CN1213369A - 喹喔啉二酮化合物 - Google Patents
喹喔啉二酮化合物 Download PDFInfo
- Publication number
- CN1213369A CN1213369A CN97192923A CN97192923A CN1213369A CN 1213369 A CN1213369 A CN 1213369A CN 97192923 A CN97192923 A CN 97192923A CN 97192923 A CN97192923 A CN 97192923A CN 1213369 A CN1213369 A CN 1213369A
- Authority
- CN
- China
- Prior art keywords
- base
- triazole
- methyl
- alkyl
- phenyl
- 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.)
- Granted
Links
- SEPKUNXLGWMPHL-UHFFFAOYSA-N quinoxaline-2,3-dione Chemical class C1=CC=CC2=NC(=O)C(=O)N=C21 SEPKUNXLGWMPHL-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 172
- 125000003118 aryl group Chemical group 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 19
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 16
- 125000005843 halogen group Chemical group 0.000 claims abstract description 13
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 12
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 8
- 230000001154 acute effect Effects 0.000 claims abstract description 6
- 230000001684 chronic effect Effects 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 132
- 239000000203 mixture Substances 0.000 claims description 99
- 238000000034 method Methods 0.000 claims description 93
- -1 pyrryl Chemical group 0.000 claims description 75
- 239000000460 chlorine Substances 0.000 claims description 68
- 229910052801 chlorine Inorganic materials 0.000 claims description 52
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 10
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 10
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 230000003042 antagnostic effect Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 7
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 claims description 6
- YRDJGSNRDMVFSV-UHFFFAOYSA-N COCC1=NN=C(C2=CC=CN=C2)N1C(C=CC=C1N(C2=O)Cl)=C1NC2=O Chemical class COCC1=NN=C(C2=CC=CN=C2)N1C(C=CC=C1N(C2=O)Cl)=C1NC2=O YRDJGSNRDMVFSV-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 230000002981 neuropathic effect Effects 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 206010003497 Asphyxia Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 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 claims description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 230000001052 transient effect Effects 0.000 claims description 3
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 claims 2
- 230000009529 traumatic brain injury Effects 0.000 claims 2
- QOAMWZMAXNNNDC-UHFFFAOYSA-N 4-(1,2-thiazol-3-yl)oxadiazole Chemical compound S1C=CC(C=2N=NOC=2)=N1 QOAMWZMAXNNNDC-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- 229940044551 receptor antagonist Drugs 0.000 abstract description 2
- 239000002464 receptor antagonist Substances 0.000 abstract description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 5
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 208000012902 Nervous system disease Diseases 0.000 abstract 1
- 208000025966 Neurological disease Diseases 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 125000001153 fluoro group Chemical group F* 0.000 abstract 1
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 abstract 1
- 239000002585 base Substances 0.000 description 236
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 112
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 112
- 239000007787 solid Substances 0.000 description 103
- 239000000243 solution Substances 0.000 description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
- 239000007921 spray Substances 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 238000003818 flash chromatography Methods 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 238000001816 cooling Methods 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 238000013459 approach Methods 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 238000010438 heat treatment Methods 0.000 description 25
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 24
- 238000010828 elution Methods 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 238000005406 washing Methods 0.000 description 23
- 239000000284 extract Substances 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- 125000004494 ethyl ester group Chemical group 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000012266 salt solution Substances 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- ABJFBJGGLJVMAQ-UHFFFAOYSA-N 1,4-dihydroquinoxaline-2,3-dione Chemical class C1=CC=C2NC(=O)C(=O)NC2=C1 ABJFBJGGLJVMAQ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- HPYZYLNQKUMLDE-UHFFFAOYSA-N 5-chloro-2,3-dimethoxyquinoxaline Chemical compound ClC1=C2N=C(C(=NC2=CC=C1)OC)OC HPYZYLNQKUMLDE-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 8
- 238000009834 vaporization Methods 0.000 description 8
- 230000008016 vaporization Effects 0.000 description 8
- 239000004471 Glycine Substances 0.000 description 7
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 6
- UQDFESHPPCTPSW-UHFFFAOYSA-N ClC=1C(=C2N=C(C(=NC2=CC1)OC)OC)N1C(=NN=C1)C=1C=NC=CC1 Chemical compound ClC=1C(=C2N=C(C(=NC2=CC1)OC)OC)N1C(=NN=C1)C=1C=NC=CC1 UQDFESHPPCTPSW-UHFFFAOYSA-N 0.000 description 5
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 229960002989 glutamic acid Drugs 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- JDJBRMNTXORYEN-UHFFFAOYSA-N 6-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)N=C1 JDJBRMNTXORYEN-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000004327 boric acid Substances 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- YOWAEZWWQFSEJD-UHFFFAOYSA-N quinoxalin-2-amine Chemical compound C1=CC=CC2=NC(N)=CN=C21 YOWAEZWWQFSEJD-UHFFFAOYSA-N 0.000 description 4
- 239000002287 radioligand Substances 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 102000003678 AMPA Receptors Human genes 0.000 description 3
- 108090000078 AMPA Receptors Proteins 0.000 description 3
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Classifications
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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Abstract
本发明提供了式(Ⅰ)化合物及其可药用盐:其中R代表包含3或4个氮杂原子的5-元环杂芳基,该杂芳基通过环碳或环氮原子与喹喔啉二酮环连接;或者代表包含1—3个氮杂原子的6-元环杂芳基,该杂芳基通过环碳原子与喹喔啉二酮环连接;所述基团中的任一个都为任选苯并稠合的,而且它们,包括苯并稠合部分,任选地被1或2个各自独立选自下列的取代基取代:C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧基,C3-C7环烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2NR3R4,芳基,芳氧基,芳基(C1-C4)烷氧基和het,其中所述C1-C4烷基任选地被C3-C7环烷基,卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷氧基,C3-C7环烷基(C1-C4)烷基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2(芳基),-SO2NR3R4,吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het取代,以及所述C2-C4链烯基被芳基任选取代;R1和R2各自独立选自H,氟,氯,溴,C1-C4烷基和卤代(C1-C4)烷基;R3和R4各自独立选自H和C1-C4烷基,或者它们一起代表C5-C7亚烷基;p为0,1或2。本发明还提供了这类化合物的制备方法,含有它们的组合物,以及它们的用途和其合成过程中所用的中间体。本发明化合物可用作治疗急性神经变性和慢性神经病学病症的NMDA受体拮抗剂。
Description
本发明涉及2,3(1H,4H)-喹喔啉二酮衍生物,它们为N-甲基-D-天冬氨酸受体的选择性拮抗剂。具体讲,本发明涉及5-杂芳基-2,3(1H,4H)-喹喔啉二酮衍生物及其制备,含有它们的组合物,以及它们的用途和其合成过程中所用的中间体。
L-谷氨酸是一种兴奋性氨基酸神经递质,其在大脑中的生理学作用包括与四种受体相互作用,所述受体中的三种是依据选择性激动剂NMDA(N-甲基-D-天冬氨酸),AMPA(2-氨基-3-羟基-5-甲基-4-异噁唑丙酸)和红藻氨酸而命名的。第四种受体称为亲代谢受体。除对谷氨酸具有结合位点外,NMDA受体还对解离性麻醉剂(如***),多胺(如精胺),甘氨酸和一些金属离子(如Mg2+,Zn2+)具有高亲和性结合位点。由于NMDA受体为发生激活而必须结合谷氨酸,因而可用谷氨酸拮抗剂作为功能性NMDA拮抗剂。
例如,在脑梗塞区域,缺氧导致释放异常高浓度谷氨酸,进而造成对NMDA受体过度刺激,从而导致神经元变性和死亡。因此,可以将已证明能够在体外和体内阻断谷氨酸神经毒性作用的NMDA受体拮抗剂用于治疗和/或预防那些其中NMDA受体激活十分重要的病理性疾病。这些疾病的实例包括由诸如中风,短暂局部缺血发作,外周手术性局部缺血,全面性局部缺血(心动停止之后)和脑或脊髓的创伤性头损伤之类情况引起的急性神经变性疾病。另外,NMDA拮抗剂可用于治疗一些慢性神经病学疾病如早老性痴呆,Parkinson病和Alzheimer病。它们还对外周神经功能受试的病症如视网膜和黄斑变性具有效用。
此外,业已证明NMDA拮抗剂具有抗惊厥和抗焦虑活性,并因此可用于治疗癫痫和焦虑。NMDA拮抗剂还可以减轻身体依赖性动物戒除酒精所带来的影响(K.A.Grant等人,药理学和实验治疗学杂志(J.Pharm/Exp.Ther.),260,1017(992)),因此NMDA拮抗剂可用于治疗酒精成瘾和疼痛。NMDA拮抗剂还可以用于治疗听力障碍(如耳鸣),偏头痛和精神障碍。
EP-A-0572852描述了适于治疗中枢神经***神经变性疾病和神经中毒性病症的吡咯-1-基-取代的2,3(1H,4H)-喹喔啉二酮衍生物。
EP-A-0556393中特别公开了咪唑基-或***基-取代的2,3(1H,4H)-喹喔啉二酮衍生物,它们具有谷氨酸受体拮抗活性,特别是NMDA-甘氨酸受体和AMPA受体拮抗活性。然而,该文献中没有具体记载5-***基-取代化合物。
本发明化合物为强有效的NMDA(甘氨酸位点)受体拮抗剂。另外,与AMPA受体相比(本发明化合物对其如果有亲和性的话也很低),本发明化合物为NMDA(甘氨酸位点)受体的高选择性拮抗剂。
R为包含3或4个氮杂原子的5-元环杂芳基,该杂芳基通过环碳或环氮原子与喹喔啉二酮环连接;或者为包含1-3个氮杂原子的6-元环杂芳基,该杂芳基通过环碳原子与喹喔啉二酮环连接;所述基团中的任一个都为任选苯并稠合的,而且它们(包括苯并稠合部分)可以被1或2个各自独立选自下列的取代基任选取代:C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧基,C3-C7环烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2NR3R4,芳基,芳氧基,芳基(C1-C4)烷氧基和het,所述C1-C4烷基任选地被C3-C7环烷基,卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷氧基,C3-C7环烷基(C1-C4)烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2(芳基),-SO2NR3R4,吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het取代,以及所述C2-C4链烯基被芳基任选取代;
R1和R2各自独立选自H,氟,氯,溴,C1-C4烷基和卤代(C1-C4)烷基;
R3和R4各自独立选自H和C1-C4烷基,或者它们一起代表C5-C7亚烷基;
p为0,1或2;
R与“het”定义中所用的“芳基”是指苯基或萘基,它们各自被1或2个彼此独立选自C1-C4烷基,C1-C4烷氧基,羟基,卤素,卤代(C1-C4烷基)和-NR3R4的取代基任选取代;R定义中所用的“het”是指呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,***基,四唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,所有这些基团各自为任选苯并稠合的,而且它们(包括苯并稠合部分)可以被1或2个各自独立选自下列的取代基任选取代:C1-C4烷基,C3-C7环烷基,C1-C4烷氧基,卤素,羟基,-COOH,C1-C4烷氧基羰基,烯丙氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2NR3R4,卤代(C1-C4)烷基,羟基(C1-C4)烷基,C1-C4烷氧基(C1-C4)烷基,R3R4NCO(C1-C4)烷基,芳基,芳烷基,het1和het1(C1-C4)烷基,和/或当“het”包括吡啶基,哒嗪基,嘧啶基或吡嗪基时其环氮杂原子被氧取代基任选取代;“het”定义中所用的“het1”是指呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,***基,四唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,它们各自被1或2个C1-C4烷基取代基任选取代。
上述定义中,“卤素”是指氟,氯,溴或碘,具有三或多个碳原子的烷基、烷氧基和亚烷基以及具有4或多个碳原子的链烯基可以为直链或支链的。
定义“C1-C4烷基”包括甲基,乙基,正丙基,异丙基,正丁基,仲丁基和叔丁基。定义“C1-C4烷氧基”包括相应的烷氧基。
当R为5-元环杂芳基时,该定义包括1,2,3-***基,1,2,4-***基和四唑基。
当R为6-元环杂芳基时,这一定义特别包括2-,3-和4-吡啶基,3-或4-哒嗪基,2-、4-或5-嘧啶基和2-吡嗪基。
当“het”代表苯并稠合杂芳基时,该基团通过“het”基团的杂芳基或苯并稠合部分连接到分子的剩余部分上。
优选R为***基或四唑基,它们各自被1或2个彼此独立选自C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧羰基,芳基和het的取代基取代,所述C1-C4烷基被卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷基(C1-C4)烷氧基,-COOH,C1-C4烷氧基羰基,-NR3R4,-SO2(芳基),吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het任选取代;或为吡啶基或嘧啶基。
较优选R为1,2,3-***-4-基,1,2,4-***-3-基,1,2,4-***-4-基或四唑-5-基,它们各自被1或2个彼此独立选自C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧羰基,芳基和het的取代基取代,所述C1-C4烷基被卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷基(C1-C4)烷氧基,-COOH,C1-C4烷氧基羰基,-NR3R4,-SO2(芳基),吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het任选取代;或为吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基或嘧啶-5-基。
更优选R为1,2,3-***-4-基,1,2,4-***-3-基,1,2,4-四唑-4-基或四唑-5-基,它们各自被1或2个彼此独立选自甲基,乙基,丙基,烯丙基,环丙基,环己基,溴,羟基,乙氧羰基,2-氯苯基,3-氯苯基,4-氯苯基,4-二甲氨基苯基,2-羟基苯基,2-甲氧基苯基,3-甲氧基苯基,4-甲氧基苯基,2-甲基苯基,苯基,4-三氟甲基苯基,2-氨基-1,3,4-噁二唑-5-基,2-羧基吡啶-5-基,1,5-二甲基-1H-吡唑-3-基,1H-咪唑-1-基,1-甲基咪唑-2-基,1-甲基咪唑-4-基,1-甲基咪唑-5-基,3-甲基异噻唑-4-基,4-甲基-1H-咪唑-5-基,3-甲基-1,2,4-噁二唑-5-基,1-甲基-1H-吡唑-4-基,5-甲基-1H-吡唑-3-基,1-甲基-1H-吡唑-5-基,1-氧化吡啶-3-基,2-甲基吡啶-3-基,2-甲基吡啶-5-基,1-苯基咪唑-4-基,5-苯基吡啶-3-基,2-苯基吡啶-5-基,1-甲基吡咯-2-基,4-甲基-1,2,3-噻二唑-5-基,2-甲基噻唑-4-基,1-甲基-1H-1,2,4-***-5-基,3-(丙-1-基)-1H-吡唑-5-基,吡嗪-2-基,1H-吡唑-4-基,哒嗪-4-基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基,噻吩-2-基,1H-1,2,4-***-5-基,1H-1,2,3-***-5-基,喹啉-3-基和喹啉-6-基的取代基取代,其中所述甲基、乙基或丙基任选被氟,羟基,甲氧基,乙氧基,2,2,2-三氟乙氧基,环己基甲氧基,环戊基甲氧基,-COOH,甲氧基羰基,二甲氨基,4-氯苯基磺酰基,吗啉代,苯基,苯氧基,苄氧基,吡啶-2-基,吡啶-3-基或吡啶-4-基取代;或R为吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基或嘧啶-5-基。
R的实例包括:
1-(2-羟基乙基)-5-苯基-1,2,3-***-4-基,
1-(2-羟基乙基)-4-苯基-1,2,3-***-5-基,
2-(2-羟基乙基)-5-苯基-1,2,3-***-4-基,
1-甲基-5-苯基-1,2,3-***-4-基,
1-甲基-4-苯基-1,2,3-***-5-基,
2-甲基-5-苯基-1,2,3-***-4-基,
5-苯基-1H-1,2,3-***-4-基,
1-甲基-1H-1,2,4-***-3-基,
2-甲基-2H-1,2,4-***-3-基,
4-(2-羟基乙基)-4H-1,2,4-***-3-基,
4-甲基-4H-1,2,4-***-3-基,
3-(2-氨基-1,3,4-噁二唑-5-基)-5-甲基-4H-1,2,4-***-4-基,
3-苄基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-苄氧基甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-溴-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(3-羧基丙-1-基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(2-羧基吡啶-5-基)-5-甲氧基甲基-4H-1,2,4-***-4-基,
3-(2-氯苯基)-5-甲氧基甲基-4H-1,2,4-***-4-基,
3-(2-氯苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(3-氯苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(4-氯苯基)-5-甲基-4H-1,2,4-***-4基,
3-(4-氯苯磺酰基甲基)-5-甲基-4H-1,2,4-***-4-基,
3-环己基甲氧基甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-环戊基甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-环丙基-5-甲基-4H-1,2,4-***-4-基,
3,5-二(甲氧甲基)-4H-1,2,4-***-4-基,
3-(N,N-二甲氨基甲基)-5-乙基-4H-1,2,4-***-4-基,
3-(N,N-二甲氨基甲基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(4-二甲氨基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(1,5-二甲基-1H-吡唑-3-基)-5-甲氧甲基-4H-1,2,4-***-4-基,
3-(1,5-二甲基-1H-吡唑-3-基)-5-甲基-4H-1,2,4-***-4-基,
3,5-二甲基-4H-1,2,4-***-4-基,
3,5-二苯基-4H-1,2,4-***-4-基,
3-(2-乙氧基乙基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-乙氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-乙氧羰基-4H-1,2,4-***-4-基,
3-乙基-5-(2-氯苯基)-4H-1,2,4-***-4-基,
3-乙基-5-(2-甲氧基苯基)-4H-1,2,4-***-4-基,
3-乙基-5-(1-甲基吡唑-5-基)-4H-1,2,4-***-4-基,
3-乙基-5-甲基-4H-1,2,4-***-4-基,
3-乙基-5-吗啉代甲基-4H-1,2,4-***-4-基,
3-乙基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-乙基-4H-1,2,4-***-4-基,
3-(2-羟基乙基)-5-甲基-4H-1,2,4-***-4-基,
3-羟甲基-5-甲基-4H-1,2,4-***-4-基,
3-羟甲基-5-苯基-4H-1,2,4-***-4-基,
3-羟甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-羟甲基-4H-1,2,4-***-4-基,
3-羟基-5-甲基-4H-1,2,4-***-4-基,
3-(2-羟基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(1H-咪唑-1-基)-5-甲基-4H-1,2,4-***-4-基,
3-(2-甲氧基乙基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(1-甲基-1H-吡唑-5-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(2-甲基吡啶-5-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(2-甲基噻唑-4-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(1-氧化吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(1-苯基咪唑-4-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(5-苯基吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(2-苯基吡啶-5-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(喹啉-3-基)-4H-1,2,4-***-4-基,
3-甲氧基甲基-5-(喹啉-6-基)-4H-1,2,4-***-4-基,
3-(2-甲氧基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(3-甲氧基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(4-甲氧基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基咪唑-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基咪唑-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基咪唑-5-基)-4H-1,2,4-***-4-基,
3-(3-甲基异噻唑-4-基)-5-甲基-4H-1,2,4-***-4-基,
3-甲基-5-(4-甲基-1H-咪唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(3-甲基-1,2,4-噁二唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基吡啶-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基吡唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(5-甲基-1H-吡唑-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基苯基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基吡咯-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(4-甲基-1,2,3-噻二唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基噻唑-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基-1H-1,2,4-***-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基-1H-吡唑-4-基)-4H-1,2,4-***-4-基,
3-(3-甲基-1,2,4-噁二唑-5-基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-苯基-4H-1,2,4-***-4-基,
3-甲基-5-(3-[丙-1-基]-1H-吡唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡嗪-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1H-吡唑-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,3-甲基-5-(吡啶-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-2-基甲基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-4-基甲基)-4H-1,2,4-***-4-基,
3-甲基-5-(哒嗪-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(嘧啶-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(噻吩-2-基)-4H-1,2,4-***-4-基,
3-甲基-4H-1,2,4-***-4-基,
3-甲基-5-(1H-1,2,3-***-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1H-1,2,4-***-5-基)-4H-1,2,4-***-4-基,
3-吗啉代甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-苯氧基甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(2-苯基乙基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(吡啶-3-基)-5-(2,2,2-三氟乙氧基)甲基-4H-1,2,4-***-4-基,
3-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(4-三氟甲基苯基)-4H-1,2,4-***-4-基,
1-烯丙基四唑-5-基,
1-苄基四唑-5-基,
1-羧甲基四唑-5-基,
1-环己基四唑-5-基,
1-乙基四唑-5-基,
1-(2-羟基乙基)四唑-5-基,
1-(3-羟基丙基)四唑-5-基,
1-甲氧羰基甲基四唑-5-基,
1-(2-甲氧基乙基)四唑-5-基,
1-甲基四唑-5-基,
1-(2-苯基乙基)四唑-5-基,
1-苯基四唑-5-基,
1-(丙-2-基)四唑-5-基,
1-(2,2,2-三氟乙基)四唑-5-基,
吡啶-2-基,
吡啶-3-基,
吡啶-4-基,
嘧啶-2-基,和
嘧啶-5-基。
最优选的R为:
1-(3-羟基丙基)四唑-5-基,
4-甲基-4H-1,2,4-噻唑-3-基,
1-(2-羟基乙基)-5-苯基-1,2,3-***-4-基,
3-甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(喹啉-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(喹啉-6-基)-4H-1,2,4-***-4-基,
或3-(1,5-二甲基-1H-吡唑-3-基)-5-甲基-4H-1,2,4-***-4-基。
优选R1和R2各自独立选自氯和C1-C4烷基,尤其是甲基或乙基。
最优选R1和R2各自为氯。
优选R3和R4各自独立选自H和C1-C4烷基。
最优选R3和R4各自为甲基。
优选“芳基”表示任选被1或2个各自独立选自甲基、甲氧基、羟基、氯、三氟甲基和二甲氨基的取代基取代的苯基。
“芳基”的实例包括2-氯苯基,3-氯苯基,4-氯苯基,4-二甲氨基苯基,2-羟基苯基,2-甲氧基苯基,3-甲氧基苯基,4-甲氧基苯基,2-甲基苯基,苯基和4-三氟甲基苯基。
优选“het”表示噻吩基,吡咯基,吡唑基,咪唑基,***基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,它们各自为任选苯并稠合的,并且被1或2个各自独立选自C1-C4烷基,-COOH,-NR3R4和苯基的取代基任选取代,和/或所述吡啶基、哒嗪基、嘧啶基或吡嗪基的环氮杂原子被氧取代基任选取代。
“het”的实例包括噻吩-2-基,1-甲基吡咯-2-基,1H-吡唑-4-基,1-甲基-1H-吡咯-4-基,5-甲基-1H-吡唑-3-基,1-甲基-1H-吡唑-5-基,1,5-二甲基-1H-吡唑-3-基,3-(丙-1-基)-1H-吡唑-5-基,1H-咪唑-1-基,1-甲基咪唑-2-基,1-甲基咪唑-4-基,1-甲基咪唑-5-基,4-甲基-1H-咪唑-5-基,1-苯基咪唑-4-基,1H-1,2,3-***-5-基,1H-1,2,4-***-5-基,1-甲基-1H-1,2,4-***-5-基,2-甲基噻唑-4-基,3-甲基异噻唑-4-基,2-氨基-1,3,4-噁二唑-5-基,3-甲基-1,2,4-噁二唑-5-就,4-甲基-1,2,3-噻二唑-5-基,吡啶-2-基,吡啶-3-基,吡啶-4-基,2-甲基吡啶-3-基,2-甲基吡啶-5-基,1-氧化吡啶-3-基,2-羧基吡啶-5-基,5-苯基吡啶-3-基,2-苯基吡啶-5-基,哒嗪-4-基,嘧啶-2-基,吡嗪-2-基,喹啉-3-基和喹啉-6-基。
式(Ⅰ)化合物的可药用盐包括其酸加成盐和碱式盐。
适宜的酸加成盐由能形成无毒盐的酸形成,其实例包括盐酸盐,氢溴酸盐,硫酸盐,硫酸氢盐,硝酸盐,磷酸盐,磷酸氢盐,乙酸盐,马来酸盐,富马酸盐,乳酸盐,酒石酸盐、柠檬酸盐,葡糖酸盐,琥珀酸盐,苯甲酸盐,甲磺酸盐,苯磺酸盐和对-甲苯磺酸盐。
适宜的碱式盐由能形成无毒盐的碱形成,其实例包括钙、锂、镁、钾、钠、锌、乙醇胺、二乙醇胺和三乙醇胺盐。
有关适宜盐的评述,请参见Berge等人的药物科学杂志(J.Pharm.Sci.),66,1-19(1977)。
式(Ⅰ)化合物可含有一个或多个不对称碳原子,因此可能以两个或多个立体异构体形式存在,或者它们可能以互变异构体形式存在。本发明包括式(Ⅰ)化合物的单一立体异构体和互变异构体以及它们的混合物。
式(Ⅰ)化合物或其合适的盐或衍生物的立体异构体混合物的非对映体分离可采用常规技术完成,例如通过分级结晶,层析或HPLC完成。式(Ⅰ)化合物的单一对映体还可以由相应的光学纯中间体制备,或者通过采用合适的手性载体经例如HPLC技术拆分相应的外消旋体制备,还可以通过分级结晶相应的外消旋体与适宜的光活性酸或碱反应所形成的非对映体盐制备。
某些式(Ⅰ)化合物可以以称作阻转异构体的特定立体异构体形式存在。阻转异构体是可分离的异构体,这只是因为围绕单键的旋转受到限制或被大大减慢(参见《高级有机化学》“Advanced Organic Chemistry”,第三版,Jerry March,John Wiley and Sons(1985))。它们可以采用诸如上段所述的常规方法分离。本发明包括式(Ⅰ)化合物的单一阻转异构体及其混合物。
式(Ⅰ)化合物的优选实例为这些化合物,其中;(ⅰ)R为1-(3-羟基丙基)四唑-5-基,R1为氯和R2为氯;(ⅱ)R为4-甲基-4H-1,2,4-***-3-基,R1为氯和R2为氯;(ⅲ)R为1-(2-羟基乙基)-5-苯基-1,2,3-***-4-
基,R1为氯和R2为氯;(ⅳ)R为3-甲基-5-(吡啶-3-基)-4H-1,2,4-***
-4-基,R1为氯和R2为氯;(ⅴ)R为3-甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,R1为氯和R2为氯;(ⅵ)R为3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-
***-4-基,R1为氯和R2为氯;(ⅶ)R为3-(1,5-二甲基-1H-吡唑-3-基)-5-甲基-
4H-1,2,4-***-4-基,R1为氯和R2为氯;(ⅷ)R为3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-
***-4-基,R1为氯和R2为甲基;(ⅸ)R为3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-
***-4-基,R1为甲基和R2为氯;(ⅹ)R为3-甲氧甲基-5-(喹啉-3-基)-4H-1,2,4-三
唑-4-基,R1为氯和R2为氯,或(ⅹⅰ)R为3-甲氧甲基-5-(喹啉-6-基)-4H-1,2,4-
***-4-基,R1为氯和R2为氯;
或任一这些化合物的单一立体异构体或可药用盐。
特别优选的式(Ⅰ)化合物包括:(ⅰ)R-(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮或其可药用盐,和(ⅱ)R-(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮的钠盐。
所有式(Ⅰ)化合物都可以通过用酸或碱水解式(Ⅱ)化合物制备:其中R,R1和R2的定义同上式(Ⅰ)化合物,R5和R6独自或一起代表在酸性或碱性条件下能水解断裂以得到式(Ⅰ)喹喔啉二酮的基团。这类基团为常规基团,其合适实例也是专业人员所公知的。
优选R5和R6各自独立选自C1-C4烷基(优选甲基或乙基)和其环上任选被1-3个彼此独立选自C1-C4烷基,C1-C4烷氧基,卤素,硝基和三氟甲基的取代基取代的苄基;或者它们一起代表C1-C6亚烷基,CH(苯基),CH(4-甲氧基苯基)或CH(3,4-二甲氧基苯基)。
优选通过酸解式(Ⅱ)化合物来进行上述反应。
在典型的方法中,式(Ⅱ)化合物是任选地在适宜的有机共溶剂如1,4-二噁烷存在下用合适的酸如无机酸(象盐酸)水溶液加以处理。反应通常是通过在高至溶剂的回流温度下加热混合物完成。
式(Ⅱ)中间体可以采用例如下文所述的各种常规方法制备。(a)其中R为取代四唑-5-基的式(Ⅱ)化合物可按照反应路线Ⅰ中所示的路线制备:反应路线Ⅰ其中R1,R3,R5和R6的定义同上式(Ⅱ)化合物,且RC为如上面式(Ⅰ)化合物中R基团部分所述的适宜取代基。
在典型的方法中,首先是在适宜溶剂(如四氢呋喃)中,用适当的碱(如二异丙基氨化锂)脱保护式(Ⅲ)化合物,随后将所得阴碳离子用二氧化碳处理。然后在合适溶剂(如二氯甲烷)中,使用草酰氯和催化量N,N-二甲基甲酰胺将所得的式(Ⅳ)羧酸转化成相应的酰氯,进而用下式胺就地处理转化为式(Ⅴ)仲酰胺:
RCNH2.
将式(Ⅴ)酰胺首先用五氯化磷在合适溶剂(如甲苯)中处理,进而将所得中间体与叠氮三甲基甲硅烷就地反应,制备式(ⅡA)化合物。(b)式(Ⅱ)中R为通过环碳原子连接于喹喔啉环的任选苯并稠合/取代5-或6-元环杂芳基的化合物可按反应路线Ⅱ中所示的路线制备:反应路线Ⅱ其中,R1,R2,R5和R6的定义同上式(Ⅱ)化合物,且RD为如上式(Ⅰ)化合物中R基团部分所述的任选苯并稠合/取代的5-或6-元环杂芳基,该基团通过环碳原子连接于喹喔啉。
在典型的方法中,首先是按上面方法(a)所述脱保护式(Ⅲ)化合物,接着就地用硼酸三甲酯处理,继之在后处理过程中加酸水解,得到式(Ⅵ)硼酸;随后将这一化合物在适当催化剂(如四(三苯膦)合钯(O))存在下于适当条件下与下式化合物反应:
RDX其中X为溴,碘,或三氟甲磺酰氧基,而RD的定义则同上,从而得到式(ⅡB)化合物。(c)其中R为任选4-取代的-4H-1,2,4-***-3-基的式(Ⅱ)化合物的制备如下:首先在适宜溶剂(如甲苯)中用五氯化磷处理式(Ⅴ)化合物,继之在适当碱(如三乙胺)存在下,使所得的中间体就地与甲酰肼反应。(d)其中R为1-或2-(任选取代的C1-C4烷基)-取代的-1,2,4-***-3-基的式(Ⅱ)化合物的制备如下:用N,N-二(C1-C4烷基)甲酰胺缩二(C1-C4烷基醇)(优选N,N-二甲基甲酰胺缩二甲醇)处理其中RC为H的式(Ⅴ)化合物,然后在适当酸(如乙酸)存在下使所得中间体甲脒与肼反应,随后先在适当溶剂(如N,N-二甲基甲酰胺)中用适当碱(如氢化钠)处理所得的5-(1H-和2H-1,2,4-***-3-基)-取代喹啉的互变混合物,继之再用合适的任选取代C1-C4烷基卤处理(如用碘甲烷处理以制备N-甲基-取代产物)。
所得的1-和2-(任选取代C1-C4烷基)-取代的-1,2,4-***-3-基产物混合物可采用常规方法(如层析法)分离。(e)其中R为任选取代1,2,4-***-4-基的式(Ⅱ)化合物可按反应路线Ⅲ中所示的路线制备:反应路线Ⅲ其中R1,R2,R5和R6的定义同上式(Ⅱ)化合物,RA和RB各自独立为H或为如上式(Ⅰ)化合物中R部分所述的适宜取代基。
在典型的方法中,式(Ⅶ)的5-氨基喹喔啉是在适当溶剂(如甲苯或二氯甲烷)中,任选地在适宜酸受体(如吡啶)存在下与下式化合物反应,以得到式(Ⅷ)酰胺:
RACOX1其中X1为合适的离去基团,如氯或溴。
式(Ⅷ)酰胺通过在适宜溶剂(如甲苯或四氢呋喃)中,用2,4-双(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂丁环-2,4-二硫化物(Lawesson试剂)处理,可转化为式(Ⅸ)硫代酰胺。
式(Ⅸ)硫代酰胺可按下所述转化为式(ⅡC)化合物:在***(Ⅱ)、任选的分子筛(如4A分子筛),和适宜溶剂(如正丁醇)存在下用下式化合物处理:
RBCONHNH2(f)式(Ⅱ)中R为通过环碳原子连接于喹喔啉环的任选苯并稠合/取代5-或6-元环杂芳基的化合物可如下制备:在适宜催化剂如四(三苯膦)合钯(O)存在下,于适宜条件下将下式化合物:其中R1,R2,R5和R6的定义同上式(Ⅱ)化合物,与式REX2化合物偶联,其中X2为Sn(C1-C4烷基)3,ZnCl,ZnBr,ZnI或-B(OH)2,RE的定义同本方法中的R。(g)其中R为任选取代1,2,3-***-4-基的式(Ⅱ)化合物可按照反应路线Ⅳ所示路线制备:反应路线Ⅳ其中R1,R2,R5和R6的定义同上式(Ⅱ)化合物,RF为H,或者RF和RG各自独立代表如上式(Ⅰ)化合物中R基团部分所述的适宜取代基。
在典型方法中,是将式(X)5-碘喹喔啉化合物在适宜条件下(如采用双(三苯膦)氯化钯(Ⅱ),碘化铜(Ⅰ)和三乙胺)与下式乙炔化物偶合:
RF-C≡CH然后将所制得的式(Ⅺ)化合物与叠氮三甲基甲硅烷反应,得到式(ⅡD)化合物,进而采用常规方法将其转化为式(ⅡE)化合物,例如,当RG为C1-C4烷基时,可通过先用适宜碱(如氢化钠)脱质子化式(ⅡD)化合物,继之再与C1-C4烷基卤(如碘甲烷)反应来进行上述转化。如果得到的为式(ⅡE)化合物的1-,2-和3-取代-1,2,3-***-4-基异构体混合物,则这些化合物可采用常规方法(如色谱法)加以分离。
应当认识到,采用常规方法如官能团互变技术,可以将某些式(Ⅰ)或(Ⅱ)化合物转化为相应的其它式(Ⅰ)或(Ⅱ)化合物。
所有上述反应和前述方法中所用的新起始物质的制备都为常规反应,而且其实施或制备以及分离所需产物步骤中用的适当试剂和反应条件通过参考以前的文献和本文中的实施例和制备例也为本领域技术人员所公知的。
如果适当的话,式(Ⅰ)化合物的可药用酸加成盐或碱式盐可以很容易地通过一同混合式(Ⅰ)化合物溶液和所需的酸或碱而制得。盐可从溶液中沉淀出并通过过滤收集,或者通过蒸发溶剂方式回收。
按照英国药学杂志(Brit.J.Pharm.),104,74(1991)所述,通过测试式(Ⅰ)化合物及其盐从大鼠脑膜上置换选择性甘氨酸位点放射性配体的能力,测定它们对NMDA受体的甘氨酸位点的结合亲和性。在这一方法的变更方法中,使用tris-乙酸盐缓冲液(pH7.4)将充分洗涤的膜蛋白与[3H]-L-689,560一起温育90分钟(Mol.Pharmacol.,41,923(1992))。使用一定浓度范围的受试化合物取代放射性配体,以求出IC50(50%抑制浓度)值。
按照J.Med.Chem.,33,789(1990)和Brit.J.Pharm.,84,381(1985)中所述的类似方法,根据化合物抑制NMDA诱导的大鼠脑皮质切片中去极化作用的能力检测体外功能性NMDA拮抗作用。在该方法的变型方法中,在一系列浓度受试化合物存在下测定对标准浓度NMDA的反应,并利用所得结果求出EC50(50%有效浓度)值。
通过测试本发明化合物从大鼠脑膜上置换放射性配体[3H]-AMPA的能力,测定它们对AMPA受体的结合亲和性。在有或无各种浓度受试化合物存在下,将膜匀浆物与放射性配体(10nM)在4℃保温45分钟。通过快速过滤分离游离和结合的放射性标记物,并利用液体闪烁计数法测定放射活性。
式(Ⅰ)化合物及其盐可以单独施用于受治疗者,但通常是以与可药用稀释剂或载体形成的混合物形式施用,其中的稀释剂或载体根据预定施用途径和标准药物实践选定。例如,它们可以以包含诸如淀粉或乳糖之类赋形剂的片剂、单独或与赋形剂混合制成的胶囊或卵状体形式,或以包含调味剂或着色剂的酏剂、溶液或悬浮液形式经口(包括舌下)施用。它们也可以通过肠胃外(例如静脉内、肌内或皮下)途径注射施用。对于肠胃外施用,它们最好以无菌水溶液形式使用,这种水溶液中可含有其它物质,例如足量盐或葡萄糖以使溶液与血液保持等渗。
本发明化合物具有通过胃肠道吸收的潜力,因此还可以以缓释制剂形式施用。
一般地,式(Ⅰ)化合物及其盐的治疗活性日剂量大约为每千克受治疗者体重0.1-100mg,优选1-20mg/kg,静脉内给药的日剂量大约为每千克受治疗者0.01-20mg,优选0.1-20mg/kg。式(Ⅰ)化合物及其盐还可以通过静脉输注施用,其剂量为大约0.01-10mg/kg/hr。
合适的话,每次可施用单片(粒)或两片(粒)或更多片(粒)本发明化合物的片剂或胶囊剂。
最适合特定患者的有效剂量将由主治医师确定,并随具体病人的年龄、体重和对药物的反应而变化。上述剂量为平均情形下的典型剂量。当然存在着需要更高或更低剂量范围的特殊病例,并且这些剂量也都在本发明范围在内。
另一方面,式(Ⅰ)化合物还可以通过吸入方式施用,或以栓剂或***栓形式施用,或者它们可以以洗剂、溶液、油膏或粉剂形式局部施用。另一种经皮施用方式为使用皮肤斑贴。例如,本发明化合物可以掺入到由聚乙二醇或液体石蜡的水乳液形成的乳油内。它们还可以以1-10wt.%浓度掺入到由白蜡或白凡士林基质以及可能需要的稳定剂和防腐剂构成的软膏内。
应当理解,治疗包括预防和缓解所述疾病的确定症状。
因此,本发明进一步提供了:ⅰ)一种药物组合物,它包括式(Ⅰ)化合物或其可药用盐以及可药用稀释剂或载体;ⅱ)用作药物的式(Ⅰ)化合物或其可药用盐或其组合物;ⅲ)式(Ⅰ)化合物,或其可药用盐或其组合物在制备通过在NMDA受体上产生拮抗作用而治疗疾病的药物中的应用;ⅳ)如(ⅲ)中所述的应用,其中所述的疾病为急性神经变性或慢性神经病学病症;ⅴ)通过在NMDA受体上产生拮抗作用来治疗哺乳动物疾病的方法,该方法包括用有效量的式(Ⅰ)化合物或其可药用盐或其组合物处理所述哺乳动物;ⅵ)如(ⅴ)中所述的方法,其中所述疾病为急性神经变性或慢性神经病学病症;和ⅶ)式(Ⅱ)化合物。
下列实施例和制备例用于说明式(Ⅰ)化合物及其合成中所用中间体的制备。
熔点采用Buchi装置在玻璃毛细管中测量,且未经校正。低分辨质谱(LRMS)数值用Fisons Trio 1000质谱仪记录(热喷雾法,采用乙酸铵/甲醇水溶液作为载体;或常压化学电离法,采用体积比为97.5∶2.5的甲醇∶乙酸,并使用氮气作为载气)。NMR数值采用Bruker AC300或Varian Unity 300 NMR仪(均为300MHz)或UNity inova-400(400MHz)仪记录,并与所确定的结构一致。快速色谱使用购自E.Merck,Darmstadt的Kieselgel 60(230-400目)进行,薄层色谱(TLC)则使用购自E.Merck的Kieselgel 60 F254板,并使用UV光或氯铂酸/碘化钾溶液显色化合物。当分析化合物为水合物时,水的存在可由质子NMR谱中出现的水的强峰而证实。化合物的纯度采用分析性TLC和质子NMR(300MHz)精心测定,而且后一技术还可用于计算溶剂化样品中的溶剂含量。在多步骤系列中,中间体的纯度和结构采用质子NMR通过光谱法确定。质子NMR位移以距四甲基硅烷的百万分之几低磁场表示。
实施例和制备例中使用了本领域技术人员熟悉的某些缩写词。
实施例16,7-二氯-5-(4-吡啶基)-2,3(1H,4H)-喹喔啉二
将6,7-二氯-2,3-二甲氧基-5-(4-吡啶基)喹喔啉(制备例2,110mg,0.327mmol),2M盐酸水溶液(1ml)和1,4-二噁烷(7ml)的混合物加热回流2小时,冷却,并减压浓缩。所得固体残渣用水研制,过滤收集并用水和***洗涤,得到标题化合物(17mg,17%),为白色固体,mp>300℃。m/z(热喷雾法)308(MH+).元素分析(%):实测值:C,49.58;H,2.36;N,12.93.C13H7Cl2N3O2.0.5H2O计算值:C,49.24;H,2.54;N,13.25.
实施例2-107
按照实施例1的类似方法,制备如下通式:的下列表示实施例,其中使用所示的相应2,3-二甲氧基喹喔啉衍生物,而且反应时间是指通过TLC检测确定起始物质完全耗尽所需的大约时间。在实施例8,82和84中,伴随有酯水解反应发生,而在实施例104-106中,三苯甲基则被裂解。
表1 附注1)反应如实施例1所述进行,但系在50℃反应9小时。粗产物采用硅胶快速色谱纯化,先用95∶5(v/v)二氯甲烷∶甲醇洗脱,然后用80∶20∶1(体积比)二氯甲烷∶甲醇∶乙酸洗脱。2)将所得固体溶于热水(4mL),冷却至0℃,过滤收集。3)所得产物为橙色油,将其溶于蒸馏水(4ml)并冻干。4)起始物质采用与制备例27类似的方法制备,酰肼中间体则按照制备例27中所述的类似方法制备。
实施例1086,7-二氯-5-(1-甲氧羰基甲基四唑-5-基)-
氮气氛下,将6,7-二氯-5-(1-羧甲基四唑-5-基)-2,3(1H,4H)-喹喔啉二酮(实施例8,42mg,0.12mmol)在饱和甲醇合氯化氢(5ml)的溶液加热回流2天。减压浓缩反应混合物,将残留物分配到水(10ml)和二氯甲烷(10ml)之内。分离水相并用二氯甲烷(2×25ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物用***研制,过滤后得到标题化合物(24mg,55%),为浅灰色固体,mp281-283℃。1H-NMR(300MHz,DMSO-d6):δ=3.60(3H,s),5.32(2H,m),7.44(1H,s),11.60(1H,brs),1.212(1H,brs).m/z(热喷雾法)371(MH+).
实施例109
6-氯-7-甲基-5-[5-甲氧甲基-3-(3-吡啶基)-
按照实施例1所述的类似方法,采用6-氯-2,3-二甲氧基-7-甲基-5-[5-甲氧基甲基-3-(吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例114)代替6,7-二氯-2,3-二甲氧基-5-(4-吡啶基)喹喔啉来制备标题化合物。将浓缩反应混合物后得到的残留物溶于1M氢氧化钠水溶液,利用2M盐酸水溶液调节混合物的pH至6,然后冷却至0℃。过滤收集所形成的固体,水洗,得到灰白色固体,mp229-231℃.元素分析(%):实测值:C,51.33;H,4.16;N,19.99.C18H15ClN6O3.0.25H2O计算值:C,51.31;H,4.19;N,19.95.
实施例110
7-氯-6-甲基-5-[5-甲氧甲基-3-(3-吡啶基)-
4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮
标题化合物按照实施例1所述的类似方法采用7-氯-2,3-二甲氧基-6-甲基-5-[5-甲氧基甲基-3-(吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例115)代替6,7-二氯-2,3-二甲氧基-5-(4-吡啶基)喹喔啉制备。将浓缩反应混合物后得到的残留物溶于1M氢氧化钠水溶液,利用2M盐酸水溶液调节混合物的pH至6,然后冷却至0℃。过滤收集所形成的固体,水洗,得到浅黄色固体,mp>300℃.m/z(热喷雾法)399(MH+).元素分析(%):实测值:C,52.60;H,3.91;N,20.34.C18H15ClN6O3.0.75H2O计算值:C,52.43;H,4.03;N,20.38.
实施例111
(+)-,(-)-和(+)-6,7-二氯-5-[3-甲氧甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(a)室温、氮气氛及搅拌下,在5-氨基-6,7-二氯-2,3-二甲氧基喹喔啉(制备例26,73.8g,0.27mol)和吡啶(26.4ml,25.8g,0.33mol)的二氯甲烷(1.2L)混合物内加入甲氧基乙酰氯(27.3mL,32.4g,0.30mol)。室温下搅拌18小时后,依次用2M盐酸水溶液和盐水洗涤混合物,随后干燥(MgSO4)并减压浓缩。残留物用甲醇研制,过滤后得到6,7-二氯-2,3-二甲氧基-5-甲氧基乙酰氨基喹喔啉(82.0g,88%),为灰白色固体,mp171-173℃。元素分析(%):实测值:C,44.97;H,3.75;N,12.03.C13H13Cl2N3O4计算值C,45.11;H,3.79;N,12.14.(b)在6,7-二氯-2,3-二甲氧基-5-甲氧基乙酰氨基喹喔啉(27g,78mmol)的四氢呋喃(480mL)溶液中加入2,4-双(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂丁环-2,4-二硫化物(Lawesson试剂)(19.5g,48.2mmol),并将混合物在室温下搅拌18小时,然后减压蒸发。残留物通过硅胶快速色谱纯化,使用己烷∶二氯甲烷(1∶1→1∶4,体积比)作为洗脱剂进行梯度洗脱,得到6,7-二氯-2,3-二甲氧基-5-甲氧基硫代乙酰氨基喹喔啉(29.1g,>100%),为白色固体,mp198-200℃,含有少量杂质。元素分析(%):实测值:C,43.06;H,3.65;N,11.59.C13H13Cl2N3O3S计算值:C,43.11;H,3.62;N,11.60.(c)将6,7-二氯-2,3-二甲氧基-5-甲氧基硫代乙酰氨基喹喔啉(25.3g,69.9mmol),烟酸酰肼(19.3g,140.8mmol),***(Ⅱ)(15.1g,69.7mmol)和1,4-二噁烷(600ml)的混合物加热回流18小时。冷却之后,通过ARBOCEL(商品名)助滤剂过滤,残留物用二氯甲烷洗涤。减压浓缩滤液,得到亮棕色固体,并将其分配到乙酸乙酯和2M盐酸水溶液内。分层,将水层用二氯甲烷(2×500mL,4×100mL)提取,干燥(MgSO4)并减压浓缩合并的二氯甲烷提取液。残留物用乙酸乙酯/甲醇重结晶,得到(±)-6,7-二氯-2,3-二甲氧基-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(11.6g,37%),为浅黄色固体,mp189-191℃.元素分析(%):实测值:C,50.10;H,3.57;N,18.53.C19H16Cl2N6O3.0.5H2O计算值:C,50.01;H,3.76;N,18.42.(d)将(±)-6,7-二氯-2,3-二甲氧基-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(3.0g,6.7mmol),2M盐酸水溶液(10mL)与1,4-二噁烷(50ml)的混合物加热回流9小时,冷却并减压浓缩。残留物溶于1M氢氧化钠水溶液,用浓盐酸酸化至pH4.5,得到白色粘稠沉淀物,进而过滤收集并水洗,得到(±)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(2.0g,68%),为灰白色固体,mp230-232℃.元素分析(%):实测值:C,46.23;H,2.93;N,19.00.C17H12Cl2N6O3.1.25H2O计算值:C,46.22;H,3.31;N,19.02.(e)(ⅰ)室温、搅拌下,向(±)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(1.9g,4.3mmol)的乙酸乙酯(400mL)悬浮液内先后加入(-)-N-甲基麻黄碱(0.88g,4.9mmol)和甲醇(66mL)。将混合物加热至其沸点。过滤混合物,浓缩滤液至其体积的3/4,然后冷却至室温。过滤收集所得固体,用乙酸乙酯洗涤。固体用乙酸乙酯/甲醇结晶,得到喹喔啉二酮起始物质的单一非对映体,系(-)-N-结晶麻黄碱盐(1.28g,43%),mp162-164℃。元素分析(%):实测值:C,55.74;H,5.38;N,14.38.C28H29Cl2N7O4.CH3CO2C2H5计算值:C,55.98;H,5.43;N,14.28.[α]25D-135°(c=0.1,乙醇).(ⅱ)将(e)(ⅰ)部分的(-)-N-甲基麻黄碱盐(1.2g,1.7mmol)的水(13ml)悬浮液在室温下用浓盐酸酸化至pH5,并搅拌悬浮液1小时。过滤收集所得固体,水洗并用水/乙醇结晶,得到(-)-6,7-二氯-5-[3-甲氧甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(0.48g,62%),为白色固体,mp220-222℃.元素分析(%):实测值:C,45.49;H,3.21;N,18.72.C17H12Cl2N6O3.1.5H2O计算值:C,45.76;H,3.39;N,18.83.[α]25D-214°(c=0.1,乙醇).(ⅲ)合并(e)(ⅰ)部分的滤液,浓缩至干。将残留物溶于水(20mL),用浓盐酸酸化至pH3,过滤收集所得固体,水洗并干燥。室温、搅拌下,向此固体(0.80g,1.87mmol)的乙酸乙酯(170mL)悬浮液中依次加入(+)-N-甲基麻黄碱(0.37g,2.06mmol)和甲醇(28ml),并加热混合物至其沸点。过滤混合物,浓缩至其体积的3/4,然后冷却至室温。过滤收集所得固体,用乙酸乙酯洗涤。固体用乙酸乙酯/甲醇结晶,得到喹喔啉二酮起始物质的单一非对映体,系(+)-N-结晶麻黄碱盐(0.93g,32%),mp165-167℃。元素分析(%):实测值:C,55.88;H,5.40;N,14.31.C28H29Cl2N7O4.0.8CH3CO2C2H5计算值:C,56.01;H,5.33;N,14.66.[α]25D+127°(c=0.1,乙醇).(ⅳ)将(e)(ⅲ)部分的(+)-N-甲基麻黄碱盐(0.90g,1.35mmol)的水(10ml)悬液在室温下用浓盐酸酸化至pH5,并搅拌悬浮液1小时。过滤收集所得固体并水洗,得到(+)-6,7-二氯-5-[3-甲氧甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(0.41g,69%),为白色固体,mp222-224℃.元素分析(%):实测值:C,46.44;H,3.18;N,19.01.C17H12Cl2N6O3.1.25H2O计算值:C,46.22;H,3.31;N,19.02.[α]25D+212°(c=0.1,乙醇).
实施例112
6-氯-7-乙基-5-[3-甲氧甲基-5-(3-吡啶基)-
4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮
按照实施例109的类似方法,利用上面所示的起始物质制备标题化合物(其中起始物质采用与制备例113,步骤(c),(d)和(e),制备例114和制备例115中所述的类似方法由6-氯-7-乙基-5-硝基-2,3(1H,4H)-喹喔啉二酮(参见WO-A-95/12417)制得)。分离得到黄色泡沫体。元素分析(%):实测值:C,48.68;H,4.18;N,17.60.C19H17N6O3Cl.HCl.H2O计算值:C,48.83;H,4.31;N,17.98.m/z(热喷雾法)413.0(MH+).
实施例113
7-氯-6-乙基-5-[3-甲氧甲基-5-(3-吡啶基)-
按照实施例109的类似方法,利用上面所示的起始物质制备标题化合物(其中起始物质采用与制备例113,步骤(c),(d)和(e),制备例114和制备例115中所述的类似方法由7-氯-6-乙基-5-硝基-2,3(1H,4H)-喹喔啉二酮(参见WO-A-95/12417)制备)。分离得到黄色泡沫体。元素分析(%):实测值:C,46.28;H,4.17;N,16.70.C19H17N6O3Cl.2HCl.1/3H2O计算值:C,46.41;H,4.03;N,17.09.m/z(热喷雾法)413.0(MH+).
实施例114
(-)-6,7-二氯-5-[3-甲氧甲基-5-(1-氧化吡啶-3-基)-4H-
1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮
将3-氯过苯甲酸(0.85g,4.93mmol)的丙酮(20ml)溶液一次性加到(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(参见实施例111)(1.0g,2.24mmol)的丙酮(40ml)悬浮液内,从而使得所有固体都溶解。室温下搅拌反应40分钟,随后有白色固体开始形成,然后在室温下搅拌反应混合物3天。过滤收集白色固体,并通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇∶冰乙酸(90∶10∶1,体积比)为洗脱剂,合并并浓缩适当部分,得到标题化合物(0.16g,17%),为白色固体,m.p.>310℃.[α]25D-235°(c=1.0,乙醇).
实施例115-129
按照实施例1的类似方法制备下述通式:的下列表示实施例,其中使用相应2,3-二甲氧基喹喔啉衍生物,而且反应时间是指通过TLC检测确定起始物质完全耗尽所需的大约时间。
实施例130
(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-
2,3(1H,4H)-喹喔啉二酮钠盐
搅拌下,在(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮(参见实施例111)(0.428g,0.959mmol)的水(10ml)悬浮液中加入氢氧化钠(0.959ml,1M水溶液,0.959mmol),并搅拌混合物0.5小时。过滤所得溶液并冻干滤液,得到白色固体标题化合物(0.43g,94%),mp260℃(分解)。元素分析(%):实测值:C,42.90;H,2.89;N,17.76.C17H11Cl2N6NaO3.1.5H2O计算值:C,42.78;H,3.17;N,17.61.[α]25D-228°(c=0.1,乙醇).
实施例131
(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-
2,3(1H,4H)-喹喔啉二酮钠盐的静脉制剂
采用(-)-6,7-二氯-5-[3-甲氧基甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮钠盐。1.5H2O(参见实施例130)(22.4mg/单位剂量),氯化钠(9.0mg/单位剂量)和注射用水(至1.0ml),制备适合静脉内注射给药用的含20mg/ml活性成分的制剂。
为制备制剂,搅拌下将氯化钠在合适容器中溶于占水总体积量75%的水中,然后加入(-)-6,7-二氯-5-[3-甲氧甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮钠盐.1.5H2O并混合溶解。随后加水补加溶液至适当体积,通过干净的0.2微米滤器过滤。利用末端净化滤器,将滤液在无菌条件下填充到10ml无菌安瓿瓶内。下列制备例用于说明上述实施例中所用的一些中间体的合成。
制备例1
6,7-二氯-2,3-二甲氧基喹喔啉
室温、氮气氛及搅拌下,在2,3,6,7-四氯喹喔啉(106g,400mmol)的甲醇(1400mL)悬浮液中加入甲醇钠溶液(25%wt/v甲醇溶液,190mL,880mmol)。反应3天后,再加入甲醇钠溶液(25%wt/v甲醇溶液,40mL,190mmol),接着加入四氢呋喃(300mL)。加热回流反应混合物5分钟,冷却,减压浓缩至少量体积,倾入水(500mL)内。过滤收集沉淀物,水洗后得到粉红色固体标题化合物(97g,95%),mp144-146℃。1H-NMR(300MHz,CDCl3):δ=4.14(6H,s),7.88(2H,s).m/z(热喷雾法)259(MH+).
制备例2
6,7-二氯-2,3-二甲氧基-5-(4-吡啶基)喹喔啉(a)-78℃,氮气氛及搅拌下,向6,7-二氯-2,3-二甲氧基喹喔啉(制备例1,2.9g,7.72mmol)的无水四氢呋喃(150mL)悬浮液内加入二异丙基氨化锂单(四氢呋喃合物)(1.5M环己烷溶液,6.18mL,9.26mmol)。在-78℃反应1小时后,加入硼酸三甲酯(1.47ml,2.0g,19.3mmol)。进一步搅拌此溶液1小时,然后放置18小时使其升温至室温。加水(50mL),用2M盐酸水溶液酸化溶液至pH1,并用二氯甲烷(3×150mL)提取。干燥(MgSO4)合并的有机提取液,并减压浓缩。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(100∶0→99∶1,体积比)作为洗脱剂进行梯度洗脱,得到6,7-二氯-2,3-二甲氧基喹喔啉-5-硼酸(0.610g,26%),为浅棕色固体。1H-NMR(300MHz,DMSO-d6):δ=3.97(3H,s),4.02(3H,s),7.88(1H,s),8.50(2H,s).m/z(热喷雾法)303(MH+).(b)氮气氛下,将6,7-二氯-2,3-二甲氧基喹喔啉-5-硼酸(0.27g,0.89mmol),4-溴吡啶(0.14g,0.89mmol)和四(三苯膦)合钯(0)(0.031g,0.026mmol)在2M碳酸钠水溶液(1mL)、乙醇(0.5mL)和甲苯(10mL)混合液中的混合物加热回流24小时。冷却后,将混合物分配到水(20ml)和二氯甲烷(20ml)内。分离各相,并将水相用二氯甲烷(3×50ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液,得到的棕色固体用硅胶快速色谱纯化,使用己烷∶乙酸乙酯(3∶1,体积比)洗脱,得到米色固体标题化合物(0.113g,38%)。1H-NMR(300MHz,CDCl3):δ=3.80(3H,s),4.17(3H,s);7.30(2H,d,J=5Hz),7.97(1H,s),8.73(2H,d,J=5Hz).m/z(热喷雾法)336(MH+).
制备例3-5
制备例6
-78℃、氮气氛及搅拌下,向6,7-二氯-2,3-二甲氧基喹喔啉(制备例1,5.0g,19.3mmol)的无水四氢呋喃(150mL)悬浮液内加入二异丙基氨化锂单(四氢呋喃合物)(1.5M环己烷溶液,15.5mL,23.3mmol)。将反应混合物在这一温度下搅拌1小时,然后在-78℃下向溶液中通无水二氧化碳1小时。加入饱和氯化铵水溶液(80ml),并将所得混合物升温至室温,用2M盐酸水溶液酸化至pH1,再用乙酸乙酯(3×50ml)提取。然后将合并的有机提取液用1M氢氧化钠溶液提取。水溶液用2M盐酸水溶液酸化至pH1并用二氯甲烷(3×50mL)提取。干燥(MgSO4)并减压浓缩合并的二氯甲烷提取液,得到浅棕色固体标题化合物(4.0g,68%),mp 230-232℃.1H-NMR(300MHz,DMSO-d6):δ=3.98(3H,s),4.04(3H,s),8.02(1H,s),13.85(1H,brs).
制备例7
室温及氮气氛下,向6,7-二氯-2,3-二甲氧基喹喔啉-5-羧酸(制备例6,0.890g,2.93mmol)的二氯甲烷(25ml)溶液内加入无水N,N-二甲基甲酰胺(50μl,47.2mg,0.64mmol),接着加入草酰氯(0.338ml,3.8mmol)。0.5小时后,减压浓缩混合物。在氮气氛及室温下,向残留物中加入二氯甲烷(10ml),继之加入甲胺(33%w/w乙醇溶液,10mL,80.3mol)。反应10分钟后,减压蒸发混合物,并将残留物分配到二氯甲烷(20ml)和1M盐酸水溶液内。干燥(MgSO4)并减压蒸发有机提取液。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(100∶0→99∶1,体积比)作为洗脱剂进行梯度洗脱,得到的固体用甲苯重结晶,得到白色固体标题化合物(0.570g,61%).1H-NMR(300MHz,CDCl3):δ=3.11(3H,d,J=3Hz),4.10(3H,s),4.05(3H,s),5.87(1H,br d,J=3Hz),7.87(1H,s).m/z(热喷雾法).
制备例8
6,7-二氯-2,3-二甲氧基-5-(1-甲基-1H-四唑-5-基)喹喔啉
在6,7-二氯-2,3-二甲氧基-5-(N-甲基氨基甲酰基)喹喔啉(制备例7,0.197g,0.62mmol)的甲苯(7ml)溶液中加入五氯化磷(0.136g,0.65mmol),并将混合物在氮气氛下加热回流1小时。冷却反应至室温,加入叠氮三甲基硅烷(123μl,0.107g,0.93mmol)。室温下搅拌18小时后,加入稀氨水溶液(20ml),混合物用二氯甲烷(3×50ml)提取。合并有机提取液,干燥(MgSO4)并减压蒸发合并的有机提取液。残留物通过硅胶快速色谱纯化,使用二氯甲烷洗脱,得到白色固体标题化合物(0.080g,38%)。1H-NMR(300MHz,CDCl3):δ=3.84(3H,s),3.90(3H,s),4.14(3H,s),8.5(1H,s).m/z(热喷雾法)341(MH+).
制备例9-17
制备例18
6,7-二氯-2,3-二甲氧基-5-(N-烯丙基氨基甲酰基)喹喔
按照制备例7所述的类似方法,使用烯丙胺代替甲胺制备标题化合物。1H-NMR(300MHz,CDCl3):δ=4.10(3H,s);4.14(3H,s),4.19(2H,m),5.20(1H,d,J=10Hz),5.38(1H,dd,J=2,10Hz),5.85(1H,br s),6.00(1H,m);7.88(1H,s).m/z(热喷雾法)342(MH+).
制备例19
6,7-二氯-2,3-二甲氧基-5-(1-烯丙基-1H-四唑-5
按照制备例8的类似方法,使用6,7-二氯-2,3-二甲氧基-5-(N-烯丙基氨基甲酰基)喹喔啉(制备例18)代替6,7-二氯-2,3-二甲氧基-5-(N-甲基氨基甲酰基)喹喔啉制备标题化合物。1H-NMR(300MHz,CDCl3):δ=3.80(3H,s),4.14(3H,s),4.80(2H,m),5.02(1H,m),5..16(1H,m),5.80(1H,m),8.10(1H,s).m/z(热喷雾法)367(MH+).
制备例20
6,7-二氯-2,3-二甲氧基-5-[1-(3-羟基丙基)-
室温及氮气氛下,向搅拌的6,7-二氯-2,3-二甲氧基-5-(1-烯丙基-1H-四唑-5-基)喹喔啉(制备例19,0.67g,1.82mmol)的无水四氢呋喃(15mL)悬浮液内加入9-硼杂二环[3.3.1]壬烷(0.5M四氢呋喃溶液,9.1mL,4.55mmol)。加热回流反应混合物18小时,冷却反应混合物,向其中分批加入三甲胺-N-氧化物(1.03g,13.7mmol),并加热回流反应混合物2小时,然后减压浓缩。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(100∶0→99.5∶0.5,体积比)梯度洗脱,得到白色固体标题化合物(0.510g,73%),mp188-189℃.1H-NMR(300MHz,CDCl3):δ=2.04(2H,m),3.60(2H,m),3.82(3H,s),4.16(3H,s),4.30(2H,m),8.12(1H,s).m/z(热喷雾法)769(MH+).
制备例21
6,7-二氯-2,3-二甲氧基-5-[1-(2-羟乙基)
-78℃、氮气氛及搅拌下,在6,7-二氯-2,3-二甲氧基-5-(1-甲氧基羰基甲基-1H-四唑-5-基)喹喔啉(制备例11,0.126g,0.32mmol)的二氯甲烷(15ml)溶液内滴加入二异丁基氢化铝(1M四氢呋喃溶液,0.7ml,0.7mmol)。1小时后,温热反应混合物至室温,再加入二异丁基氢化铝(1M四氢呋喃溶液,0.7ml,0.7mmol),30分钟后,进一步加入二异丁基氢化铝(1M四氢呋喃溶液,0.7ml,0.7mmol)。进一步反应0.25小时,向混合物中加入饱和氯化铵溶液(20ml),水相用二氯甲烷(2×25ml)提取。合并的有机提取液用盐水(50ml)洗涤,干燥(MgSO4)并减压浓缩。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(99∶1,体积比)洗脱,得到白色固体标题化合物(93mg,79%)。1H-NMR(300MHz,CDCl3):δ=3.84(3H,s),4.08(2H,m),4.18(3H,s),4.28(2H,m),8.14(1H,s).m/z(热喷雾法)371(MH+).
制备例22
6,7-二氯-2,3-二甲氧基-5-[4-(2-羟乙基)-4H-
1,2,4-***-3-基]喹喔啉(a)室温及搅拌下,在6,7-二氯-2,3-二甲氧基-5-(N-烯丙基氨基甲酰基)喹喔啉(制备例18,1.0g,2.93mmol)的甲苯(40ml)悬浮液内加入五氯化磷(0.67g,3.22mmol),然后加热回流1小时。冷却后,加入甲酰肼(0.585g,8.79mmol)和三乙胺(0.592g,8.79mmol),并加热回流混合物1小时。冷却之后,将混合物分配到乙酸乙酯(60ml)和10%w/w碳酸钾水溶液(60ml)内。分离各相,并将水相用乙酸乙酯(2×40ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用甲苯∶乙酸乙酯(1∶0→1∶1,体积比)梯度洗脱,得到6,7-二氯-2,3-二甲氧基-5-(4-烯丙基-4H-1,2,4-***-3-基)喹喔啉(0.112g,10%),为白色固体,mp206-208℃。1H-NMR(300MHz,CDCl3):δ=3.88(3H,s),4.14(3H,s),4.37(2H,d,J=3Hz),5.16(2H,m),5.79(1H,m),8.06(1H,s),8.34(1H,s).m/z(热喷雾法)366(MH+).(b)将6,7-二氯-2,3-二甲氧基-5-(4-烯丙基-4H-1,2,4-***-3-基)喹喔啉(0.1g,0.273mmol)的二氯甲烷(3ml)溶液冷却至-70℃,通臭氧/氧气流0.5小时。然后通氮气流0.25小时,随后加入甲醇(3ml)和硼氢化钠(0.026g,0.683mmol)。温热至室温后,将混合物分配到二氯甲烷(10ml)和盐水(10ml)内。分离各相,水相用乙酸乙酯(2×10ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用乙酸乙酯∶甲醇(100∶0→95∶5,体积比)梯度洗脱,得到标题化合物(0.042g,40%),系灰白色固体,mp212-214℃。1H-NMR(300MHz,CDCl3):δ=3.78(2H,m),3.87(3H,s),3.92(2H,m),4.18(3H,s),8.07(1H,s),8.63(1H,s).m/z(热喷雾法)370(MH+).
制备例23
6,7-二氯-2,3-二甲氧基-5-(4-甲基-
4H-1,2,4-***-3-基)喹喔啉
按照制备例22,步骤(a)所述的类似方法,使用6,7-二氯-2,3-二甲氧基-5-(N-甲基氨基甲酰基)喹喔啉(制备例7)代替6,7-二氯-2,3-二甲氧基-5-(N-烯丙基氨基甲酰基)喹喔啉来制备标题化合物。通过硅胶快速色谱纯化,使用甲苯∶乙酸乙酯(1∶1→0∶1,体积比)梯度洗脱,得到灰白色固体。1H-NMR(300MHz,CDCl3):δ=3.52(3H,s),3.88(3H,s),4.17(3H),8.07(1H,s),8.37(1H,s).m/z(热喷雾法)340(MH+).
制备例24
按照制备例7的类似方法,使用气体氨代替甲胺制备标题化合物,得到浅黄色固体(后处理过程中不一定必需进行层析)。1H-NMR(300MHz,DMSO-d6):δ=4.00(3H,s),4.06(3H,s),7.80(1H,br.s),7.92(1H,br.s),8.00(1H,s).m/z(热喷雾法)302(MH+).
制备例256,7-二氯-2,3-二甲氧基-5-(2-甲基-2H-1,2,4-***-3-基)喹喔啉(异构体1)和6,7-二氯-2,3-二甲氧基-5-(1-甲基-1H-1,2,4-***-3-基)喹喔啉(异构体2) (a)将6,7-二氯-2,3-二甲氧基喹喔啉-5-甲酰胺(制备例24,1.96g,6.49mmol)的N,N-二甲基甲酰胺缩二甲醇(25ml)溶液加热回流2小时。冷却之后,减压浓缩混合物,并将残留物用***研制,得到N1,N1-二甲基-N2-[6,7-二氯-2,3-二甲氧基喹喔啉-5-基羰基]甲脒(2.14g,92%),为浅黄色固体。1H-NMR(300MHz,CDCl3):δ=3.18(3H,s),3.24(3H,s),4.09(3H,s),4.15(3H,s),7.88(1H,s),8.62(1H,s).m/z(热喷雾法)357(MH+).(b)将N1,N1-二甲基-N2-[6,7-二氯-2,3-二甲氧基喹喔啉-5-基羰基]甲脒(2.14g,5.99mmol)和水合肼(0.599g,11.98mmol)在冰乙酸(80ml)中的混合物加热回流2小时。冷却之后,过滤收集固体,并用***洗涤。取部分此固体(1.108g),然后在氮气氛下于室温悬浮到无水N,N-二甲基甲酰胺(80ml)中,用氢化钠(80%w/w油分散物,0.122g,4.08mmol)处理。搅拌0.25小时后,加入碘甲烷(0.579g,4.08mmol)并在50℃下加热混合物6小时。冷却混合物,过滤并减压浓缩滤液。将残留物分配到二氯甲烷(80ml)和盐水(80ml)内。分离各相,水相用二氯甲烷(2×80ml)提取。残留物通过硅胶快速色谱纯化,使用甲苯∶乙酸乙酯(4∶1→1∶1,体积比)梯度洗脱,得到第一洗脱产物,即异构体1,暂称作6,7-二氯-2,3-二甲氧基-5-(2-甲基-2H-1,2,4-***-3-基)喹喔啉(0.18g,10%),为白色固体,mp208-210℃。1H-NMR(300MHz,CDCl3):δ=3.73(3H,s),3.89(3H,s),4.18(3H,s),8.10(1H,s),8.13(1H,s).m/z(热喷雾法)340(MH+).
得到的第二洗脱产物(即异构体2)为白色固体(0.11g,6%),该产物暂称作6,7-二氯-2,3-二甲氧基-5-(1-甲基-1H-1,2,4-***-3-基)喹喔啉,mp184-186℃.1H-NMR(300MHz,CDCl3):δ=3.90(3H,s),4.09(3H,s),4.16(3H,s),8.02(1H,s),8.28(1H,s).m/z(热喷雾法)340(MH+).
制备例26
5-氨基-6,7-二氯-2,3-二甲氧基喹喔啉 (a)将6,7-二氯-5-硝基-2,3(1H,4H)-喹喔啉二酮(WO-A-94/00124的实施例1,84g,0.34mol),亚硫酰氯(840ml)和二甲基甲酰胺(0.5ml)的混合物加热回流3小时,冷却并减压浓缩。加入乙酸乙酯(300ml)并减压蒸发除去,然后用石油醚(bp100-120℃)重复这一步骤。所得固体残留物用石油醚(bp100-120℃)重结晶,得到2,3,6,7-四氯-5-硝基喹喔啉(78g,73%),为亮黄色固体。1H-NMR(300MHz,CDCl3):δ=8.6(1H,s).(b)向2,3,6,7-四氯-5-硝基喹喔啉(96.2g,0.31mol)的乙酸乙酯(1.8L)溶液中加入氯化锡(Ⅱ)二水合物(346.3g,1.54mol)。加热回流混合物4小时,冷却,然后小心倒入过量饱和碳酸氢钠水溶液内。混合物通过CELITE(商品名)过滤,并用乙酸乙酯充分洗涤。滤饼进一步用乙酸乙酯浸解并滤出固体物质。合并的乙酸乙酯相用硫酸镁干燥,并减压浓缩,得到5-氨基-2,3,6,7-四氯喹喔啉(73.4g,84%),为黄色固体。1H-NMR(300MHz,CDCl3):δ=5.45(2H,br.s),7.47(1H,s).m/z(热喷雾法)385(MH+).(在另一种制备方法中,此还原步骤可采用铁屑在乙酸水溶液中进行)。(c)在5-氨基-2,3,6,7-四氯喹喔啉(72.4g,0.256mol)的无水甲醇(1L)悬浮液内加入甲醇钠溶液(25%w/w甲醇溶液,274ml,1.28mol),并加热回流所得混合物30分钟。冷却混合物,减压浓缩,并将残留物分配到水和乙酸乙酯(总体积量为8L)内。干燥(MgSO4)并减压浓缩有机提取液。粗产物用甲醇研制,然后溶于二氯甲烷(2L)并过滤。减压浓缩滤液,得到黄色固体标题化合物(55.0g,79%)。1H-NMR(300MHz,CDCl3):δ=4.13(3H,s),4.14(3H,s),5.07(2H,br.s),7.26(1H,s).m/z(热喷雾法)274(MH+).
制备例27
6,7-二氯-2,3-二甲氧基-5-[3-(3-氯苯基)-5-
甲基-4H-1,2,4-***-4-基]喹喔啉(a)在强烈搅拌下,向5-氨基-6,7-二氯-2,3-二甲氧基喹喔啉(制备例26,20.49g,64.8mmol)的甲苯(500ml)悬浮液内加入乙酰氯(5.71ml,6.30g,80.3mmol),并加热回流所得混合物2小时。冷却后,过滤收集产物,用甲苯洗涤,抽吸干燥15小时,得到5-乙酰氨基-6,7-二氯-2,3-二甲氧基喹喔啉(20.49g,89%),为米色固体。1H-NMR(300MHz,DMSO-d6):δ=2.11(3H,s),4.04(3H,s),4.05(3H,s),7.91(1H,s),9.80(1H,s).m/z(热喷雾法)316(MH+).(b)室温及氮气氛下,向搅拌着的2,4-双(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂丁环-2,4-二硫化物(Lawesson试剂)(15.7g,38.9mmol)的甲苯(432ml)悬浮液内加入5-乙酰氨基-6,7-二氯-2,3-二甲氧基喹喔啉(20.49g,64.8mmol)。加热回流混合物25分钟,并在回流温度下进一步保持90分钟。冷却之后,减压浓缩混合物,残留物通过硅胶快速色谱纯化,使用二氯甲烷洗脱。得到黄色泡沫体6,7-二氯-2,3-二甲氧基-5-硫代乙酰氨基喹喔啉(17.54g,81%).1H-NMR(300MHz,DMSO-d6):δ=2.70(3H,s),3.99(3H,s),4.05(3H,s),8.05(1H,s),11.74(1H,s).m/z(热喷雾法)332(MH+).(c)将6,7-二氯-2,3-二甲氧基-5-硫代乙酰氨基喹喔啉(250mg,0.753mmol),3-氯苯酰肼(167mg,0.978mmol),***(Ⅱ)(163mg,0.753mmol),4A分子筛粉末(175mg)与正丁醇(7ml)的混合物加热回流18小时。冷却后,通过ARBOCEL(商品名)滤器过滤混合物,残留物用二氯甲烷洗涤。减压浓缩滤液,将得到的绿色固体溶于二氯甲烷,依次用2M盐酸水溶液和盐水洗涤,然后干燥(MgSO4)并减压浓缩。残留物通过硅胶快速色谱纯化,用二氯甲烷∶甲醇(98∶2,体积比)洗脱,得到标题化合物(120mg,35%),为浅黄色固体。1H-NMR(300MHz,CDCl3):δ=2.21(3H,s),3.84(3H,s),4.14(3H,s),7.13(2H,s),7.25(1H,掩蔽),7.49(1H,s),8.08(1H,s).m/z(热喷雾法)450(MH+).
制备例28-95
按照制备例27的类似方法,使用5-氨基-6,7-二氯-2,3-二甲氧基喹喔啉和适当的酰氯(RACOCl)和酰肼(RBCONHNH2)制备下列表示化合物。 附注:1)使用肼基甲酸乙酯作为“酰肼”起始物质进行制备。最终的结晶是通过在二甲苯中加热进行2)根据制备例118的酰肼进行的反应,该产物为意外产物。
制备例966,7-二氯-2,3-二甲氧基-5-[3-(3-甲基-1,2,4-
室温、氮气氛及搅拌下,向6,7-二氯-2,3-二甲氧基-5-[3-乙氧羰基-5-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例94,250mg,0.53mmol)的无水甲苯(15ml)悬浮液中先后加入乙酰胺肟(120mg,1.62mmol)和氢化钠(80%w/w油分散物,8mg,0.27mmol)。加热回流混合物3.5小时,冷却并将溶液分配到乙酸乙酯和盐水内。水相用乙酸乙酯(2×20ml)提取,干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用己烷∶乙酸乙酯(7∶3→1∶1,体积比)梯度洗脱,得到标题化合物(21mg,82%),系白色固体。1H-NMR(300MHz,CDCl3):δ=2.25(3H,s),3.77(3H,s),4.14(3H,s),7.28(1H,m,掩蔽),7.93(1H,m),8.10(1H,s),8.58(2H,m).m/z(热喷雾法)485(MH+).
制备例97
6,7-二氯-2,3-二甲氧基-5-[5-甲基-3-(3-
甲基-1,2,4-噁二唑-5-基)-4H-1,2,4-***-4-基]喹喔啉
按照制备例96的类似方法,使用6,7-二氯-2,3-二甲氧基-5-(3-乙氧羰基-5-甲基-4H-1,2,4-***-4-基)喹喔啉(制备例67)代替6,7-二氯-2,3-二甲氧基-5-[3-乙氧羰基-5-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉制备标题化合物。采用硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→95∶5,体积比)梯度洗脱,得到白色固体。1H-NMR(300MHz,CDCl3):δ=2.26(3H,s),2.33(3H,s),3.79(3H,s),4.20(3H,s),8.15(1H,s).m/z(热喷雾法)422(MH+).
制备例986,7-二氯-2,3-二甲氧基-5-[3-(3-吡啶基)-4H-
1,2,4-***-4-基]喹喔啉
10℃及搅拌下,向6,7-二氯-2,3-二甲氧基-5-[3-乙氧羰基-5-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例94,8.2g,17.25mmol)在1,4-二噁烷(68ml)和水(50ml)中的溶液内逐滴加入1M氢氧化钠水溶液(17.25ml,17.25mmol)。温热溶液至室温并搅拌20小时。加水(50ml)稀释,用冰乙酸酸化,接着用乙酸乙酯(1×100ml,2×50ml)提取。合并的有机提取液用盐水洗涤,干燥(MgSO4)并减压浓缩。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→9∶1,体积比)梯度洗脱,得到白色固体标题化合物(5.82g,84%),mp206-207℃.元素分析(%):实测值C,50.49;H,3.06;N,20.44.C17H12Cl2N6O2计算值:C,50.63;H,3.00;N,20.84.
制备例996,7-二氯-2,3-二甲氧基-5-[5-溴-3-(3-吡啶基)-
室温及氮气氛下,向搅拌着的6,7-二氯-2,3-二甲氧基-5-[3-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例98,102mg,0.25mmol)的1,1,1-三氯乙烷(6ml)悬浮液中加入N-溴代琥珀酰亚胺(58mg,0.33mmol),并加热回流混合物18小时。减压浓缩混合物,将残留物通过硅胶快速色谱纯化,使用己烷∶乙酸乙酯(7∶3→1∶1,体积比)梯度洗脱,得到白色固体标题化合物(87mg,71%)。1H-NMR(300MHz,CDCl3):δ=3.86(3H,s),4.16(3H,s),7.28(1H,m,掩蔽),7.88(1H,m),8.12(1H,s),8.49(1H,m),8.58(1H,m).m/z(热喷雾法)481(MH+).
制备例1006,7-二氯-2,3-二甲氧基-5-[3-(1-咪唑基)-5-
甲基-4H-1,2,4-***-4-基]喹喔啉 (a)按照制备例99的类似方法,使用6,7-二氯-2,3-二甲氧基-5-(3-甲基-4H-1,2,4-***-4-基)喹喔啉(制备例78,50mg,0.147mmol)代替6,7-二氯-2,3-二甲氧基-5-[3-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉,制备6,7-二氯-2,3-二甲氧基-5-(3-溴-5-甲基-4H-1,2,4-***-4-基)喹喔啉,所得产物为浅棕色固体(53mg,86%)。1H-NMR(300MHz,DMSO-d6):δ=2.27(3H,s),3.91(3H,s),4.19(3H,s),8.16(1H,s).m/z(热喷雾法)419(MH+).(b)将咪唑(78mg,1.15mmol)与6,7-二氯-2,3-二甲氧基-5-(3-溴-5-甲基-4H-1,2,4-***-4-基)喹喔啉(48mg,0.115mmol)的混合物在100℃加热1小时,然后在120℃加热3小时。冷却后,将混合物分配到水(15ml)和二氯甲烷(2×15ml)内。干燥(MgSO4)合并的有机提取液,过滤并减压浓缩。将残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(98∶2→95∶5,体积比)梯度洗脱,得到棕色固体标题化合物(15mg,32%).1H-NMR(300MHz,DMSO-d6):δ=2.27(3H,s),4.11(6H,s),7.16(2H,brs),7.79(1H,brs),7.95(1H,s).m/z(热喷雾法)406(MH+).
制备例1016,7-二氯-2,3-二甲氧基-5-[3-羟甲基-5-(3-吡啶基)
在密封容器中,将6,7-二氯-2,3-二甲氧基-5-[3-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例98,1.008g,2.5mmol)和多聚甲醛(0.75g,25mmol)的乙酸(14ml)悬浮液于125℃加热3小时。冷却后,减压浓缩混合物,并将残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→95∶5,体积比)梯度洗脱,得到白色固体标题化合物(0.60g,56%),mp209-210℃.元素分析(%):实测值:C,49.86;H,3.31;N,19.18.C18H14Cl2N6O3计算值:C,49.90;H,3.26;N,19.39.
制备例1026,7-二氯-2,3-二甲氧基-5-[3-羟甲基-5-甲基-
按照制备例101的类似方法,使用6,7-二氯-2,3-二甲氧基-5-(3-甲基-4H-1,2,4-***-4-基)喹喔啉(制备例78)代替6,7-二氯-2,3-二甲氧基-5-[3-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉,制得白色固体标题化合物。1H-NMR(300MHz,DMSO-d6):δ=2.20(3H,s),3.89(3H,s),4.18(3H,s),4.54(2H,s),8.11(1H,s).m/z(热喷雾法)370(MH+).
制备例1036,7-二氯-2,3-二甲氧基-5-[3-二甲氨基甲基-5-(3-
将6,7-二氯-2,3-二甲氧基-5-[3-(3-吡啶基)-4H-1,2,4-***-4-基]喹喔啉(制备例98,101mg,0.25mmol),多聚甲醛(15mg,0.5mmol)和盐酸二甲胺(22mg,0.27mmol)在乙酸(5ml)中的混合物加热回流5小时。冷却之后,减压浓缩混合物,加水(20ml),此溶液用碳酸钾水溶液碱化,并用乙酸乙酯(3×20ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→95∶5,体积比)梯度洗脱,得到白色固体标题化合物(75mg,65%),mp192-194℃.1H-NMR(300MHz,CDCl3):δ=2.0(6H,s),3.48(2H,m),3.82(3H,s),4.15(3H,s),7.2(1H,m),7.85(1H,m),8.05(1H,s),8.5(2H,m).m/z(热喷雾法)460(MH+).
制备例1046,7-二氯-2,3-二甲氧基-5-[3-吗啉代甲基-5-(3-吡
啶基)-4H-1,2,4-***-4-基]喹喔啉
按照制备例103的类似方法,使用吗啉盐酸盐代替二甲胺盐酸盐制备标题化合物。所得产物为白色固体,mp178-179℃.1H-NMR(300MHz,CDCl3):δ=2.10(4H,s),3.10(4H,m),3.56(2H,m),3.80(3H,s),4.18(3H,s),7.21(1H,m),7.80(1H,m),8.05(1H,s),8.55(2H,m).m/z(热喷雾法)502(MH+).
制备例1056,7-二氯-2,3-二甲氧基-5-(3-羟甲基-5-苯基-
室温、氮气氛下,在6,7-二氯-2,3-二甲氧基-5-(3-乙氧羰基-5-苯基-4H-1,2,4-***-4-基)喹喔啉(制备例93,237mg,0.5mmol)的二氯甲烷(10ml)溶液中加入二异丁基氢化铝(1M四氢呋喃溶液,2.5ml,2.5mmol)。1小时后,再加入一份二异丁基氢化铝(1M四氢呋喃溶液,1ml,1mmol)。进一步搅拌混合物1小时,然后加入饱和氯化铵水溶液(10ml)。加入二氯甲烷(50ml)和水(50ml),并通过ARBOCEL(商品名)过滤,残留物用热二氯甲烷∶甲醇(9∶1,体积比,100ml)洗涤。分离有机层,干燥(MgSO4)并减压蒸发。残留物通过硅胶快速色谱纯化,使用己烷∶乙酸乙酯∶甲醇(1∶1∶0→0∶1∶0→0∶95∶5,体积比)梯度洗脱,得到灰白色固体标题化合物(70mg,79%)。1H-NMR(300MHz,CDCl3):δ=2.78(1H,s),3.85(3H,s),4.14(3H,s),4.6(2H,m),7.25(2H,m),7.32(2H,m),7.38(1H,m),8.08(1H,s).m/z(热喷雾法)432(MH+).
制备例106
6,7-二氯-2,3-二甲氧基-5-(3-羟甲基-4H-
按照制备例105的类似方法,使用6,7-二氯-2,3-二甲氧基-5-(3-乙氧羰基-4H-1,2,4-***-4-基)喹喔啉(制备例92)代替6,7-二氯-2,3-二甲氧基-5-(3-乙氧羰基-5-苯基-4H-1,2,4-***-4-基)喹喔啉,制得灰白色固体标题化合物。1H-NMR(300MHz,CDCl3):δ=3.89(3H,s),4.14(3H,s),4.64(2H,m),8.08(1H,s),8.16(1H,s).m/z(热喷雾法)356(MH+).
制备例1076,7-二氯-2,3-二甲氧基-5-[3-(2-羟基乙基)-
5-甲基-4H-1,2,4-***-4-基]喹喔啉
按照制备例105的类似方法,使用6,7-二氯-2,3-二甲氧基-5-[3-乙氧羰基甲基-5-甲基-4H-1,2,4-***-4-基]喹喔啉(制备例68)代替6,7-二氯-2,3-二甲氧基-5-(3-乙氧羰基-5-苯基-4H-1,2,4-***-4-基)喹喔啉制备标题化合物。反应在替代二氯甲烷的甲苯中进行,并通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→95∶5,体积比)梯度洗脱。经二异丙醚结晶后得到灰白色固体。1H-NMR(300MHz,CDCl3):δ=2.1(3H,s),2.5(2H,m),3.5(2H,m),3.9(3H,s),4.18(3H,s),8.1(1H,s).m/z(热喷雾法)384(MH+).
制备例108
0℃下,向机械搅拌的5-氨基-6,7-二氯-2,3-二甲氧基喹喔啉(制备例26,38.12g,0.14mol)的丙酮溶液内加入2M盐酸水溶液(396ml,0.79mol),接着滴加入1M亚硝酸钠水溶液(208ml,0.28mol)。在0℃反应0.25小时后,加入5M碘化钾水溶液(278ml,1.39mol),保持反应温度低于5℃。然后在0.5小时内温热混合物至10℃,减压除去丙酮,将残留物分配到水和乙酸乙酯内。有机提取液用10%亚硫酸氢钠水溶液洗涤和饱和碳酸氢钠水溶液依次洗涤,干燥(MgSO4)并减压浓缩。将残留物通过硅胶快速色谱纯化,使用甲苯洗脱,得到标题化合物(16.9g,32%).1H-NMR(300MHz,CDCl3):δ=4.17(3H,s),4.24(3H,s),7.91(1H,s)
将6,7-二氯-2,3-二甲氧基-5-碘喹喔啉(制备例108,0.2g,0.519mmol),3-吡啶硼酸(Rec.Trav.Chim.Pays-Bas.,84,439(1965))(0.077g,0.623mmol),四(三苯膦)合钯(0)(0.03g,0.026mmol)和碳酸钾(0.143g,1.038mol)在1,4-二噁烷(12ml)和水(4ml)中的混合物加热回流16小时。冷却之后,减压浓缩混合物,随后将残留物分配到乙酸乙酯(20ml)和水(20ml)内。分离各相,将水相用乙酸乙酯(2×40ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→99∶1,体积比)梯度洗脱,得到黄色固体标题化合物(0.051g,29%).1H-NMR(300MHz,CDCl3):δ=3.84(3H,s),4.18(3H,s),7.42(1H,m),7.75(1H,m),7.99(1H,s),8.63(2H,m).m/z(热喷雾法)336(MH+).
制备例110
6,7-二氯-2,3-二甲氧基-5-[5-苯基-1H-
1,2,3-***-4-基]喹喔啉(a)将6,7-二氯-2,3-二甲氧基-5-碘喹喔啉(制备例108,5.0g,13mmol),苯乙炔(3.98g,39mmol),双(三苯膦)氯化钯(Ⅱ)(0.913g,1.3mmol)和碘化铜(Ⅰ)(0.248g,1.3mmol)在三乙胺(100ml)中的混合物加热回流4小时。冷却之后,减压浓缩混合物,并将残留物分配到二氯甲烷(200ml)和盐水(200ml)内。分离各相,并将水相用二氯甲烷(2×100ml)提取。合并的有机提取液用硫酸镁干燥并减压浓缩。残留物通过硅胶快速色谱纯化,使用己烷∶二氯甲烷(1∶0→1∶1,体积比)梯度洗脱,得到6,7-二氯-2,3-二甲氧基-5-(2-苯乙炔基)喹喔啉(3.60g,77%),系黄色固体,mp170-172℃.1H-NMR(300MHz,CDCl3):δ=4.14(3H,s),4.26(3H,s),7.39(3H,m),7.67(2H,m),7.87(1H,s).m/z(热喷雾法)359(MH+).(b)将6,7-二氯-2,3-二甲氧基-5-(2-苯乙炔基)喹喔啉(2.0g,5.57mmol)和叠氮三甲基硅烷(20ml)的混合物在密封容器内于170℃加热18小时。冷却之后,加入20ml水,然后加入50ml饱和碳酸氢钠水溶液,混合物用乙酸乙酯(3×50ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用二氯甲烷∶甲醇(1∶0→98∶2,体积比)梯度洗脱,得到标题化合物(1.3g,58%),为棕色泡沫体。1H-NMR(300MHz,CDCl3):δ=3.67(3H,s),4.13(3H,s),7.23(3H,m),7.40(2H,m),8.02(1H,s).m/z(热喷雾法)402(MH+).
制备例1116,7-二氯-2,3-二甲氧基-5-[2-甲基-5-苯基-2H-1,2,3-***-4-基]喹喔啉(异构体1),6,7-二氯-2,3-二甲氧基-5-[1-甲基-5-苯基-1H-1,2,3-***-4-基]喹喔啉(异构体2)和6,7-二氯-2,3-二甲氧基-5-[1-甲基-4-苯基-1H-1,2,3-***-5-基]喹喔啉(异构体3)
0℃、氮气氛及搅拌下,在6,7-二氯-2,3-二甲氧基-5-[5-苯基-1H-1,2,3-***-4-基]喹喔啉(制备例110,0.5g,1.24mmol)的无水N,N-二甲基甲酰胺(20ml)溶液中加入氢化钠(80%w/w油分散物,0.041g,1.37mmol)。在0℃反应0.5小时后,加入碘甲烷(0.194g,1.37mmol)。混合物在0℃搅拌0.5小时,然后在室温下搅拌0.5小时。加入50ml盐水,将混合物用二氯甲烷(3×50ml)提取。干燥(MgSO4)并减压浓缩合并的有机提取液。残留物通过硅胶快速色谱纯化,使用甲苯∶乙酸乙酯(1∶0→9∶1,体积比),得到第一洗脱产物,即异构体1,暂称作6,7-二氯-2,3-二甲氧基-5-[2-甲基-5-苯基-2H-1,2,3-***-4-基]喹喔啉(0.19g,37%),系浅黄色固体,mp233-235℃.1H-NMR(300MHz,CDCl3):δ=3.67(3H,s),4.14(3H,s),4.38(3H,s),7.23(3H,m),7.38(2H,m),8.05(1H,s).m/z(热喷雾法)416(MH+).
得到的第二洗脱产物(即异构体2)为浅黄色固体(0.135g,26%),该化合物暂称作6,7-二氯就-2,3-二甲氧基-5-[1-甲基-5-苯基-1H-1,2,3-***-4-基]喹喔啉,mp 189-190℃.1H-NMR (300MHz,CDCl3):δ=3.75(3H,s),3.84(3H,s),4.17(3H,s),7.26(3H,m),7.48(2H,m),8.13(1H,s).m/z(热喷雾法)416(MH+).
得到的第三洗脱产物(即异构体3)为橙色油状物(0.046g,9%),该异构体暂时称作6,7-二氯-2,3-二甲氧基-5-[1-甲基-4-苯基-1H-1,2,3-***-5-基]喹喔啉。1H-NMR(300MHz,CDCl3):δ=3.84(3H,s),4.11(3H,s),4.16(3H,s),7.20(3H,m),7.33(2H,m),7.96(1H,s).m/z(热喷雾法)416(MH+).
制备例1126,7-二氯-2,3-二甲氧基-5-[5-苯基-2-(2-(三苯基甲氧基)乙基)-2H-1,2,3-***-4-基]喹喔啉(异构体1),6,7-二氯-2,3-二甲氧基-5-[5-苯基-1-(2-(三苯基甲氧基)乙基)-1H-1,2,3-***-4-基]喹喔啉(异构体2)和6,7-二氯-2,3-二甲氧基-5-[4-苯基-1-(2-(三苯基甲氧基)乙基)-1H-1,
标题化合物按照制备例111的类似方法制备,其中使用2-(三苯基甲氧基)乙基溴(Liebigs Ann.,635,3(1960))代替碘甲烷,纯化通过硅胶快速色谱进行,使用甲苯∶***(1∶0→9∶1,体积比)梯度洗脱,得到白色固体第一洗脱产物,即异构体1(0.336g,45%),该异构体暂时称作6,7-二氯-2,3-二甲氧基-5-[5-苯基-2-(2-(三苯基甲氧基)乙基)-2H-1,2,3-***-4-基]喹喔啉。1H-NMR(300MHz,CDCl3):δ=3.32(3H,s),3.73(2H,m),4.11(3H,s),4.73(2H,m),7.22(12H,m),7.40(6H,m),7.47(2H,m),8.02(1H,s).m/z(热喷雾法)688(MH+).
得到的第二洗脱产物(即异构体2)为白色固体(0.104g,14%),该异构体暂时称作6,7-二氯-2,3-二甲氧基-5-[5-苯基-1-(2-(三苯基甲氧基)乙基)-1H-1,2,3-***-4-基]喹喔啉。1H-NMR(300MHz,CDCl3):δ=3.40(2H,m),3.44(3H,s),4.17(3H,s),4.25(2H,m),7.22(18H,m),7.39(2H,m),8.02(1H,s).m/z(热喷雾法)688(MH+).
得到的第三洗脱产物(即异构体3)为灰白色固体(0.037g,5%),该异构体暂时称作6,7-二氯-2,3-二甲氧基-5-[4-苯基-1-(2-(三苯基甲氧基)乙基)-1H-1,2,3-***-4-基]喹喔啉。1H-NMR(300MHz,CDCl3):δ=3.47(3H,s),3.73(2H,m),4.10(3H,s),4.58(2H,m),7.24(20H,m),7.94(1H,s).m/z(热喷雾法)688(MH+).
制备例1135-氨基-6-氯-2,3-二甲氧基-7-甲基喹喔啉和5-氨基-7
-氯-2,3-二甲氧基-6-甲基喹喔啉(a)将1,2-二氨基-4-氯-5-甲基苯盐酸盐(1.90g,9.84mmol),草酸(1.24g,13.8mmol)和4M盐酸水溶液(49ml)的混合物加热回流4.5小时。冷却后,过滤收集固体沉淀物,用水充分洗涤,然后在80℃下减压干燥,得到6-氯-7-甲基-2,3(1H,4H)-喹喔啉二酮(1.68g,81%),为暗灰色固体,mp>330℃.元素分析(%):实测值:C,51.58;H.2.98;N,13.27.C9H7ClN2O2计算值C,51.32;H,3.35;N,13.30.(b)室温下,将6-氯-7-甲基-2,3(1H,4H)-喹喔啉二酮(1.26g,5.98mmol)在3分钟内分批加到强烈搅拌的浓硝酸(10ml,d=1.42)内。然后将所得的非均相混合物温热至40℃并搅拌12小时。冷却后,将此黄色混合物倒入冰水(100ml)中,搅拌30分钟。过滤收集所得黄色沉淀物,水洗并抽吸干燥,得到6-氯-7-甲基-5-硝基-2,3(1H,4H)-喹喔啉二酮和7-氯-6-甲基-5-硝基-2,3(1H,4H)-喹喔啉二酮混合物(摩尔比1∶2,1.35g,88%),为黄色固体。1H-NMR(300MHz,CDCl3):δ=2.23(2H,s),2.35(1H,s),7.19(0.3H,s),7.30(0.7H,s),11.9-12.25(2H,brm).(c)将上述6-氯-7-甲基-5-硝基-2,3(1H,4H)-喹喔啉二酮和7-氯-6-甲基-5-硝基-2,3(1H,4H)-喹喔啉二酮混合物(1.35g,5.73mmol),亚硫酰氯(12.5ml,20.4g,0.172mol)和二甲基甲酰胺(44μl,42mg,0.573mmol)一起加热回流4小时。冷却后,将混合物小心加到强烈搅拌的冰水(300ml)中。过滤收集所得沉淀物,水洗,抽吸干燥后,得到2,3,7-三氯-6-甲基-5-硝基喹喔啉与2,3,6-三氯-7-甲基-5-甲基-5-硝基喹喔啉的混合物(2∶1摩尔比,1.45g,87%),系草黄色粉末。考虑到表征目的,将此混合物非常困难地通过硅胶时快速色谱分离,使用己烷∶二氯甲烷(9∶1→3∶1,体积比)梯度洗脱,得到第一洗脱异构体-2,3,7-三氯-6-甲基-5-硝基喹喔啉,为白色固体,mp164-165℃.元素分析(%):实测值:C,36.76;H,1.37;N,14.43.C9H4Cl3N3O2计算值:C,36.96;H,1.38;N,14.37.
得到的第二洗脱异构体2,3,6-三氯-7-甲基-5-硝基喹喔啉为草黄色固体,mp121-122℃.元素分析(%):C,39.78;H,2.02;N,13.23.C9H4Cl3N3O2 0.22己烷:计算值:C,39.80;H,2.29;N,13.49.(d)氮气氛下,将上述2,3,7-三氯-6-甲基-5-硝基喹喔啉和2,3,6-三氯-7-甲基-5-硝基喹喔啉混合物(250mg,0.855mmol)与氯化锡二水合物(1.35g,5.98mmol)在乙酸乙酯(8.5ml)中加热回流3小时。冷却后,将混合物用乙酸乙酯(50ml)稀释,并用10%碳酸钠水溶液(2×25ml)、盐水(25ml)洗涤,干燥(MgSO4),过滤并减压浓缩,得到5-氨基-2,3,7-三氯-6-甲基喹喔啉和5-氨基-2,3,6-三氯-7-甲基喹喔啉混合物(2∶1摩尔比,217mg,97%),系橙色固体。1H-NMR(300MHz,CDCl3):δ=2.41(2H,s),2.55(1H,s),5.03(1.3H,brs),5.08(0.7H,brs),7.23(0.3H,s),7.44(0.7H,s).m/z(热喷雾法)262(MH+).(e)0℃及氮气氛下,在上述5-氨基-2,3,7-三氯-6-甲基喹喔啉与5-氨基-2,3,6-三氯-7-甲基喹喔啉混合物(200mg,0.788mol)的无水四氢呋喃(7.9ml)溶液内逐滴加入25%w/w甲醇钠/甲醇溶液(433μl),1.89mmol)。搅拌混合物3小时,然后用乙酸乙酯(30ml)稀释,依次用水(2×10ml)及盐水(10ml)洗涤,干燥(MgSO4),过滤并减压浓缩。固体残留物通过硅胶快速色谱纯化,使用己烷∶乙酸乙酯(95∶5→1∶1,体积比)梯度洗脱,得到第一洗脱异构体-5-氨基-6-氯-2,3-二甲氧基-7-甲基喹喔啉(48mg,25%),系灰白色固体,mp169-170℃.元素分析(%):实测值:C,53.80;H,5.16;N,16.18.C11H12ClN3O2 0.15己烷计算值:C,53.61;H,5.33;N,15.75.
得到的第二洗脱异构体,即5-氨基-7-氯-2,3-二甲氧基-6-甲基喹喔啉(85mg,44%),为橙色固体,mp181-182℃.元素分析(%):实测值:C,52.55;H,4.72;N,16.61.C11H12ClN3O2 0.05己烷计算值:C,52.61;H,4.96;N,16.29.
制备例114
6-氯-2,3-二甲氧基-7-甲基-5-[5-甲氧基甲基-
3-(3-吡定基)-4H-1,2,4-***-4-基]喹喔啉(a)0℃下,将甲氧基乙酰氯(2.16ml,2.57g,23.66mmol)加到5-氨基-6-氯-2,3-二甲氧基-7-甲基喹喔啉(制备例113,5g,19.72mmol)和吡啶(1.91ml,1.89g,23.66mmol)的二氯甲烷(80ml)溶液内。在此温度下进一步反应1小时后,用2M盐酸水溶液及盐水洗涤混合物,干燥(MgSO4)并减压浓缩。残留物用二异丙醚研制,过滤后得到6-氯-2,3-二甲氧基-5-甲氧基乙酰氨基-7-甲基喹喔啉(6.06g,98%),为灰白色固体,mp170-171℃.1H-NMR(300MHz,CDCl3):δ=2.55(3H,s),3.6(3H,s),4.1(3H,s),4.13(3H,s),4.18(2H,s),7.61(1H,s),8.47(1H,brs).m/z(热喷雾法)326(MH+).(b)在6-氯-2,3-二甲氧基-5-甲氧基乙酰氨基-7-甲基喹喔啉(6g,18.43mmol)的四氢呋喃(120ml)溶液中加入2,4-双(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂丁环-2,4-二硫化物(Lawesson试剂)(4.47g,11.06mmol),并搅拌混合物18小时,然后减压蒸发。残留物通过硅胶快速色谱纯化,使用己烷∶二氯甲烷(1∶1→1∶4→0∶1,体积比)洗脱,得到6-氯-2,3-二甲氧基-5-甲氧基硫代乙酰氨基-7-甲基喹喔啉(5.48g,87%),系黄色泡沫物,mp174-176℃.1H-NMR(300MHz,CDCl3):δ=2.55(3H,s),3.65(3H,s),4.05(3H,s),4.15(3H,s),4.55(2H,s),7.7(1H,s),9.65(1H,brs).m/z(热喷雾法)342(MH+).(c)将6-氯-2,3-二甲氧基-5-甲氧基硫代乙酰氨基-7-甲基喹喔啉(1.45g,4.25mmol),烟酰肼(1.16g,8.5mmol),***(Ⅱ)(1.84g,8.5mmol),4A分子筛粉末(1.06g)与正丁醇(60ml)的混合物加热回流8小时。冷却后,通过ARBOCEL(商品名)助滤剂过滤混合物,残留物用二氯甲烷洗涤。减压浓缩滤液,得到亮棕色固体,随后将其分批到乙酸乙酯和2M盐酸水溶液内。水层用二氯甲烷(4×50ml)提取,干燥(MgSO4)并减压浓缩合并的二氯甲烷提取液。残留物用二异丙醚/甲醇结晶,得到一固体(394mg)。减压蒸发结晶母液,并将残留物通过硅胶快速色谱纯化,使用乙酸乙酯为洗脱剂,在经二异丙醚研制后,进一步得到一定数量固体(364mg)。合并两批固体,得到标题化合物(740mg,41%),系浅黄色固体,mp183-184℃.1H-NMR(300MHz,CDCl3):δ=2.5(3H,s),3.18(3H,s),3.8(3H,s),4.16(3H,s),4.45(2H,m),7.58(1H,m),7.86(1H,s),8.35(1H,m),8.45(1H,m),8.65(1H,m).m/z(热喷雾法)427(MH+).
制备例115
7-氯-2,3-二甲氧基-6-甲基-5-[5-甲氧甲基-3-
按照制备例114的类似方法,使用5-氨基-7-氯-2,3-二甲氧基-6-甲基喹喔啉(制备例113)代替5-氨基-6-氯-2,3-二甲氧基-7-甲基喹喔啉制备标题化合物。得到灰白色固体,mp166-168℃.1H-NMR(300MHz,CDCl3):δ=2.25(3H,s),3.2(3H,s),3.78(3H,s),4.15(3H,s),4.35(2H,m),7.2(1H,m),7.82(1H,m),8.0(1H,s),8.45(1H,m),8.55(1H,m).m/z(热喷雾法)427(MH+).
制备例116
氮气氛下,将2-甲氧羰基吡啶-5-羧酸(Chem.Abstr.68,68840h(1968))(0.40g,2.2mmol)与N-乙氧羰基-2-乙氧基-1,2-二氢喹啉(0.60g,2.4mmol)的二氯甲烷(10ml)混合物在室温下搅拌0.75小时。然后加入水合肼(0.110ml,2.2mmol),5分钟后,过滤收集所形成的沉淀物,用二氯甲烷洗涤并干燥,得到白色固体标题化合物(0.349g,81%),mp177-180℃.1H-NMR(300MHz,DMSO-d6):δ=4.90(3H,s),5.00(2H,br s),8.10(1H,d,J=10Hz),8.27(1H,dd,J=2和10Hz),9.05(1H,d,J=2Hz),10.05(1H,brs)m/z(热喷雾法)196(MH+).
制备例117
嘧啶-2-甲酰肼
将嘧啶-2-羧酸乙酯(Ann.Chim.,5,351(1960))(0.866g,5.7mmol)和水合肼(0.332ml,6.8mmol)在乙醇(20ml)中的混合物加热回流3小时,然后减压浓缩。残留物用***研制,过滤收集并用乙酸乙酯洗涤,得到黄色固体标题化合物(0.542g,69%),mp173-175℃.1H-NMR(300MHz,DMSO-d6):δ=4.20(2H,br s),7.50(1H,t,J=4Hz),8.83(2H,d,J=4Hz),9.93(1H,brs).m/z(热喷雾法)139(MH+).
制备例118-132
将2-溴吡啶-5-羧酸(J.Org.Chem.,12,456(1947))(2.32g,11.49mmol)和N-乙氧羰基-2-乙氧基-1,2-二氢喹啉(3.12g,12.64mmol)在二氯甲烷(30ml)中的混合物在室温和氮气氛下搅拌1小时。加入无水乙醇(5ml),并搅拌混合物30分钟,然后减压浓缩。将残留物分配到二氯甲烷(40ml)和10%w/w碳酸钾水溶液(40ml)内。水层用二氯甲烷(25ml)提取,干燥(MgSO4)并减压浓缩合并的有机层。硅胶快速色谱纯化,使用二氯甲烷洗脱,得到2-溴吡啶-5-羧酸乙酯(2.18g,83%),为无色油状物。元素分析(%):实测值:C,41.57;H,3.45;N,5.98.C8H8NO2Br计算值:C,41.77;H,3.50;N,6.09.(ⅱ)2-苯基吡啶-5-羧酸乙酯
氮气氛下,将2-溴吡啶-5-羧酸乙酯(参见(ⅰ)部分)(1.855g,8.065mmol),苯基三甲锡(3.89g,16.13mmol),双(三苯膦)氯化钯(Ⅱ)(371mg)和氯化锂(1.03g,24.95mmol)在无水二甲基甲酰胺(40ml)中的混合物于100℃加热1.5小时。冷却后,减压浓缩混合物,并将残留物通过硅胶快速色谱纯化,使用己烷∶乙酸乙酯(10∶1,体积比)洗脱,得到白色固体标题化合物(0.843g,46%)。1H-NMR(300MHz,CDCl3):δ=1.43(3H,t,J=8Hz),4.42(2H,q,J=8Hz),7.49(3H,m),7.80(1H,m),8.07(2H,m),8.36(1H,m),9.29(1H,m).m/z(热喷雾法)228(MH+).
制备例134
氮气氛下,将1H-咪唑-4-羧酸乙酯(J.Het.Chem.,19,253(1982))(584mg,4.17mmol),4-氟硝基苯(588mg,4.17mmol)及无水碳酸钠(487mg,4.59mmol)在无水二甲基甲酰胺(100ml)中的混合物于50℃加热24小时。冷却至室温后,将混合物倾入冰冷水(60ml)中,过滤收集所得固体,水洗并于60℃下减压干燥,得到1-(4-硝基苯基)咪唑-4-羧酸乙酯(980mg,90%),为灰白色固体,mp198-200℃。元素分析(%):实测值:C,55.06;H,4.21;N,15.99.C12H11N3O4计算值:C,55.17;H,4.24;N,16.08.(ⅱ)1-(4-氨基苯基)咪唑-4-羧酸乙酯
氮气氛下,将1-(4-硝基苯基)咪唑-4-羧酸乙酯(参见部分(ⅰ))(950mg,3.64mmol)和氯化锡(Ⅱ)(4.11g,18.2mmol)在无水乙醇(30ml)中的混合物加热回流30分钟。冷却至室温后,减压浓缩混合物,然后分配到乙酸乙酯(30ml)和饱和碳酸氢钠溶液(20ml)内。水层用乙酸乙酯(30ml)提取,并干燥(MgSO4)和减压浓缩合并的有机层,得到1-(4-氨基苯基)咪唑-4-羧酸乙酯(810mg,96%),为黄色油状物。1H-NMR(300MHz,CDCl3):δ=1.40(3H,t,J=7Hz),2.86(2H,brs),4.39(2H,q,J=7Hz),6.76(2H,d,J=9Hz),7.18(2H,d,J=9Hz),7.72(1H,s),7.83(1H,s).m/z(热喷雾法)232(MH+).(ⅲ)1-苯基咪唑-4-羧酸乙酯
将亚硝酸叔丁酯(535mg,5.19mmol)的无水二甲基甲酰胺(15ml)溶液在氮气氛下加热至65℃,然后在10分钟内滴加入1-(4-氨基苯基)咪唑-4-羧酸乙酯(参见部分(ⅱ))(800mg,3.463mmol)的无水二甲基甲酰胺(5ml)溶液。在65℃下进一步加热混合物20分钟,然后冷却至室温。将混合物倾入饱和盐水(50ml)内,用二氯甲烷(3×20ml)提取。干燥(MgSO4)并减压浓缩合并的有机层。经硅胶快速色谱纯化(使用二氯甲烷为洗脱剂)后,得到标题化合物(520mg,70%),为灰白色固体。1H-NMR(400MHz,CDCl3):δ=1.43(3H,t,J=7Hz),4.42(2H,q,J=7Hz),7.45(3H,m),7.54(2H,m),7.88(1H,s),7.98(1H,s).m/z(热喷雾法)217(MH+).
制备例135-149
制备例1505-氨基-6,7-二氯-2,3-二甲氧基喹喔啉(a)在回流温度下,向2,3,6,7-四氯喹喔啉(175g,0.653mol)的甲醇(1.4L)悬浮液内加入25%w/w甲醇钠甲醇溶液(700ml,5.15mol),并将混合物在此温度下保持4小时。冷却混合物,加入2.1L水。过滤浆状物,固体用水(0.35L)和异丙醇(0.175L)洗涤,得到6,7-二氯-2,3-二甲氧基喹喔啉(159g,94%),系米色固体,m.p.146-148℃.1H-NMR(300MHz,CDCl3):δ=4.13(6H,s),7.83(2H,s).(b)将发烟硝酸(0.113L)预冷至-5℃,向其中分批加入6,7-二氯-2,3-二甲氧基喹喔啉(25g,0.096mol)。温热溶液至10℃并续搅拌2小时。然后将溶液倾入冰/水混合物(0.5L)。过滤浆状物,用水和异丙醇(0.05L)洗涤所得固体,得到6,7-二氯-2,3-二甲氧基-5-硝基喹喔啉(27g,92%),系米色固体,m.p.184-186℃。1H-NMR(300MHz,CDCl3):δ=4.12(3H,s),4.17(3H,s),7.98(1H,s).(c)将6,7-二氯-2,3-二甲氧基-5-硝基喹喔啉(20g,0.066mol)和5%w/w钯-炭(50%湿度)(1.2g)悬浮在四氢呋喃(0.12L)和乙酸乙酯(0.12L)混合物中。在60℃和414 kPa(60psi)压力下氢化混合物22小时,冷却,加二氯甲烷(0.48L)稀释,并通过celite(商品名)助滤剂滤除催化剂。减压浓缩溶液,同时逐渐加入甲苯。然后过滤混合物并将固体用甲苯(20ml)洗涤,得到棕色固体标题化合物(14.2g,78%),m.p.182-4℃.1H-NMR(300MHz,CDCl3):δ=4.13(3H,s),4.14(3H,s),5.07(2H,brs),7.26(1H,s).
药理学数据
采用本说明书第20页所述的[3H]-L-689,560方法,测定所选择的实施例化合物对NMDA受体的甘氨酸位点的结合亲和性。所得结果列于下表内。
实施例 | IC50(nM) |
5 | 3 |
20 | 19 |
73 | 4 |
Claims (28)
R代表包含3或4个氮杂原子的5-元环杂芳基,该杂芳基通过环碳或环氮原子与喹喔啉二酮环连接;或者代表包含1-3个氮杂原子的6-元环杂芳基,该杂芳基通过环碳原子与喹喔啉二酮环连接;所述基团中的任一个都为任选苯并稠合的,而且它们,包括苯并稠合部分,被1或2个各自独立选自下列的取代基任选取代:C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧基,C3-C7环烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)P(C1-C4烷基),-SO2NR3R4,芳基,芳氧基,芳基(C1-C4)烷氧基和het,所述C1-C4烷基任选地被C3-C7环烷基,卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷氧基,C3-C7环烷基(C1-C4)烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2(芳基),-SO2NR3R4,吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het取代,以及所述C2-C4链烯基被芳基任选取代;
R1和R2各自独立选自H,氟,氯,溴,C1-C4烷基和卤代(C1-C4)烷基;
R3和R4各自独立选自H和C1-C4烷基,或者它们一起代表C5-C7亚烷基;
p为0,1或2;
R与“het”定义中所用的“芳基”是指苯基或萘基,它们各自被1或2个彼此独立选自C1-C4烷基,C1-C4烷氧基,羟基,卤素,卤代(C1-C4烷基)和-NR3R4的取代基任选取代;
R定义中所用的“het”是指呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,***基,四唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,所有这些基团各自为任选苯并稠合的,而且它们,包括苯并稠合部分,可以被1或2个各自独立选自下列的取代基任选取代:C1-C4烷基,C3-C7环烷基,C1-C4烷氧基,卤素,羟基,-COOH,C1-C4烷氧基羰基,烯丙氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2NR3R4,卤代(C1-C4)烷基,羟基(C1-C4)烷基,C1-C4烷氧基(C1-C4)烷基,R3R4NCO(C1-C4)烷基,芳基,芳烷基,het1和het1(C1-C4)烷基,和/或当“het”包括吡啶基,哒嗪基,嘧啶基或吡嗪基时其环氮杂原子被氧取代基任选取代;以及“het”定义中所用的“het1”是指呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,***基,四唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,它们各自被1或2个C1-C4烷基取代基任选取代。
2.权利要求1的化合物,其中R为***基或四唑基,它们各自被1或2个彼此独立选自C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧羰基,芳基和het的取代基取代,所述C1-C4烷基任选被卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷基(C1-C4)烷氧基,-COOH,C1-C4烷氧基羰基,-NR3R4,-SO2(芳基),吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het取代;或为吡啶基或嘧啶基。
3.权利要求1或2的化合物,其中R为1,2,3-***-4-基,1,2,4-***-3-基,1,2,4-***-4-基或四唑-5-基,它们各自被1或2个彼此独立选自C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧羰基,芳基和het的取代基取代,所述C1-C4烷基被卤素,羟基,C1-C4烷氧基,卤代(C1-C4)烷氧基,C3-C7环烷基(C1-C4)烷氧基,-COOH,C1-C4烷氧基羰基,-NR3R4,-SO2(芳基),吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het任选取代;或为吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基或嘧啶-5-基。
4.前述权利要求中任何一项的化合物,其中R3和R4各自独立选自H和C1-C4烷基。
5.前述权利要求中任何一项的化合物,其中“芳基”表示被1或2个各自独立选自甲基、甲氧基、羟基、氯、三氟甲基和二甲氨基的取代基任选取代的苯基。
6.前述权利要求中任何一项的化合物,其中“het”表示噻吩基,吡咯基,吡唑基,咪唑基,***基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,它们各自为任选苯并稠合的,并且可被1或2个彼此独立选自C1-C4烷基,-COOH,-NR3R4和苯基的取代基任选取代,和/或所述吡啶基、哒嗪基、嘧啶基或吡嗪基的环氮杂原子被氧取代基任选取代。
7.前述权利要求中任何一项的化合物,其中R为1,2,3-***-4-基,1,2,4-***-3-基,1,2,4-***-4-基或四唑-5-基,它们各自被1或2个彼此独立选自甲基,乙基,丙基,烯丙基,环丙基,环己基,溴,羟基,乙氧羰基,2-氯苯基,3-氯苯基,4-氯苯基,4-二甲氨基苯基,2-羟基苯基,2-甲氧基苯基,3-甲氧基苯基,4-甲氧基苯基,2-甲基苯基,苯基,4-三氟甲基苯基,2-氨基-1,3,4-噁二唑-5-基,2-羧基吡啶-5-基,1,5-二甲基-1H-吡唑-3-基,1H-咪唑-1-基,1-甲基咪唑-2-基,1-甲基咪唑-4-基,1-甲基咪唑-5-基,3-甲基异噻唑-4-基,4-甲基-1H-咪唑-5-基,3-甲基-1,2,4-噁二唑-5-基,1-甲基-1H-吡唑-4-基,5-甲基-1H-吡唑-3-基,1-甲基-1H-吡唑-5-基,1-氧化吡啶-3-基,2-甲基吡啶-3-基,2-甲基吡啶-5-基,1-苯基咪唑-4-基,5-苯基吡啶-3-基,2-苯基吡啶-5-基,1-甲基吡咯-2-基,4-甲基-1,2,3-噻二唑-5-基,2-甲基噻唑-4-基,1-甲基-1H-1,2,4-***-5-基,3-(丙-1-基)-1H-吡唑-5-基,吡嗪-2-基,1H-吡唑-4-基,哒嗪-4-基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基,噻吩-2-基,1H-1,2,4-***-5-基,1H-1,2,3-***-5-基,喹啉-3-基和喹啉-6-基的取代基取代,其中所述甲基、乙基或丙基任选被氟,羟基,甲氧基,乙氧基,2,2,2-三氟乙氧基,环己基甲氧基,环戊基甲氧基,-COOH,甲氧基羰基,二甲氨基,4-氯苯磺酰基,吗啉代,苯基,苯氧基,苄氧基,吡啶-2-基,吡啶-3-基或吡啶-4-基取代;或R为吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶-2-基或嘧啶-5-基。
8.前述权利要求中任何一项的化合物,其中R为:
1-(2-羟基乙基)-5-苯基-1,2,3-***-4-基,
1-(2-羟基乙基)-4-苯基-1,2,3-***-5-基,
2-(2-羟基乙基)-5-苯基-1,2,3-***-4-基,
1-甲基-5-苯基-1,2,3-***-4-基,
1-甲基-4-苯基-1,2,3-***-5-基,
2-甲基-5-苯基-1,2,3-***-4-基,
5-苯基-1H-1,2,3-***-4-基,
1-甲基-1H-1,2,4-***-3-基,
2-甲基-2H-1,2,4-***-3-基,
4-(2-羟基乙基)-4H-1,2,4-***-3-基,
4-甲基-4H-1,2,4-***-3-基,
3-(2-氨基-1,3,4-噁二唑-5-基)-5-甲基-4H-1,2,4-***-4-基,
3-苄基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-苄氧基甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-溴-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(3-羧基丙-1-基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(2-羧基吡啶-5-基)-5-甲氧甲基-4H-1,2,4-***-4-基,
3-(2-氯苯基)-5-甲氧基甲基-4H-1,2,4-***-4-基,
3-(2-氯苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(3-氯苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(4-氯苯基)-5-甲基-4H-1,2,4-***-4基,
3-(4-氯苯磺酰基甲基)-5-甲基-4H-1,2,4-***-4-基,
3-环己基甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-环戊基甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-环丙基-5-甲基-4H-1,2,4-***-4-基,
3,5-二(甲氧甲基)-4H-1,2,4-***-4-基,
3-(N,N-二甲氨基甲基)-5-乙基-4H-1,2,4-***-4-基,
3-(N,N-二甲氨基甲基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(4-二甲氨基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(1,5-二甲基-1H-吡唑-3-基)-5-甲氧甲基-4H-1,2,4-***-4-基,
3-(1,5-二甲基-1H-吡唑-3-基)-5-甲基-4H-1,2,4-***-4-基,
3,5-二甲基-4H-1,2,4-***-4-基,
3,5-二苯基-4H-1,2,4-***-4-基,
3-(2-乙氧基乙基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-乙氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-乙氧羰基-4H-1,2,4-***-4-基,
3-乙基-5-(2-氯苯基)-4H-1,2,4-***-4-基,
3-乙基-5-(2-甲氧基苯基)-4H-1,2,4-***-4-基,
3-乙基-5-(1-甲基吡唑-5-基)-4H-1,2,4-***-4-基,
3-乙基-5-甲基-4H-1,2,4-***-4-基,
3-乙基-5-吗啉代甲基-4H-1,2,4-***-4-基,
3-乙基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-乙基-4H-1,2,4-***-4-基,
3-(2-羟基乙基)-5-甲基-4H-1,2,4-***-4-基,
3-羟甲基-5-甲基-4H-1,2,4-***-4-基,
3-羟甲基-5-苯基-4H-1,2,4-***-4-基,
3-羟甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-羟甲基-4H-1,2,4-***-4-基,
3-羟基-5-甲基-4H-1,2,4-***-4-基,
3-(2-羟基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(1H-咪唑-1-基)-5-甲基-4H-1,2,4-***-4-基,
3-(2-甲氧基乙基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(1-甲基-1H-吡唑-5-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(2-甲基吡啶-5-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(2-甲基噻唑-4-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(1-氧化吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(1-苯基咪唑-4-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(5-苯基吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(2-苯基吡啶-5-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(喹啉-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(喹啉-6-基)-4H-1,2,4-***-4-基,
3-(2-甲氧基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(3-甲氧基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-(4-甲氧基苯基)-5-甲基-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基咪唑-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基咪唑-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基咪唑-5-基)-4H-1,2,4-***-4-基,
3-(3-甲基异噻唑-4-基)-5-甲基-4H-1,2,4-***-4-基,
3-甲基-5-(4-甲基-1H-咪唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(3-甲基-1,2,4-噁二唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基吡啶-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基吡唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(5-甲基-1H-吡唑-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基苯基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基吡咯-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(4-甲基-1,2,3-噻二唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(2-甲基噻唑-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基-1H-1,2,4-***-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1-甲基-1H-吡唑-4-基)-4H-1,2,4-***-4-基,
3-(3-甲基-1,2,4-噁二唑-5-基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-苯基-4H-1,2,4-***-4-基,
3-甲基-5-(3-[丙-1-基]-1H-吡唑-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡嗪-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1H-吡唑-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-2-基甲基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-4-基甲基)-4H-1,2,4-***-4-基,
3-甲基-5-(哒嗪-4-基)-4H-1,2,4-***-4-基,
3-甲基-5-(嘧啶-2-基)-4H-1,2,4-***-4-基,
3-甲基-5-(噻吩-2-基)-4H-1,2,4-***-4-基,
3-甲基-4H-1,2,4-***-4-基,
3-甲基-5-(1H-1,2,3-***-5-基)-4H-1,2,4-***-4-基,
3-甲基-5-(1H-1,2,4-***-5-基)-4H-1,2,4-***-4-基,
3-吗啉代甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-苯氧基甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(2-苯基乙基)-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-(吡啶-3-基)-5-(2,2,2-三氟乙氧基)甲基-4H-1,2,4-***-4-基,
3-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(4-三氟甲基苯基)-4H-1,2,4-***-4-基,
1-烯丙基四唑-5-基,
1-苄基四唑-5-基,
1-羧甲基四唑-5-基,
1-环己基四唑-5-基,
1-乙基四唑-5-基,
1-(2-羟基乙基)四唑-5-基,
1-(3-羟基丙基)四唑-5-基,
1-甲氧羰基甲基四唑-5-基,
1-(2-甲氧基乙基)四唑-5-基,
1-甲基四唑-5-基,
1-(2-苯基乙基)四唑-5-基,
1-苯基四唑-5-基,
1-(丙-2-基)四唑-5-基,
1-(2,2,2-三氟乙基)四唑-5-基,
吡啶-2-基,
吡啶-3-基,
吡啶-4-基,
嘧啶-2-基,和
嘧啶-5-基。
9.权利要求1的化合物,其中R为:
1-(3-羟基丙基)四唑-5-基,
4-甲基-4H-1,2,4-***-3-基,
1-(2-羟基乙基)-5-苯基-1,2,3-***-4-基,
3-甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(喹啉-3-基)-4H-1,2,4-***-4-基,
3-甲氧甲基-5-(喹啉-6-基)-4H-1,2,4-***-4-基,
或3-(1,5-二甲基-1H-吡唑-3-基)-5-甲基-4H-1,2,4-***-4-基。
10.前述权利要求中任何一项的化合物,其中R1和R2各自独立选自氯和C1-C4烷基。
11.前述权利要求中任何一项的化合物,其中R1和R2各自为氯。
12.权利要求1的化合物,其中:(ⅰ)R为1-(3-羟基丙基)四唑-5-基,R1为氯和R2为氯;(ⅱ)R为4-甲基-4H-1,2,4-***-3-基,R1为氯和R2为氯;(ⅲ)R为1-(2-羟基乙基)-5-苯基-1,2,3-***-4-
基,R1为氯和R2为氯;(ⅳ)R为3-甲基-5-(吡啶-3-基)-4H-1,2,4-***
-4-基,R1为氯和R2为氯;(ⅴ)R为3-甲基-5-(吡啶-3-基甲基)-4H-1,2,4-***-4-基,R1为氯和R2为氯;(ⅵ)R为3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-
***-4-基,R1为氯和R2为氯;(ⅶ)R为3-(1,5-二甲基-1H-吡唑-3-基)-5-甲基-
4H-1,2,4-***-4-基,R1为氯和R2为氯;(ⅷ)R为3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-
***-4-基,R1为氯和R2为甲基;(ⅸ)R为3-甲氧甲基-5-(吡啶-3-基)-4H-1,2,4-
***-4-基,R1为甲基和R2为氯;(ⅹ)R为3-甲氧甲基-5-(喹啉-3-基)-4H-1,2,4-三
唑-4-基,R1为氯和R2为氯,或(ⅹⅰ)R为3-甲氧甲基-5-(喹啉-6-基)-4H-1,2,4-
***-4-基,R1为氯和R2为氯;
或任一这些化合物的单一立体异构体或可药用盐。
13.权利要求1的化合物,所述化合物为:R-(-)-6,7-二氯-5-[3-甲氧甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮或其可药用盐。
14.权利要求1的化合物,所述化合物为:R-(-)-6,7-二氯-5-[3-甲氧甲基-5-(3-吡啶基)-4H-1,2,4-***-4-基]-2,3(1H,4H)-喹喔啉二酮的钠盐。
15.一种药物组合物,该组合物包括权利要求1-14中任一项所述的式(Ⅰ)化合物,或其可药用盐以及可药用的稀释剂或载体。
16.用作药物的权利要求1-14中任一项以及权利要求15中分别要求的式(Ⅰ)化合物,或其可药用盐或其组合物。
17.权利要求1-14中任一项和权利要求15分别要求的式(Ⅰ)化合物,或其可药用盐或其组合物在制备通过在NMDA受体上产生拮抗作用而治疗疾病的药物中的应用。
18.如权利要求17的应用,其中所述疾病为急性神经变性或慢性神经病学病症。
19.权利要求1-14中任一项和权利要求15分别要求的式(Ⅰ)化合物,或其可药用盐或其组合物在制备治疗中风,短暂局部缺血发作,外周手术性局部缺血或创伤性头损伤的药物中的应用。
20.通过在NMDA受体上产生拮抗作用来治疗哺乳动物疾病的方法,该方法包括用有效量的权利要求1-14中任一项和权利要求15分别要求的式(Ⅰ)化合物或其可药用盐或其组合物处理所述哺乳动物。
21.如权利要求20的方法,其中所述疾病为急性神经变性或慢性神经病学病症。
22.治疗哺乳动物的中风、短暂局部缺血发作、外周手术性局部缺血或创伤性头损伤的方法,该方法包括用有效量的权利要求1-14中任一项和权利要求15分别要求的式(Ⅰ)化合物或其可药用盐或其组合物处理所述哺乳动物。
24.权利要求23的化合物,其中R5和R6各自独立选自C1-C4烷基和其环上任选被1-3个彼此独立选自C1-C4烷基,C1-C4烷氧基,卤素,硝基和三氟甲基的取代基取代的苄基;或者它们一起代表C1-C6亚烷基,CH(苯基),CH(4-甲氧基苯基)或CH(3,4-二甲氧基苯基)。
25.权利要求1所述的式(Ⅰ)化合物的制备方法,其中R,R1和R2的定义同权利要求1,该方法包括用酸或碱水解式(Ⅱ)化合物:其中R,R1和R2的定义同本权利要求的式(Ⅰ)化合物,R5和R6独自或一起代表在酸性或碱性条件下能水解断裂以得到式(Ⅰ)化合物的基团;随后任选地转化所得式(Ⅰ)化合物形成其可药用盐。
26.权利要求25的方法,其中R5和R6各自独立选自C1-C4烷基和其环上任选地被1-3个彼此独立选自C1-C4烷基,C1-C4烷氧基,卤素,硝基和三氟甲基的取代基取代的苄基;或者它们一起代表C1-C6亚烷基,CH(苯基),CH(4-甲氧基苯基)或CH(3,4-二甲氧基苯基)。
27.权利要求25或26的方法,其中反应通过酸解式(Ⅱ)化合物进行。
28.权利要求1的化合物,其中R代表包含3或4个氮杂原子的5-元环杂芳基,该杂芳基通过环碳或环氮原子与喹喔啉二酮环连接;或者代表包含1-3个氮杂原子的6-元环杂芳基,该杂芳基通过环碳原子与喹喔啉二酮环连接;所述基团中的任一个都为任选苯并稠合的,而且它们,包括苯并稠合部分,被1或2个各自独立选自下列的取代基任选取代:C1-C4烷基,C2-C4链烯基,C3-C7环烷基,卤素,羟基,C1-C4烷氧基,C3-C7环烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2NR3R4,芳基,芳氧基,芳基(C1-C4)烷氧基和het,其中所述C1-C4烷基任选地被C3-C7环烷基,卤素,羟基,C1-C4烷氧基,C3-C7环烷氧基,-COOH,C1-C4烷氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2(芳基),-SO2NR3R4,吗啉代,芳基,芳氧基,芳基(C1-C4)烷氧基或het取代,以及所述C2-C4链烯基被芳基任选取代;R1和R2各自独立选自H,氟,氯,溴和C1-C4烷基;R3和R4各自独立选自H和C1-C4烷基,或者它们一起代表C5-C7亚烷基;p为0,1或2;R与“het”定义中所用的“芳基”是指苯基或萘基,它们各自被1或2个彼此独立选自C1-C4烷基,C1-C4烷氧基,羟基,卤素,卤代(C1-C4烷基)和-NR3R4的取代基任选取代;R定义中所用的“het”是指呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,***基,四唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,它们各自被1或2个彼此独立选自下列的取代基任选取代:C1-C4烷基,C3-C7环烷基,C1-C4烷氧基,卤素,羟基,-COOH,C1-C4烷氧基羰基,烯丙氧基羰基,-CONR3R4,-NR3R4,-S(O)p(C1-C4烷基),-SO2NR3R4,卤代(C1-C4)烷基,羟基(C1-C4)烷基,C1-C4烷氧基(C1-C4)烷基,R3R4NCO(C1-C4)烷基,芳基,芳烷基,het1和het1(C1-C4)烷基;以及“het”定义中所用的“het1”是指呋喃基,噻吩基,吡咯基,吡唑基,咪唑基,***基,四唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,噁二唑基,噻二唑基,吡啶基,哒嗪基,嘧啶基或吡嗪基,它们各自被1或2个C1-C4烷基取代基任选取代。
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ATE282608T1 (de) * | 1997-02-27 | 2004-12-15 | Pfizer | Chinoxalindionen |
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US6340758B1 (en) * | 1997-05-16 | 2002-01-22 | Warner-Lambert Company | Conformationally semi-constrained quinoxaline 2,3-diones as neuroprotective agents |
DE10005150A1 (de) | 2000-02-07 | 2001-08-09 | Merck Patent Gmbh | Verfahren zur Herstellung von 5-Arylnicotinaldehyden |
SK16242002A3 (sk) * | 2000-05-19 | 2003-04-01 | Merck Patent Gmbh | Derivát triazolu a farmaceutický prostriedok, ktorý ho obsahuje |
US7732162B2 (en) | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
WO2005006945A2 (en) * | 2003-07-03 | 2005-01-27 | The Salk Institute For Biological Studies | Methods for treating neural disorders and compounds useful therefor |
MY145368A (en) * | 2004-01-13 | 2012-01-31 | Nissan Chemical Ind Ltd | Aminoquinoxaline compounds and polyaminoquinoxaline compounds, and use thereof |
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JP2007223901A (ja) * | 2004-03-24 | 2007-09-06 | Takeda Chem Ind Ltd | 複素環化合物およびその用途 |
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WO2007112347A1 (en) * | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
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CA2686816A1 (en) | 2007-01-16 | 2008-07-24 | The Johns Hopkins University | Use of various glutamate receptor antagonists for delaying or preventing platelet activity or for treating or preventing a thrombotic disease or disorder |
KR20090115951A (ko) | 2007-03-01 | 2009-11-10 | 프로비오드룩 아게 | 글루타미닐 사이클라제 저해제의 신규 용도 |
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ES2586231T3 (es) | 2010-03-03 | 2016-10-13 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
DK2545047T3 (da) | 2010-03-10 | 2014-07-28 | Probiodrug Ag | Heterocycliske inhibitorer af glutaminylcyclase (QC, EC 2.3.2.5) |
EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
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CN111548320A (zh) * | 2019-10-09 | 2020-08-18 | 贵州大学 | 一类1,3,4-噁二唑酰肼类化合物及其制备方法和应用 |
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