2002-01-10 PL PL02363101A patent/PL363101A1/xx not_active Application Discontinuation
-
2003
- 2003-06-30 IL IL156713A patent/IL156713A/en not_active IP Right Cessation
- 2003-06-30 HR HR20030533A patent/HRP20030533A2/hr not_active Application Discontinuation
- 2003-07-09 NO NO20033146A patent/NO328475B1/no not_active IP Right Cessation
-
2004
- 2004-06-15 HK HK04104319.2A patent/HK1061206A1/xx not_active IP Right Cessation
-
2006
- 2006-08-22 US US11/507,625 patent/US7405219B2/en not_active Expired - Lifetime
-
2007
- 2007-12-20 US US12/003,110 patent/US7589097B2/en not_active Expired - Lifetime
-
2008
- 2008-12-02 JP JP2008308004A patent/JP5202259B2/ja not_active Expired - Lifetime
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100398542C (zh) * | 2005-03-18 | 2008-07-02 | 北京大学 | 具有抗hiv活性的取代1,2,3-三唑并嘧啶新化合物,制备方法及用途 |
CN106883191A (zh) * | 2017-01-19 | 2017-06-23 | 华侨大学 | 一种n‑取代苯并三氮唑衍生物的制备方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1496262A (zh) | 三唑并[4,5-d]嘧啶衍生物及其作为嘌呤能受体拮抗剂的应用 | |
US7875600B2 (en) | Pyrimidine compounds as purine receptor antagonist | |
CN1617871A (zh) | 作为嘌呤能受体拮抗剂的嘌呤衍生物 | |
CN1150195C (zh) | 双环氮杂环 | |
CN1168721C (zh) | 5-氰基-2-氨基嘧啶衍生物 | |
CN1289499C (zh) | 吡嗪并(氮杂)吲哚衍生物 | |
TWI295670B (en) | Vanilloid receptor ligands and their use in treatments | |
CN1503673A (zh) | 消炎药 | |
CN1610547A (zh) | 用作5-ht6受体拮抗剂的n-(2-芳乙基)苄胺 | |
CN1284948A (zh) | 治疗活性化合物中的儿茶酚的吲唑生物等排物置换 | |
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 | |
CN1446217A (zh) | 用作磷酸二酯酶抑制剂的β-咔啉衍生物 | |
CN1871008A (zh) | 用于治疗神经病变性疼痛的三唑并-哒嗪化合物和它们的衍生物 | |
CN1234031A (zh) | 吲唑衍生物及其作为磷酸二酯酶(pde)iv型和肿瘤坏死因子(tnf)产生的抑制剂的应用 | |
CN1407985A (zh) | 用作钾通道抑制剂的杂环二氢嘧啶 | |
CN1596114A (zh) | 取代的1,4-苯并二氮杂䓬类及其在治疗癌症中的应用 | |
KR20130101040A (ko) | 모노아실글리세롤 리파아제 억제제로서의 다이-아제티디닐 다이아미드 | |
KR20140041583A (ko) | Lrrk2 키나제 활성의 억제제 | |
CN101068776A (zh) | 作为5ht2a拮抗剂的芳基磺酰基萘衍生物 | |
CN1260781A (zh) | 具有综合的5ht1a、5ht1b和5ht1d受体拮抗剂活性的吲哚衍生物 | |
CN1525974A (zh) | 用作腺苷A2a受体的配体的三唑基-咪唑并吡啶和三唑基嘌呤类的衍生物及其作为药物的应用 | |
CN1845915A (zh) | 作为亲代谢谷氨酸受体-5的调节剂的联吡啶胺和醚类化合物 | |
CN1863789A (zh) | 取代的异喹啉酮 | |
US20230227449A1 (en) | Amidopyrimidone derivatives | |
TW201103914A (en) | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20040512 |