CN1137886C - 新的2,3-二氧-1,2,3,4-四氢-喹喔啉基衍生物 - Google Patents
新的2,3-二氧-1,2,3,4-四氢-喹喔啉基衍生物 Download PDFInfo
- Publication number
- CN1137886C CN1137886C CNB961965819A CN96196581A CN1137886C CN 1137886 C CN1137886 C CN 1137886C CN B961965819 A CNB961965819 A CN B961965819A CN 96196581 A CN96196581 A CN 96196581A CN 1137886 C CN1137886 C CN 1137886C
- Authority
- CN
- China
- Prior art keywords
- dioxo
- nitro
- tetrahydroquinoxalin
- ylmethyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 2,3-Dioxo-1,2,3,4-tetrahydro-quinoxalinyl Chemical class 0.000 claims abstract description 749
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 77
- 150000002367 halogens Chemical class 0.000 claims abstract description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 72
- 239000001257 hydrogen Substances 0.000 claims abstract description 70
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 50
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 232
- 125000002947 alkylene group Chemical group 0.000 claims description 97
- 150000003839 salts Chemical class 0.000 claims description 64
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 9
- 239000004471 Glycine Substances 0.000 claims description 5
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 5
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 102000003678 AMPA Receptors Human genes 0.000 claims description 4
- 108090000078 AMPA Receptors Proteins 0.000 claims description 4
- 102000000079 Kainic Acid Receptors Human genes 0.000 claims description 4
- 108010069902 Kainic Acid Receptors Proteins 0.000 claims description 4
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 3
- DPFHVUSPVHRVFL-UHFFFAOYSA-N 1-[(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]ethylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C(Br)C=C2CNC(C)P(O)(O)=O DPFHVUSPVHRVFL-UHFFFAOYSA-N 0.000 claims description 2
- NVQLTEKPZZTDBI-UHFFFAOYSA-N [(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]methylphosphonic acid Chemical compound BrC1=CC(CNCP(O)(O)=O)=C2N=C(O)C(O)=NC2=C1 NVQLTEKPZZTDBI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- PYCHKUAUWGWKOT-UHFFFAOYSA-N [(3-hydroxyphenyl)-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]methyl]phosphonic acid;hydrobromide Chemical compound Br.OC1=CC=CC(C(NCC=2C=3NC(=O)C(=O)NC=3C=C(C=2)[N+]([O-])=O)P(O)(O)=O)=C1 PYCHKUAUWGWKOT-UHFFFAOYSA-N 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 171
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 60
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 49
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 46
- 125000002252 acyl group Chemical group 0.000 abstract description 44
- 239000002253 acid Substances 0.000 abstract description 39
- 125000001931 aliphatic group Chemical group 0.000 abstract description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 31
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 18
- 125000003118 aryl group Chemical group 0.000 abstract description 14
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 abstract description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001450 anions Chemical class 0.000 abstract description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 150000003008 phosphonic acid esters Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 194
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 192
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 172
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 154
- 150000003254 radicals Chemical class 0.000 description 135
- 239000000203 mixture Substances 0.000 description 101
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 70
- 239000007787 solid Substances 0.000 description 68
- 238000000354 decomposition reaction Methods 0.000 description 67
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 65
- 235000002639 sodium chloride Nutrition 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 229960000583 acetic acid Drugs 0.000 description 60
- 229940093499 ethyl acetate Drugs 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 56
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 56
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000007858 starting material Substances 0.000 description 44
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 43
- 238000000034 method Methods 0.000 description 43
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 238000001704 evaporation Methods 0.000 description 40
- 230000008020 evaporation Effects 0.000 description 40
- 125000003545 alkoxy group Chemical group 0.000 description 38
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 36
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 238000010992 reflux Methods 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 239000012074 organic phase Substances 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- 239000000725 suspension Substances 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 25
- 239000012267 brine Substances 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 23
- 239000004480 active ingredient Substances 0.000 description 22
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 241000790917 Dioxys <bee> Species 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 18
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- WIQNHLFZBWOETQ-UHFFFAOYSA-N 5-(bromomethyl)-2,3-dimethoxy-7-nitroquinoxaline Chemical compound [O-][N+](=O)C1=CC(CBr)=C2N=C(OC)C(OC)=NC2=C1 WIQNHLFZBWOETQ-UHFFFAOYSA-N 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 16
- 125000003282 alkyl amino group Chemical group 0.000 description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 16
- 229910052794 bromium Inorganic materials 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 125000005236 alkanoylamino group Chemical group 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 235000015424 sodium Nutrition 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 125000005530 alkylenedioxy group Chemical group 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 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 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 125000004450 alkenylene group Chemical group 0.000 description 12
- 125000003277 amino group Chemical group 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical group C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 11
- 150000007513 acids Chemical class 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000007796 conventional method Methods 0.000 description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 10
- 125000002541 furyl group Chemical group 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 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 10
- DBXRCHXKTJHESM-UHFFFAOYSA-N 2,3-dimethoxy-5-[(2-methylaziridin-1-yl)methyl]-7-nitroquinoxaline Chemical compound C=12N=C(OC)C(OC)=NC2=CC([N+]([O-])=O)=CC=1CN1CC1C DBXRCHXKTJHESM-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 9
- 150000001735 carboxylic acids Chemical class 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 125000004076 pyridyl group Chemical group 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 125000003831 tetrazolyl group Chemical group 0.000 description 9
- ALDVLDSZTBKTQX-UHFFFAOYSA-N 7-bromo-5-(bromomethyl)-2,3-dimethoxyquinoxaline Chemical compound BrC1=CC(CBr)=C2N=C(OC)C(OC)=NC2=C1 ALDVLDSZTBKTQX-UHFFFAOYSA-N 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- 108010010803 Gelatin Proteins 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 8
- 239000008273 gelatin Substances 0.000 description 8
- 229920000159 gelatin Polymers 0.000 description 8
- 229940014259 gelatin Drugs 0.000 description 8
- 235000019322 gelatine Nutrition 0.000 description 8
- 235000011852 gelatine desserts Nutrition 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- 125000001624 naphthyl group Chemical group 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 125000001544 thienyl group Chemical group 0.000 description 8
- GPMRDSHBSYWDAV-UHFFFAOYSA-N 7-bromo-5-methyl-1,4-dihydroquinoxaline-2,3-dione Chemical compound N1C(=O)C(=O)NC2=C1C=C(Br)C=C2C GPMRDSHBSYWDAV-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 7
- ULFNAOHBWGRYLW-UHFFFAOYSA-N 1-cyclononylazonane Chemical group C1CCCCCCCC1N1CCCCCCCC1 ULFNAOHBWGRYLW-UHFFFAOYSA-N 0.000 description 6
- XGUOQIARSDZLAZ-UHFFFAOYSA-N 2-[(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methoxy]acetic acid Chemical compound OC1=C(O)N=C2C(COCC(=O)O)=CC(Br)=CC2=N1 XGUOQIARSDZLAZ-UHFFFAOYSA-N 0.000 description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical group OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 6
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 6
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- 125000000335 thiazolyl group Chemical group 0.000 description 6
- 125000005505 thiomorpholino group Chemical group 0.000 description 6
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- QNZVAJAEXIYEKC-UHFFFAOYSA-N tert-butyl 1-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]pyrrole-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CN1CC1=CC([N+]([O-])=O)=CC2=C1NC(=O)C(=O)N2 QNZVAJAEXIYEKC-UHFFFAOYSA-N 0.000 description 1
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- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- TWQLHXSOTFRECS-UHFFFAOYSA-N tert-butyl n-[2-[(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]-2-oxoethyl]carbamate Chemical compound N1C(=O)C(=O)NC2=C1C=C(Br)C=C2CNC(=O)CNC(=O)OC(C)(C)C TWQLHXSOTFRECS-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
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- 229940078499 tricalcium phosphate Drugs 0.000 description 1
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- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JUDXOKKZTISQDJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 JUDXOKKZTISQDJ-UHFFFAOYSA-N 0.000 description 1
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
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- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- GSQBIOQCECCMOQ-UHFFFAOYSA-N β-alanine ethyl ester Chemical compound CCOC(=O)CCN GSQBIOQCECCMOQ-UHFFFAOYSA-N 0.000 description 1
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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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Abstract
本发明涉及用于制备治疗对阻断AMPA,红藻氨酸盐和/或NMDA受体的甘氨酸部位敏感的病理学疾病的药物的式I表示的2,3-二氧-1,2,3,4-四氢-喹喔啉基衍生物及其可药用盐,其中基团R1和R2之一是R5基团,另一个是-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-N+(R8)(R9)-X-R7A-(Id),-alk-O-X-R7(Ie)或-alk-S-X-R7(If),R3,R4和R5分别是氢,低级烷基,卤素,三氟甲基,氰基或硝基,R6是未被取代或低级烷基化和/或低级烷酰基化的氨基,R7是氢;脂族,脂环族或杂环脂族基团;氰基;从碳酸或碳酸的半酯或半酰胺,或从硫酸或脂族或芳族磺酸,或从磷酸或磷酸酯衍生的酰基;未被取代,脂族或芳脂族取代的和/或脂族,芳脂族或芳族酰基取代的氨基;或芳族或杂芳族基团,R8是氢;脂族或芳脂族基团;或从脂族或芳脂族羧酸,或从碳酸的脂族或芳脂族半酯衍生的酰基,或R7和R8与X和连接R8和X的氮原子一起形成一个通过氮原子连接的未取代或取代的一-或二-氮杂环烷基,氮硫杂环烷基或任意氧化的硫杂环烷基,或未取代或取代的,任意部分氢化的芳基或杂芳基,R9是脂族或芳脂族基团,或R7,R8和R9与X和连接R8,R9和X的氮原子一起形成一个未取代或取代的由季氮原子连接的季杂芳基,且A-是质子酸的阴离子,alk是低级亚烷基,及X(除非与R7,R8和连接R8和X的氮原子一起,或与连接R8,R9和X的氮原子一起,它构成上述环体系之一部分)是二价脂族,脂环族或芳脂族基团或直键。
Description
本发明涉及式I表示的2,3-二氧-1,2,3,4-四氢-喹喔啉基衍生物及其可药用盐在制备治疗对阻断AMPA,红藻氨酸盐(kainate)和/或NMDA受体的甘氨酸结合部位敏感的病理学疾病的药物中的用途及制备它们的方法和包含它们的药物组合物,其中基团R1和R2之一是R5基团,另一个是式-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-N+(R8)(R9)-X-R7A-(Id),-alk-O-X-R7(Ie)或-alk-S-X-R7(If)的基团,R3,R4和R5分别是氢,低级烷基,卤素,三氟甲基,氰基或硝基,R6是未被取代或低级烷基化和/或低级烷酰基化的氨基,R7是氢;脂族,脂环族或杂脂环族基团;氰基;从碳酸或碳酸的半酯或半酰胺,或从硫酸或脂族或芳族磺酸,或从磷酸或磷酸酯衍生的酰基;未被取代或被脂族或芳脂族取代的和/或被脂族,芳脂族或芳族酰基取代的氨基;或芳族或杂芳族基团,R8是氢;脂族或芳脂族基团;从脂族或芳脂族羧酸,或从碳酸的脂族或芳脂族半酯衍生的酰基,或R7和R8与X和连接R8和X的氮原子一起形成一个通过氮原子连接的未取代或取代的一-或二-氮杂环烷基,氮氧杂环烷基,氮硫杂环烷基或任意氧化的硫杂环烷基,或未取代或取代的,任意部分氢化的芳基或杂芳基,R9是脂族或芳脂族基团,或R7,R8和R9与X和连接R8,R9和X的氮原子一起形成一个未取代或取代的由季氮原子连接的季(氮)杂芳基,且A-是质子酸的阴离子,alk是低级亚烷基,及X(除非与R7,R8和连接R8和X的氮原子一起,或与连接R8,R9和X的氮原子一起,它构成上述环体系之一部分)是二价脂族,脂环族或芳脂族基团或直键,条件是在R1是式Ic基团,R2和R3分别是氟,氯,溴,甲基,乙基或三氟甲基,且R4是氢的式I化合物中,如果alk是亚甲基,亚乙基或亚丙基,则基团-N(R8)-X-R7不是由氮原子连接的5-员一-,二-,三-或四-氮杂芳基,而是任意由有至多6个(包括6个)碳原子的烷基苯并稠合和/或取代的,或在ω-位被式-N(Ra)-Rb基团取代的基团,其中Ra和Rb分别是氢,烷基,环烷基,苯基-低级烷基或吡啶基-低级烷基,或与连接它们的氮原子一起形成吡咯烷子基,哌啶子基,哌嗪子基,N’-低级烷基哌嗪子基,吗啉代或吖庚因子基,还涉及式I化合物及其盐,以及其制备方法和含有该化合物的药物组合物,条件是在R1,R3和R4是氢且R2是式Ib基团的式I化合物中,如果alk是亚甲基,则R6不是氨基或R7不是羧基,进一步的条件是,在R1,R3和R4是氢且R2是式Ic基团的式I化合物中,如果alk是亚甲基,则基团-N(R8)-X-R7不是1-咪唑基,或当alk是亚乙基时,-N(R8)-X-R7不是氨基,二丙氨基,N-(2-苯基乙基)-N-丙基-氨基和N’-(2-氯苯基)哌嗪子基,最后的条件是,在R1是式Ic基团,R2和R3分别是氟,氯,溴,甲基,乙基或三氟甲基,且R4是氢的式I化合物中,如果alk是亚甲基,亚乙基(CH3CH=)或亚丙基(CH3CH2CH=),则基团-N(R8)-X-R7不是由氮原子连接的5-员一-,二-,三-或四-氮杂芳基,而是任意由有至多6个(包括6个)碳原子的烷基苯并稠合和/或取代的,或在ω-位被式-N(Ra)-Rb基团取代的基团,其中Ra和Rb分别是氢,烷基,环烷基,苯基-低级烷基或吡啶基-低级烷基,或与连接它们的氮原子一起形成吡咯烷子基,哌啶子基,哌嗪子基,N’-低级烷基哌嗪子基,吗啉代或吖庚因子基。
未被取代或低级烷基化和/或低级烷酰基化的氨基是,例如,氨基,低级烷基氨基,低级烷酰基氨基,N-低级烷基-N-低级烷酰基-氨基或二-低级烷基氨基。
脂肪族基团是,例如,低级烷基,氨基-低级烷基,低级烷基氨基-低级烷基,二-低级烷基氨基-低级烷基,低级烷酰基氨基-低级烷基,羟基-低级烷基,低级烷酰氧基-低级烷基,多卤代-低级烷基,低级烷氧基-低级烷基,羟基-低级烷氧基-低级烷基,低级烷氧基-低级烷氧基-低级烷基或多卤代-低级烷氧基-低级烷基。
脂环族基团是,例如,3-至8-员,尤其是3-至7-员未取代或被游离的或脂族酯化的羧基,和/或未取代或低级烷基化和/或低级烷酰基化的氨基取代的环烷基,如相应的环烷基,羧基环烷基,低级烷氧羰基环烷基,氨基环烷基或一-或二-低级烷基氨基环烷基,具体地有环丙基,环丁基,环戊基,环己基,环庚基,环辛基,2-氨基环己基,4-羧基环己基,3-羧基环己基或2-羧基环戊基。
杂环脂族基团是,例如,有3-8(包括8),尤其是3-6个环员的未被取代或被氧,羟基和/或游离的或脂族酯化的羧基取代的一-或二-氮杂环烷基,氮氧杂环烷基或氮硫杂环烷基,如吡咯烷-1-基(吡咯烷子基),吡咯烷-2-基,哌啶-1-基(哌啶子基),哌啶-2-基,吗啉代,硫杂吗啉代,或未被取代或低级烷基化或低级烷酰基化的哌啶子基,例如,吡咯烷子基,氧杂吡咯烷基,哌啶子基,羧基哌啶子基,低级烷氧羰基哌啶子基,吗啉代或硫杂吗啉代,尤其是吗啉代,5-氧杂吡咯烷-2-基或2-羧基吡咯烷子基。
从碳酸或从碳酸的半酯或半酰胺衍生的酰基是,例如,从碳酸的脂族或芳脂族半酯,或未被取代或脂族,芳脂族或芳香族取代的酰胺衍生的,而且是,例如,游离的或脂族或芳脂族酯化的羧基,如低级烷氧羰基,或未被取代或被低级烷基,低级烷氧基,羟基,卤素和/或三氟甲基取代的苯基-低级烷氧羰基,或未被取代或脂族,芳脂族或芳香族取代的氨基甲酰基,如氨基甲酰基,低级烷基-氨基甲酰基,二-低级烷基氨基甲酰基,低级烷氧羰基-低级烷基氨基甲酰基,羧基-低级烷基氨基甲酰基,氨基甲酰基-低级烷基氨基甲酰基,N-氨基甲酰基-低级烷基-N-低级烷基-氨基甲酰基,或未被取代或被低级烷基,低级烷氧基,多卤代-低级烷氧基,羟基卤素,硝基,羧基,低级烷氧羰基,苯基,苯氧基和/或三氟甲基取代的苯基氨基甲酰基或苯基-低级烷基氨基甲酰基。
从硫酸或从脂族或芳族磺酸衍生的酰基是,例如,磺基,低级烷磺酰基,或未被取代或被低级烷基,低级烷氧基,卤素,三氟甲基,羧基和/或低级烷氧羰基取代的苄基磺酰基,或未被取代或被二-低级烷基氨基取代的萘磺酰基。
从磷酸或从磷酸酯衍生的酰基是,例如,膦酰基或三-低级烷基膦酰基。
未被取代或被脂族,芳脂族或芳香族酰基进行脂族或芳脂族取代的和/或取代的氨基是,例如,氨基,低级烷基氨基,二-低级烷基氨基,低级烷酰基氨基,或未被取代或被低级烷基,低级烷氧基,卤素和/或三氟甲基取代的苯基-低级烷基-,苯甲酰基-或萘甲酰-氨基,或脲基或脒基。
未取代或取代的芳族基团是,例如,未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,氨磺酰基,低级烷氧羰基氨基,低级烷酰基,卤素和/或三氟甲基取代的苯基或萘基。
未取代或取代的杂芳族基团是任意被部分氢化的5-或6-员单环或由5-或6-员环组成的双环杂芳基,如相应的呋喃基,低级烷基呋喃基,例如4-甲基呋喃-2-基,噻吩基,咪唑基,例如咪唑-4-基,噁唑基,羧基-低级烷基(氧)噁唑基,例如2,5-二氢-3-氧-1,2-噁唑基,噻唑基,二氢噻唑基,例如4,5-二氢-噻唑基,羧基-低级烷基噻唑基,例如4-羧基甲基噻唑基,低级烷氧羰基-低级烷基噻唑基,例如4-甲氧羰基甲基噻唑基或4-乙氧羰基甲基噻唑基,四唑基,吡啶基,吡嗪基,吲哚基,例如吲哚-3-基,喹啉基,例如喹啉-4-基,苯并吖庚因基或羧基-低级烷基-2,3,4,5-四氢-1H-1-苯并吖庚因基,例如1-羧甲基-2,3,4,5-四氢-1H-1-苯并吖庚因基。
芳脂族基团是,例如,未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级烷基。
从脂族或芳脂族羧酸衍生的酰基是,例如,低级烷酰基,低级烯酰基(alkenoyl),或未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级烷酰基。
从羧酸的脂族或芳脂族半酯衍生的酰基是,例如,低级烷氧羰基,或未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级烷氧羰基。
由R7和R8与X和连接R8和X的氮原子一起并通过氮原子连接形成的未取代或取代的一-或二-氮杂环烷基,氮氧杂环烷基,氮硫杂环烷基或任意氧化的硫杂环烷基是,例如,3-7员,尤其是5-7员一-或二-氮杂环烷基,氮氧杂环烷基,氮硫杂环烷基或任意氧化的硫杂环烷基,或由5-和/或6-员环组成的双环氮杂环烷基,优选未被取代或被下列基团取代的吡咯烷子基,咪唑烷子基,四氢噻唑基,哌啶子基,吗啉代,硫杂吗啉代,哌嗪子基,高哌啶子基或1-氮杂双环壬基,所说的取代基包括:脂族,芳脂族或芳香族基团,如低级烷基和羟基-低级烷基,未取代或取代的苯基低级烷基或苯基,游离的,酯化的或酰胺化的羧基,如羧基,低级烷氧羰基,未取代或取代的苯基氨基甲酰基,未取代的或低级烷基化的和/或低级烷酰基化的氨基,如二-低级烷基氨基或低级烷酰基氨基,2-氧杂咪唑烷子基,游离的或酯化的膦酰基,如膦酰基或三-低级烷基-膦酰基,四唑基,从脂族或芳香族羧酸衍生的酰基,如低级烷酰基或未取代或取代的苯甲酰基,例如,氟代苯甲酰基,羟基,氧代和/或低级烷氧基,如吡咯烷子基,低级烷基吡咯烷子基,羧酸吡咯烷子基,例如,2-羧基吡咯烷子基,低级烷氧羰基吡咯烷子基,羟基吡咯烷子基,例如,3-羟基吡咯烷子基,羟基-低级烷基吡咯烷子基,例如,2-羟基甲基吡咯烷子基,--或二-氧杂吡咯烷子基,例如,2-氧杂吡咯烷子基或2,5-二氧杂吡咯烷子基,低级烷基(氧杂)吡咯烷子基,例如,2-甲基-5-氧杂-吡咯烷子基,羟基-低级烷基(氧杂)吡咯烷子基,例如,2-羟基甲基-5-氧杂-吡咯烷子基,羧基(氧杂)吡咯烷子基,例如,5-羧基-2-氧杂-吡咯烷子基,2-羧基-4-羟基-吡咯烷子基或2-羧基-3-羟基-吡咯烷子基,低级烷氧羰基(氧杂)吡咯烷子基,2-氧杂咪唑烷子基,例如,2-氧杂-3-苯基咪唑烷子基,四氢噻唑基,例如,四氢噻唑-1-基,哌啶子基,低级烷基哌啶子基,例如,4-甲基哌啶子基,3-甲基哌啶子基或4-丁基哌啶子基,二-低级烷基哌啶子基,例如,2,6-二甲基哌啶子基,羧基哌啶子基,例如,4-羧基哌啶子基,2-羧基哌啶子基或3-羧基哌啶子基,低级烷氧羰基哌啶子基,例如,4-乙氧羰基哌啶子基或2-乙氧羰基哌啶子基,苯基氨基甲酰基哌啶子基,例如,3-苯基氨基甲酰基哌啶子基,2-苯基氨基甲酰基哌啶子基或4-苯基氨基甲酰基哌啶子基,氧杂哌啶子基,例如,4-氧杂哌啶子基,二氧杂哌啶子基,例如,3,6-氧杂(苯基-低级烷基)哌啶子基,如2-苄基-4-氧杂-哌啶子基,二氧杂哌啶子基,氧杂(苯基)哌啶子基,例如,2-氧杂-3-苯基-哌啶子基或2-氧杂-5-苯基-哌啶子基,羟基哌啶子基,例如,4-羟基哌啶子基或3-羟基哌啶子基,羟基(苯基-低级烷基)哌啶子基,例如,2-苄基-4-羟基-哌啶子基,羧基(羟基)哌啶子基,例如,2-羧基-4-羟基-哌啶子基,二-低级烷基氨基哌啶子基,例如,4-二甲氨基哌啶子基,低级烷酰胺基哌啶子基,例如,4-乙酰胺基哌啶子基,低级烷酰胺基(苯基-低级烷基)哌啶子基,例如,4-乙酰胺基-2-苄基-哌啶子基,低级烷酰胺基(苯基)哌啶子基,例如,4-乙酰胺基-2-苯基-哌啶子基,苯基哌啶子基,例如,4-苯基哌啶子基,低级烷氧基哌啶子基,例如,4-甲氧基哌啶子基,低级烷氧基(低级烷基)哌啶子基,例如,4-甲氧基-4-甲基-哌啶子基,二-低级烷氧基哌啶子基,例如,4,4-二甲氧基哌啶子基,二-低级烷氧基(低级烷基)哌啶子基,例如,2-苄基-4,4-二甲氧基哌啶子基,低级亚烷基二氧基哌啶子基,例如,4-亚乙基二氧基哌啶子基,羟基-低级烷基哌啶子基,例如,2-(2-羟乙基)哌啶子基,2-羟甲基哌啶子基,4-(1-羟乙基)哌啶子基,4-羟甲基哌啶子基,未取代的或卤化的苯甲酰基哌啶子基,例如,4-(4-氟苯甲酰基)哌啶子基,低级烷酰基哌啶子基,例如,4-乙酰基哌啶子基,或氧杂咪唑烷子基哌啶子基,例如,4-(2-氧杂咪唑烷子基)哌啶子基,高哌啶子基,氧杂高哌啶子基,例如,2-氧杂高哌啶子基,氮杂双环壬基,例如,1-氮杂双环壬基,哌嗪子基,低级烷基哌嗪子基,例如,4-甲基哌嗪子基,氧杂哌嗪子基,例如,3-氧杂哌嗪子基,二氧哌嗪子基,例如,3,5-二氧哌嗪子基,未取代或低级烷氧基化的苯基哌嗪子基,例如,4-(4-甲氧基苯基)哌嗪子基,吗啉代,二-低级烷基吗啉代,例如,3,5-二甲基吗啉代,或硫杂吗啉代。
由R7和R8与X和连接R8和X的氮原子一起形成的未取代或取代的,任意部分氢化的芳基是,例如,未被取代或被低级烷基,低级烷氧基,羟基,卤素,羧基,低级烷氧羰基和/或三氟甲基取代的苯基,环己二烯基,萘基或四氢萘基,如苯基,4-羟基苯基,3-甲氧基苯基,3-羧基苯基,4-氟苯基,2-氟苯基,3-氟苯基,3,5-双三氟甲基苯基,环己-1,3-二烯-5-基或1,2,3,4-四氢萘基。
由R7和R8与连接R8和X的氮原子一起形成的未取代或取代的,任意部分氢化的杂芳基是,例如,未被取代或被羧基,低级烷氧羰基和/或低级烷酰基取代的任意部分氢化的吡咯基,如吡咯-1-基,1,5-二氢吡咯-1-基,羧基吡咯基,例如,2-羧基吡咯-1基或3-羧基吡咯-1-基,低级烷氧羰基吡咯基,例如,3-甲氧羰基吡咯-1-基,3-乙氧羰基吡咯-1-基或3-丁氧羰基吡咯-1-基,低级烷酰基吡咯基,例如,3-乙酰基吡咯-1-基;呋喃基,例如,呋喃-2-基;噻吩基,例如,噻吩-2-基或噻吩-3-基;未被取代或被低级烷基,羟基-低级烷基,羧基,羧基低级烷基和/或低级烷氧羰基氨基-低级烷基取代的咪唑基,如咪唑-1-基,低级烷基咪唑基,例如,4-甲基咪唑-1-基,2-甲基咪唑-1-基或2-乙基咪唑-1-基,二-低级烷基咪唑基,例如,2-乙基-4-甲基-咪唑-1-基,羟基-低级烷基咪唑基,例如,4-羟基甲基咪唑基,羧基-低级烷基咪唑基,例如,羧基甲基咪唑-1-基,羧基(低级烷氧羰基氨基-低级烷基)咪唑基,例如,4-(3-叔丁氧羰基氨基丙-1-基)-2-(2-羧基乙基)-咪唑基-1-基;未被取代或被羧基-低级烷基和/或低级烷氧羰基-低级烷基取代的任意部分氢化的噻唑基,如噻唑-2-基,3,4-二氢噻唑-2-基,羧基-低级烷基噻唑基,例如,4-羧基甲基噻唑-2-基,低级烷氧羰基-低级烷基噻唑基,例如,4-乙氧羰基乙基噻唑基-2-基;未被取代或低级烷基取代的吡唑基,如吡唑-1-基,或二-低级烷基吡唑基,例如,3,5-二甲基吡唑-1-基;三唑基,如1,2,4-三唑-1-基;未被取代或氧取代的,任意部分氢化的吡啶基,如吡啶基,例如,吡啶-2-基,1,2,5,6-四氢吡啶-1-基,氧杂二氢吡啶基,例如,2-氧-1,2-二氢-吡啶-1-基,氧杂四氢吡啶基,例如,2-氧-1,2,3,4-四氢-嘧啶-1-基;吡嗪基,例如,吡嗪-2-基;未被取代或被羧基,羧基-低级烷基,低级烷氧羰基,低级烷氧羰基-低级烷基,氰基-低级烷基和/或硝基取代的吲哚基,如吲哚-2-基,羧基吲哚基,例如,2-羧基吲哚-1-基或3-羧基吲哚-1-基,羧基-低级烷基吲哚基,例如,3-羧基甲基吲哚-1-基,低级烷氧羰基吲哚基,例如,3-甲氧羰基吲哚-1-基或2-丁氧羰基吲哚-1-基,低级烷氧羰基-低级烷基吲哚基,例如,3-乙氧羰基甲基吲哚-1-基,氰基-低级烷基吲哚基,例如,3-氰基甲基吲哚-1-基,硝基吲哚基,例如,5-硝基吲哚-1-基;苯并呋喃基,例如,苯并呋喃-2-基;未被取代或硝基取代的苯并咪唑基,如苯并咪唑基,5-硝基苯并咪唑-1-基或6-硝基苯并咪唑-1-基;四氢喹啉基,如1,2,3,4-四氢喹啉-1-基;未被取代或氧取代的四氢异喹啉基,如1,2,3,4-四氢异喹啉-1-基或2-氧-1,2,3,4-四氢异喹啉-1-基,或四氢苯并吖庚因基,如2,3,4,5-四氢-1H-1-苯并吖庚因-1-基。
二价脂族基团X是,例如,未被取代或被氧,羟基和/或氨基取代的低级亚烷基,低级亚烯基和低级亚烷基(RCH=),如低级亚烷基,低级亚烷基(RCH=),低级亚烯基,氧代-低级亚烷基(包括羰基),氧代-低级亚烷基(RCH=),二氧-低级亚烷基,氧代-低级亚烯基,羟基-低级亚烷基(RCH=),氧代(羟基)-低级亚烷基,氨基-低级亚烷基,氨基-低级亚烷基(RCH=),羧基-低级亚烷基,羧基-低级亚烷基(RCH=),氨基甲酰基-低级亚烷基(RCH=),低级烷氧羰基-低级亚烷基(RCH=),低级烷氧羰基-低级亚烷基或ω-氮杂-α-氧代-低级亚烷基或ω-氮杂-α-氧代-低级亚烯基。
二价脂环族基团X是,例如,3-7员,优选3-5员亚环烷基,如亚环丙基,亚环丁基或亚环戊基。
二价芳脂族基团X是,例如,未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级亚烷基(RCH=)或苯基-低级亚烷基。
上下文中所说“低级”基团和化合物可理解为含有多至7个(包括7个),尤其是多至4个(包括4个)碳原子的基团。
氨基-低级烷基是,例如,氨基-C1-C4烷基,如氨基甲基,2-氨基乙基,3-氨基丙基或4-氨基丁基。
氨基-低级亚烷基是,例如,氨基-C1-C4亚烷基,如氨基亚甲基,2-氨基亚乙基,3-氨基亚丙基或4-氨基亚丁基。
氨基-低级亚烷基(RCH=)是,例如,氨基-C1-C7亚烷基(RCH=),如氨基亚甲基,2-氨基亚乙基(CH3CH=),3-氨基亚丙基(CH3CH2CH=)或4-氨基亚丁基(CH3CH2CH2CH=)。
氨基甲酰基-低级烷基氨基甲酰基是,例如,氨基甲酰基-C1-C4烷基氨基甲酰基,如氨基甲酰基甲基氨基甲酰基,2-氨基甲酰基乙基氨基甲酰基,3-氨基甲酰基丙基氨基甲酰基或4-氨基甲酰基丁基氨基甲酰基。
氨基甲酰基-低级亚烷基(RCH=)是,例如,氨基甲酰基-C1-C7亚烷基(RCH=),如氨基甲酰基亚甲基,2-氨基甲酰基亚乙基(CH3CH=),3-氨基甲酰基亚丙基(CH3CH2CH=),4-氨基甲酰基亚丁基(CH3CH2CH2CH=),5-氨基甲酰基亚戊基(CH3CH2CH2CH2CH=)或6-氨基甲酰基亚己基(CH3CH2CH2CH2CH2CH=)。
N-氨基甲酰基-低级烷基-N-低级烷基-氨基甲酰基是,例如,N-氨基甲酰基-C1-C4烷基-N-C1-C4烷基-氨基甲酰基,如尤其是N-氨基甲酰基甲基N-甲基氨基甲酰基。
羧基-低级烷基是,例如,羧基-C1-C4烷基,如羧甲基,1-或2-羧乙基,3-羧丙基或4-羧丁基。
羧基-低级烷基氨基甲酰基是,例如,羧基-C1-C4烷基氨基甲酰基,如羧甲基氨基甲酰基,2-羧乙基氨基甲酰基,3-羧丙基氨基甲酰基或4-羧丁基氨基甲酰基。
羧基-低级亚烷基是,例如,羧基亚甲基,1-或2-羧基亚乙基,1,3-(1-羧基)亚丙基,1,3-(3-羧基)亚丙基或1,4-(4-羧基)亚丁基。
羧基-低级亚烷基(RCH=)是,例如,羧基-C1-C7亚烷基(RCH=),如羧基亚甲基,2-羧基亚乙基(CH3CH=),3-羧基亚丙基(CH3CH2CH=),4-羧基亚丁基(CH3CH2CH2CH=),5-羧基亚戊基(CH3CH2CH2CH2CH=)或6-羧基亚己基(CH3CH2CH2CH2CH2CH=)。
氰基-低级烷基是,例如,氰基-C1-C4烷基,如氰基甲基,1-或2-氰基乙基,3-氰基丙基或4-氰基丁基。
二-低级烷基氨基环烷基是,例如,二-C1-C4烷基氨基环烷基,如二甲氨基环烷基,二乙氨基环烷基,N-乙基-N-甲基-氨基环烷基,N-丙基-N-甲基-氨基环烷基,N-异丙基-N-甲基-氨基环烷基或N-丁基-N-甲基-氨基环烷基,其中环烷基是,例如,环丙基,环丁基,环戊基或环己基。
二-低级烷基氨基是,例如,二-C1-C4烷基氨基,如二甲氨基,二乙氨基,N-乙基-N-甲基-氨基,N-丙基-N-甲基-氨基,N-异丙基-N-甲基-氨基或N-丁基-N-甲基-氨基。
二-低级烷基氨基-低级烷基是,例如,二-C1-C4烷基氨基-C1-C4烷基,如二甲氨基甲基,二乙氨基甲基,N-乙基-N-甲基-氨基甲基,N-丙基-N-甲基-氨基甲基,N-异丙基-N-甲基-氨基甲基或N-丁基-N-甲基-氨基甲基。
二-低级烷基氨基甲酰基是,例如,二-C1-C4烷基氨基甲酰基,如二甲氨基甲酰基,二乙氨基甲酰基,N-乙基-N-甲基-氨基甲酰基,N-丙基-N-甲基-氨基甲酰基,N-异丙基-N-甲基-氨基甲酰基或N-丁基-N-甲基-氨基甲酰基。
二氧-低级亚烷基是,例如,二氧-C2-C4亚烷基,1,2-二氧亚乙基(乙二酸酰基(oxalo)),1,3-(1,2-二氧)亚丙基,1,3-(2,3-二氧)亚丙基或1,4-(1,2-二氧)亚丙基。
卤素是,例如,原子序数多至35(包括35)的卤素,如氯,氟或溴。
羟基-低级烷氧基-低级烷基是,例如,羟基-C1-C4烷氧基-C1-C4烷基,如2-羟基乙氧基甲基,2-羟基甲氧基乙基,2-(2-羟基乙氧基)乙基或3-羟基-甲氧基丙基。
羟基-低级烷基是,例如,羟基-C1-C4烷基,如羟甲基,2-羟乙基,3-羟丙基或4-羟丁基。
羟基-低级亚烷基(RCH=)是,例如,羟基-C1-C4亚烷基(RCH=),如羟基亚甲基,2-羟基亚丙基(CH3CH2CH=),2-羟基亚乙基(CH3CH=),3-羟基亚丙基(CH3CH2CH=)或4-羟基亚丁基(CH3CH2CH2CH=)。
N-低级烷基-N-低级烷酰基-氨基是,例如,N-C1-C7烷酰基-N-C1-C4烷基-氨基,如N-乙酰基-N-甲基-氨基,N-丙酰基-N-甲基-氨基,N-丁酰基-N-甲基-氨基,N-异丁酰基-N-甲基-氨基或N-新戊酰基-N-甲基-氨基。
低级亚烷基(RCH=)二氧基是,例如,C1-C4亚烷基(RCH=)二氧基,如亚甲基二氧基,亚乙基(CH3CH=)二氧基或异亚丙基(CH3CH2CH=)二氧基;低级亚烷基二氧基,例如,C1-C4亚烷基二氧基,如亚乙基二氧基或1,3-亚丙基二氧基。
低级烷酰基是,例如,C1-C7烷酰基,如乙酰基,丙酰基,丁酰基,异丁酰基或新戊酰基。
低级烷酰胺基是,例如,C1-C7烷酰胺基,如乙酰胺基,丙酰胺基,丁酰胺基,异丁酰胺基或新戊酰胺基。
低级烷酰胺基-低级烷基是,例如,C1-C7烷酰胺基-C1-C4烷基,如乙酰胺基甲基,丙酰胺基甲基,丁酰胺基甲基或异丁酰胺基甲基及新戊酰胺基甲基。
低级烷酰氧基-低级烷基是,例如,C1-C7烷酰氧基-C1-C4烷基,如乙酰氧基甲基,丙酰氧基甲基,丁酰氧基甲基或异丁酰氧基甲基及新戊酰氧基甲基。
低级烯酰基是,例如,C3-C7烯酰基,如丙烯酰基,异丁烯酰基,巴豆酰基或乙烯基乙酰基。
低级亚烯基,例如,C2-C7亚烯基,如乙烯基,1,3-丙-2-亚烯基,1,2-丙-2-亚烯基,1,4-丁-2-亚烯基,1,2-丁-3-亚烯基,1,2-戊-4-亚烯基,1,2-己-4-亚烯基或1,2-己-5-亚烯基。
低级烷氧基是,例如,C1-C7烷氧基,优选C1-C4烷氧基,如甲氧基,乙氧基,丙氧基,异丙氧基或丁氧基,但也可以是异丁氧基,仲丁氧基,叔丁氧基或戊氧基,己氧基或庚氧基。
低级烷氧羰基是,例如,C1-C7烷氧羰基,优选C1-C4烷氧羰基,如甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基或丁氧羰基,但也可以是异丁氧羰基,仲丁氧羰基,叔丁氧羰基或戊氧羰基,己氧羰基或庚氧羰基。
低级烷氧羰基氨基是,例如,C1-C7烷氧羰基氨基,优选C1-C4烷氧羰基氨基,如甲氧羰基氨基,乙氧羰基氨基,丙氧羰基氨基,异丙氧羰基氨基或丁氧羰基氨基。
低级烷氧羰基氨基-低级烷基是,例如,C1-C7烷氧羰基氨基-C1-C4烷基,优选C1-C4烷氧羰基氨基-C1-C4烷基,如甲氧羰基氨基甲基,乙氧羰基氨基甲基,丙氧羰基氨基甲基,异丙氧羰基氨基甲基或丁氧羰基氨基甲基。
低级烷氧羰基-低级烷基氨基甲酰基是,例如,C1-C7烷氧羰基-C1-C4烷基氨基甲酰基,优选C1-C4烷氧羰基-C1-C4烷基氨基甲酰基,如甲氧羰基甲基氨基甲酰基,乙氧羰基甲基氨基甲酰基,丙氧羰基甲基氨基甲酰基,异丙氧羰基甲基氨基甲酰基或丁氧羰基甲基氨基甲酰基。
低级烷氧羰基环烷基是,例如,C1-C7烷氧羰基环烷基,优选C1-C4烷氧羰基环烷基,如甲氧羰基环烷基,乙氧羰基氨基甲酰基环烷基,丙氧羰基环烷基,异丙氧羰基环烷基或丁氧羰基环烷基,其中环烷基是,例如,环丙基,环丁基,环戊基或环己基。
低级烷氧羰基-低级烷基是,例如,C1-C7烷氧羰基-C1-C4烷基,优选C1-C4烷氧羰基-C1-C4烷基,如甲氧羰基甲基,甲氧羰基乙基,乙氧羰基甲基,乙氧羰基乙基,甲氧羰基丙基,乙氧羰基丙基,丙氧羰基甲基,丙氧羰基乙基,异丙氧羰基甲基,异丙氧羰基乙基或丁氧羰基甲基。
低级烷氧羰基-低级亚烷基是,例如,C1-C7烷氧羰基-C2-C4亚烷基,优选C1-C4烷氧羰基-C2-C4亚烷基,如1-甲氧羰基亚乙基,1-乙氧羰基亚乙基,1,3-(甲氧羰基)亚丙基,1,3-(乙氧羰基)亚丙基,1,3-(丙氧羰基)亚丙基,1,3-(丁氧羰基)亚丙基,1,3-(叔丁氧羰基)亚丙基或1,3-(叔丁氧羰基)亚丙基。
低级烷氧羰基-低级亚烷基(RCH=)是,例如,C1-C7烷氧羰基-C1-C7亚烷基(RCH=),如甲氧羰基亚甲基,乙氧羰基亚甲基,2-甲氧羰基亚乙基(CH3CH=),2-乙氧羰基亚乙基(CH3CH=),3-甲氧羰基亚丙基(CH3CH2CH=),3-乙氧羰基亚丙基(CH3CH2CH=),4-甲氧羰基亚丁基(CH3CH2CH2CH=),4-乙氧羰基亚丁基(CH3CH2CH2CH=),5-甲氧羰基亚戊基(CH3CH2CH2CH2CH=),5-乙氧羰基亚戊基(CH3CH2CH2CH2CH=),6-甲氧羰基亚己基(CH3CH2CH2CH2CH2CH=),6-乙氧羰基亚己基(CH3CH2CH2CH2CH2CH=)。
低级烷氧基-低级烷氧基-低级烷基是,例如,C1-C4烷氧基-C1-C4烷氧基-C1-C4烷基,如2-甲氧基乙氧基甲基,2-乙氧基乙氧基甲基,2-(2-甲氧基乙氧基)乙基或2-(乙氧基乙氧基)乙基。
低级烷氧基-低级烷基是,例如,C1-C4烷氧基-C1-C4烷基,如2-甲氧基乙基,乙氧基甲基,2-甲氧基乙基,2-乙氧基乙基,3-甲氧基丙基或4-甲氧基丁基。
低级烷基氨基环烷基是,例如,C1-C4烷基氨基环烷基,如甲氨基环烷基,乙氨基环烷基,丙氨基环烷基,异丙氨基环烷基或丁氨基环烷基,其中环烷基是,例如,环丙基,环丁基,环戊基或环己基。
低级烷基是,例如,C1-C7烷基,优选C1-C4烷基,如首选甲基,次选乙基,丙基,异丙基或丁基,但也可以是异丁基,仲丁基,叔丁基或C5-C7烷基,如戊基,己基或庚基。
低级烷基氨基是,例如,C1-C4烷基氨基,如甲氨基,乙氨基,丙氨基,异丙氨基或丁氨基。
低级烷氨基-低级烷基是,例如,C1-C4烷氨基-C1-C4烷基,如甲氨基甲基,乙氨基甲基,2-甲氨基乙基,2-乙氨基乙基,丙氨基甲基,异丙氨基甲基或丁氨基甲基。
低级烷氨基氨基甲酰基是,例如,C1-C4烷氨基氨基甲酰基,如甲氨基氨基甲酰基,乙氨基氨基甲酰基,丙氨基氨基甲酰基,异丙氨基氨基甲酰基或丁氨基氨基甲酰基。
低级亚烷基可以是直链或支链并且可以在任何位置连接的,例如,直链或支链C1-C4亚烷基,如首选亚甲基,也可以是1,2-亚乙基,1,3-或1,2-亚丙基,或1,4-,1,3-或2,3-亚丁基。
低级亚烷基(RCH=)可以是直链或支链并且可以在任何位置成对连接的,例如,直链或支链C1-C4亚烷基,如首选亚甲基,也可以是1,1-亚乙基(CH3CH=),1,1-或2,2-亚丙基(CH3CH2CH=)或1,1-亚丁基(CH3CH2CH2CH=)。
N-低级烷基-N-低级烷酰基-氨基是,例如,N-C1-C7烷酰基-N-C1-C4烷基-氨基,如N-乙酰基-N-甲基-氨基,N-丙酰基-N-甲基-氨基,N-丁酰基-N-甲基-氨基,N-异丁酰基-N-甲基-氨基或N-新戊酰基-N-甲基-氨基。
低级烷磺酰基是,例如,C1-C4烷磺酰基,如甲磺酰基,乙磺酰基或丙磺酰基。
氧代(羟基)-低级亚烷基是,例如,氧代(羟基)-C2-C4亚烷基,如1-氧代-2-羟基亚乙基,1,3-(1-氧代-2-羟基)亚丙基,1,3-(1-氧代-3-羟基)亚丙基,1,3-(2-氧代-3-羟基)亚丙基或1,4-(1-氧代-2-羟基)亚丁基。
氧代-低级亚烷基,包括羰基,最好通过带氧基的碳原子连接到-N(R8)-或氧基或硫基,例如是,对应的氧代-C1-C4亚烷基,如羰基,1,2-(1-氧代)亚乙基,也可以是1,3-(1-氧代)亚丙基或1,4-(1-氧代)亚丁基。
苯基-低级烷氧羰基是,例如,苯基-C1-C4烷氧羰基,如未被取代或被C1-C4烷基,C1-C4烷氧基,羟基,卤素和/或三氟甲基取代的苄氧羰基或1-苯基乙氧羰基。
苯基-低级烷基是,例如,苯基-C1-C4烷基,如未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苄基,1-或2-苯基乙基,3-苯基丙基或4-苯基丁基。
苯基-低级烷基氨基是,例如,苯基-C1-C4烷基氨基,如未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苄氨基,1-或2-苯基乙氨基,3-苯基丙氨基或4-苯基丁氨基。
苯基-低级亚烷基是,例如,苯基-C2-C4亚烷基,如未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基亚乙基,1-或2-苯基亚丙基,或1-或2-苯基亚丁基。
苯基-低级亚烷基(RCH=)是,例如,苯基-C1-C7亚烷基(RCH=),如亚苄基,2-苯基亚乙基(CH3CH=),3-苯基亚丙基(CH3CH2CH=),4-苯基亚丁基(CH3CH2CH2CH=),5-苯基亚戊基(CH3CH2CH2CH2CH=)或6-苯基亚己基(CH3CH2CH2CH2CH2CH=)。
多卤代-低级烷氧基-低级烷基是,例如,三氟甲氧基-C1-C4烷基,如三氟甲氧基甲基,2-三氟甲氧基乙基,3-三氟甲氧基丙基或4-三氟甲氧基丁基。
多卤代-低级烷基是,例如,三氟甲基。
三-低级烷基膦酰基是,例如,三-C1-C7烷基膦酰基,优选三-C1-C4烷基膦酰基,如首选三甲基膦酰基,或次选三乙基膦酰基,三丙基膦酰基,三异丙基膦酰基或三丁基膦酰基。
ω-氮杂-α-氧代-低级亚烯基是,例如,1,3-(3-氮杂-1-氧代)丙-2-亚烯基。
ω-氮杂-α-氧代-低级亚烷基是,例如,1,3-(3-氮杂-1-氧代)亚丙基。
有酸性基团的式I化合物可以与碱形成盐。有碱性基团的式I化合物还可以形成酸加成盐,另外,如果至少有一个酸性基团存在,还可以形成内盐。
式I化合物与碱形成的盐是,例如,与可药用碱形成的盐,如由基团Ia,Ib,IIa和IIb的金属衍生的无毒金属盐,例如,碱金属盐,尤其是钠或钾盐,碱土金属盐,尤其是钙或镁盐,也可以是与氨或有机胺或季铵碱形成的铵盐,如任意C-羟基化的脂族胺,尤其是一-,二-或三-低级烷基胺,例如,甲基-,乙基-或二乙基-胺,一-,二-或三-(羟基-低级烷基)胺,如乙醇胺,二乙醇胺或三乙醇胺,三(羟甲基)甲胺或2-羟基-叔丁胺,或N-(羟基-低级烷基)-N,N-二-低级烷基-胺或N-(多羟基-低级烷基)-N-低级烷基胺,如2-(二甲氨基)乙醇或D-葡糖胺或胆碱,或氢氧化脂肪族季铵(quaternary aliphaticammonium hydroxides),例如,氢氧化四丁基铵。
式I化合物的酸加成盐是,例如,与适当的无机酸如氢卤酸,硫酸或磷酸形成的可药用盐,如盐酸盐,氢溴酸盐,硫酸盐,硫酸氢盐或磷酸盐,与适当羧酸,例如,任意羟基化的低级链烷酸如乙酸,乙醇酸,丙酸,乳酸或新戊酸,任意羟基化和/或氧取代的低级烷二羧酸如草酸,琥珀酸,富马酸,马来酸,酒石酸,柠檬酸,丙酮酸,苹果酸,抗坏血酸形成的盐,也可以是与芳香族,杂芳族或芳脂族羧酸如苯甲酸,烟酸或扁桃酸形成的盐,以及与适当脂族或芳香族磺酸或N-取代的氨基磺酸形成的盐,例如,甲磺酸盐,苯磺酸盐或N-环己基氨基磺酸盐(环己基氨基磺酸盐类)。
还包括全盐和部分盐,也就是说,相应于每摩尔式I酸与1,2或3当量,优选2当量碱形成的盐,或相应于每摩尔式I碱与1,2或3当量,优选1当量酸形成的盐。
为了分离或纯化目的可以使用药物上不可接受的盐。但只有药物上可接受的无毒盐能用于治疗,因此,它们是优选的。
式I化合物具有有价值的药理学性质。它们表现出对AMPA受体,红藻氨酸盐受体和/或NMDA受体的甘氨酸结合部位较强的亲和力。对于上述受体的亲和力是普遍性的或根据结构是有选择性的。选择的式I化合物尤其表现出对AMPA和/或红藻氨酸盐的结合部位有强亲和力,而对NMDA受体的甘氨酸结合部位的亲和力不强。
可在鼠(小鼠,大鼠)脑膜内用体外放射照相技术根据[3H]-AMPA,[3H]-红藻氨酸盐或[3H]-DCKA(5,7-二氯犬尿喹啉酸)的位移测定本发明制备的化合物及其盐的结合能力,对50%位移所需的浓度(IC50)要经过对几种浓度进行测定。
为了测定对AMPA受体的结合力可以采用,例如,Honore T.,Lauridson J.和Krongsgaard-Larson,《神经化学杂志》(J.Neurochem),38,p.173-178,所述放射性受体测定法进行测定,测定结果表明式I化合物的IC50值约为0.05-5μM。例如,对于N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-2-噻唑啉氢溴酸盐,测得IC50值为0.3微摩尔/升。对红藻氨酸盐受体结合力的测定可以采用,例如,Simon J.R,Contrere J.F.和Kuhn M.J.,《神经化学杂志(J.Neurochem)》,
26,p.141-147,所述放射性受体测定法进行测定,测定结果表明式I化合物的IC50值约为0.5-5μM。
式I化合物对NMDA受体甘氨酸结合部位结合力的测定可以采用,例如,Baron M.B.,Siegel B.W.等人,《欧洲药理学杂志,分子药理学部分》(Eur.J.Pharmacol.,Molec.Pharmacol.Section),
206,p.149-154(1991)和Canton T.,Doble A.等人,《药物药理学杂志》(J.Pharm.Pharmacol.),
44,p.812-816(1992),所述放射性受体测定法对鼠皮质层和鼠海马膜进行测定。在该实验过程中式I化合物的IC50值在约0.005-5μM范围内。例如,对于N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-噻吩基-乙酰胺,测得IC50值为0.007微摩尔/升。
利用这些性质的优点式I化合物有显著的抗惊厥性(例如,通过对小鼠体内测定可得到这个结论)。根据它们对电休克或戊四氮引起的惊厥的明显的保护作用,例如,可以采用根据Schmutz等人,Naunyn-Schmiedeberg’s Arch.Pharmacal.,342,p.61-66(1990)已建立好的电休克鼠模型或戊四氮引起惊厥的鼠模型进行测定。
据此,式I化合物及其可药用盐极适于预防和治疗阻断上述一种或多种类型刺激性氨基酸受体所产生的病变,例如,神经变性疾病,如由中风,低血糖,缺氧或脑麻痹综合征引起的神经变性病;脑局部缺血病,如脑局部缺血,心外科或心动停止时的脑局部缺血,产期窒息,癫痫发作,亨廷顿舞蹈病,阿尔茨海默病和帕金森病,肌萎缩性侧索硬化,脊柱和脑损伤,以及由神经毒素或滥用药物引起的中毒综合征;眼局部缺血病;血管和肌肉痉挛,如偏头痛,或局部或全身性痉挛;惊厥,如癫痫;及焦虑不安和疼痛,如三叉神经痛。
其中基团R1或R2不是R5的结构较简单的式I化合物是,例如,氨基-低级烷基或羟基-低级烷基,也可以用作制备有侧链或较复杂结构的式I化合物的中间体,通过用常规方法取代前者,例如,采用常规的亲核取代方法取代氨基或羟基。
本发明尤其涉及这样的式I化合物及其盐,其中基团R1和R2之一是R5基团,另一个是-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-N+(R8)(R9)-X-R7A-(Id),-alk-O-X-R7(Ie)或-alk-S-X-R7(If),R3,R4和R5分别是氢,低级烷基,卤素,三氟甲基,氰基或硝基,R6是氨基,低级烷基氨基,低级烷酰基氨基,N-低级烷基-N-低级烷酰基-氨基或二-低级烷基氨基,R7是氢,低级烷基,氨基-低级烷基,低级烷基氨基-低级烷基,二-低级烷基氨基-低级烷基,低级烷酰基氨基-低级烷基,羟基-低级烷基,低级烷酰氧基-低级烷基,多卤代-低级烷基,低级烷氧基-低级烷基,羟基-低级烷氧基-低级烷基,低级烷氧基-低级烷氧基-低级烷基或多卤代-低级烷氧基-低级烷基,3-8员环烷基,羧基环烷基,低级烷氧羰基环烷基,氨基环烷基或一-或二-低级烷基氨基环烷基,吡咯烷子基,氧杂吡咯烷基,羧基吡咯烷子基,哌啶子基,羧基哌啶子基,低级烷氧羰基哌啶子基,吗啉代或硫杂吗啉代,羧基,低级烷氧羰基;未被取代或被低级烷基,低级烷氧基,羟基,卤素和/或三氟甲基取代的苯基-低级烷氧羰基;氨基甲酰基,氰基,低级烷基氨基甲酰基,二-低级烷基氨基甲酰基,低级烷氧羰基-低级烷基氨基甲酰基,羧基-低级烷基氨基甲酰基,氨基甲酰基-低级烷基氨基甲酰基,N-氨基甲酰基-低级烷基-N-低级烷基-氨基甲酰基;未被取代或被低级烷基,低级烷氧基,多卤代-低级烷氧基,羟基,卤素,硝基,羧基,低级烷氧羰基,苯基,苯氧基和/或三氟甲基取代的苯基氨基甲酰基;硫基,低级烷磺酰基;未被取代或被低级烷基,低级烷氧基,卤素,三氟甲基,羧基和/或低级烷氧羰基取代的苄磺酰基;未取代或二-低级烷基氨基取代的萘磺酰基,膦酰基,三-低级烷基膦酰基,氨基,低级烷基氨基,二-低级烷基氨基,低级烷酰基氨基;未被取代或被低级烷基,低级烷氧基,卤素和/或三氟甲基取代的苯基-低级烷基氨基,苯甲酰胺基或萘甲酰胺基;脲基,脒基;未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,氨磺酰基,低级烷氧羰基氨基,低级烷酰基,卤素和/或三氟甲基取代的苯基或萘基;呋喃基,低级烷基呋喃基,噻吩基,咪唑基,噁唑基,噁唑啉基(二羟基噁唑基),羧基-低级烷基(氧杂)噁唑啉基,噻唑基,噻唑啉基(二羟基噻唑基),羧基-低级烷基噻唑基,低级烷氧羰基-低级烷基-噻唑基,四唑基,吡啶基,吡嗪基,吲哚基,喹啉基,苯并吖庚因基或羧基-低级烷基-2,3,4,5-四氢-1H-1-苯并吖庚因基,R8是氢,低级烷基,氨基-低级烷基,低级烷基氨基-低级烷基,二-低级烷基氨基-低级烷基,低级烷酰基氨基-低级烷基,羟基-低级烷基,低级烷酰氧基-低级烷基,多卤代-低级烷基,低级烷氧基-低级烷基,羟基-低级烷氧基-低级烷基,低级烷氧基-低级烷氧基-低级烷基,多卤代-低级烷氧基-低级烷基;未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级烷基;低级烷酰基,低级烯酰基;未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级烷酰基;低级烷氧羰基,或未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级烷氧羰基,或R7和R8与X和连接R8和X的氮原子一起形成一个未被取代或被低级烷基,羟基-低级烷基,未取代或取代的苯基-低级烷基或苯基,羧基,低级烷氧羰基,未取代或取代的苯基氨基甲酰基,二-低级烷基氨基,低级烷酰基氨基,2-氧杂咪唑烷子基,膦酰基,三-低级烷基膦酰基,四唑基,低级烷酰基,未取代或取代的苯甲酰基,羟基,氧杂和/或低级烷氧基取代的吡咯烷子基,咪唑烷子基,四氢噻唑基,哌啶子基,吗啉代,硫杂吗啉代,哌嗪子基,高哌啶子基或1-氮杂双环壬基;未被取代或被羧基,低级烷氧羰基和/或低级烷酰基取代的任意部分氢化的吡咯基;呋喃基;噻吩基;未被取代或被低级烷基,羟基-低级烷基,羧基,羧基-低级烷基和/或低级烷氧羰基氨基-低级烷基取代的咪唑基;未被取代和被羧基-低级烷基和/或低级烷氧羰基-低级烷基取代的任意部分氢化的噻唑基;未取代或低级烷基取代的吡唑基;三唑基;未取代或氧杂取代的任意部分氢化的吡啶基;未取代或氧杂取代的任意部分氢化的嘧啶基;吡嗪基;未被取代或被羧基,羧基-低级烷基,低级烷氧羰基,低级烷氧羰基-低级烷基,氰基-低级烷基和/或硝基取代的吲哚基;苯并呋喃基;未取代或硝基取代的苯并咪唑基;四氢喹啉基;未取代或氧杂取代的四氢异喹啉基;四氢苯并吖庚因基;或未被取代或被低级烷基,低级烷氧基,羟基,卤素,羧基,低级烷氧羰基和/或三氟甲基取代的苯基,环己二烯基,萘基或四氢萘基;R9是低级烷基,低级烯基,低级炔基,或未被取代或被低级烷基,低级烷氧基,卤素和/或三氟甲基取代的苯基-低级烷基;R7,R8和R9与X和连接R8,R9和X的氮原子一起形成一个未被取代或被C1-C4烷基,氨基,C1-C4烷基氨基或二-C1-C4烷基氨基取代的吡啶鎓基团,且A-是氢卤酸,低级烷磺酸,或未取代或低级烷基-或卤代-取代的苯磺酸的阴离子,alk是低级亚烷基,及X(除非与R7,R8和连接R8和X的氮原子一起,或与连接R8,R9和X的氮原子一起,它构成上述环体系之一部分)是低级亚烷基,低级亚烷基(RCH=),低级亚烯基,包括羰基的氧代-低级亚烷基,氧代-低级亚烷基(RCH=),二氧-低级亚烷基,氧代-低级亚烯基,羟基-低级亚烷基(RCH=),氧代(羟基)-低级亚烷基,氨基-低级亚烷基,氨基-低级亚烷基(RCH=),羧基-低级亚烷基,羧基-低级亚烷基(RCH=),氨基甲酰基-低级亚烷基(RCH=),低级烷氧羰基-低级亚烷基(RCH=),低级烷氧羰基-低级亚烷基,ω-氮杂-α-氧代-低级亚烷基或ω-氮杂-α-氧代-低级亚烯基,3-7员亚环烷基(RCH=),或未被取代或被低级烷基,低级烷氧基,低级亚烷基二氧基,低级亚烷基(RCH=)二氧基,羟基,低级烷氧羰基,羧基,氨基甲酰基,低级烷酰基,卤素和/或三氟甲基取代的苯基-低级亚烷基(RCH=)或苯基-低级亚烷基。
另一方面,本发明尤其涉及这样的式I化合物及其盐,其中基团R1和R2之一是R5基团,另一个是-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-O-X-R7(Ie)或-alk-S-X-R7(If),R3,R4和R5分别是氢,低级烷基,卤素,氰基或硝基,R6是氨基,低级烷基氨基,低级烷酰基氨基,N-低级烷基-N-低级烷酰基-氨基或二-低级烷基氨基,R7是羧基,低级烷氧羰基;未被取代或被低级烷基,低级烷氧基,羟基,卤素和/或三氟甲基取代的苯基-低级烷氧羰基;氨基甲酰基;未被取代或被低级烷基,低级烷氧基,羟基,卤素,硝基,羧基,低级烷氧羰基,苯基,苯氧基和/或三氟甲基取代的苯基氨基甲酰基;膦酰基,一-,二-或三-低级烷基膦酰基,或四唑基,R8是氢,低级烷基,或与X和连接R8和X的氮原子一起形成一个亚吡咯烷基(pyrrolidinylene),亚哌啶基或亚哌嗪基,alk是低级亚烷基,及X是低级亚烷基,包括羰基的氧代-低级亚烷基,低级亚烷基(RCH=),氨基-低级亚烷基(RCH=),羧基-低级亚烷基(RCH=),低级烷氧羰基-低级亚烷基(RCH=),氨基甲酰基-低级亚烷基(RCH=),或与N(R8)一起通过α-碳原子连接成ω-氮杂-α-氧代-低级亚烷基或ω-氮杂-α-氧代-低级亚烯基;或是未被取代或被低级烷基,低级烷氧基,卤素和/或三氟甲基取代的苯基-低级亚烷基(RCH=),或在式Ic中,与R8和连接R8和X的氮原子一起形成吡咯烷基,哌啶基或哌嗪基。
另一方面,本发明尤其涉及这样的式I化合物及其盐,其中基团R1和R2之一是R5基团,另一个是-alk-N(R8)-X-R7(Ic),R3,R4和R5分别是氢,低级烷基,卤素,氰基或硝基,R7是未被取代或被低级烷基,低级烷氧基,羧基,低级烷氧羰基,未取代或低级烷基-,低级烷氧基-,羟基-,卤素-和/或三氟甲基-取代的苯基-低级烷氧羰基,氨基甲酰基,未取代或低级烷基-,低级烷氧基-,羟基-,卤素-,硝基-,羧基-,低级烷氧羰基-,苯基-,苯氧基-和/或三氟甲基-取代的苯基氨基甲酰基,氰基,硝基,卤素和/或三氟甲基取代的苯基,萘基,呋喃基,噻吩基,吡啶基或3-8员环烷基,或是低级烷基,氨基-低级烷基,低级烷基氨基-低级烷基,二-低级烷基氨基-低级烷基,低级烷酰基氨基-低级烷基,羟基-低级烷基,低级烷酰氧基-低级烷基,多卤代-低级烷基,低级烷氧基-低级烷基,羟基-低级烷氧基-低级烷基,低级烷氧基-低级烷氧基-低级烷基或多卤代-低级烷氧基-低级烷基,R8是氢或低级烷基,alk是低级亚烷基,及X是氧代-低级亚烷基。
本发明尤其涉及这样的式I化合物及其盐,其中基团R1和R2之一是R5基团,另一个是-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-N+(R8)(R9)-X-R7A-(Id),-alk-O-X-R7(Ie)或-alk-S-X-R7(If),R3,R4和R5分别是氢,C1-C4烷基,如甲基或乙基,原子序数不超过35(包括35)的卤素,如氯,氟,或溴,三氟甲基,氰基或硝基,R6是氨基,C1-C4烷基氨基,C1-C4烷酰基氨基,N-C1-C4烷基-N-C1-C4烷酰基-氨基或二-C1-C4烷基氨基,R7是氢,C1-C7烷基,如甲基,乙基,异丙基,丁基,叔丁基,戊-4-基,庚-4-基,羟基-C1-C4烷基,如2-羟乙基,多卤代-C1-C4烷基,如三氟甲基,C1-C4烷氧基-C1-C4烷基,如甲氧基甲基或2-甲氧基乙基,3-6员环烷基,如环丙基或环己基,3-6员羧基环烷基,如2-羧基环戊基或3-或4-羧基环己基,3-6员氨基环烷基,如2-氨基环己基,吡咯烷子基,羧基吡咯烷子基,例如2-羧基吡咯烷子基,氧杂吡咯烷基,例如5-氧代吡咯烷-2-基,哌啶子基,羧基哌啶子基,吗啉代或硫杂吗啉代,羧基,C1-C4烷氧羰基,如甲氧羰基,乙氧羰基或叔丁氧羰基,苯基-C1-C4烷氧羰基,如苄氧羰基,氨基甲酰基,氰基,C1-C4烷基氨基甲酰基,如甲基氨基甲酰基,C1-C4烷氧羰基氨基甲酰基,如乙氧羰基甲基氨基甲酰基或2-乙氧羰基乙基氨基甲酰基,羧基-C1-C4烷基氨基甲酰基,如羧甲基氨基甲酰基,氨基甲酰基-C1-C4烷基氨基甲酰基,N-氨基甲酰基-C1-C4烷基-N-C1-C4烷基-氨基甲酰基,N-羧基-C1-C4烷基-N-C1-C4烷基-氨基甲酰基,如N-羧甲基-N-甲基-氨基甲酰基,氨基甲酰基-C1-C4烷基氨基甲酰基,如氨基甲酰基甲基氨基甲酰基,未取代或羧基取代的苯基-C1-C4烷基氨基甲酰基,如苄基氨基甲酰基或1-羧基-3-苯基-丙基氨基甲酰基;未被取代或被C1-C4烷氧基,硝基,多卤代-C1-C4烷氧基,苯氧基或C1-C4烷氧羰基取代的苯基氨基甲酰基,如苯基-氨基甲酰基,4-三氟甲氧基苯基氨基甲酰基,4-甲氧基苯基氨基甲酰基,2-甲氧基苯基氨基甲酰基,4-乙氧羰基苯基氨基甲酰基,3-乙氧羰基苯基氨基甲酰基,4-苯氧基苯基氨基甲酰基或4-硝基苯基氨基甲酰基;硫基,C1-C4烷磺酰基,如甲磺酰基;未被取代或被C1-C4烷基,C1-C4烷氧基和/或羧基取代的苄磺酰基,如苯磺酰基,甲苯磺酰基,2-羧基苄磺酰基或4-甲氧基苯磺酰基;未取代或二-C1-C4烷基氨基取代的萘磺酰基,如5-二甲氨基萘磺酰基,膦酰基,氨基,C1-C4烷基氨基,二-C1-C4烷基氨基,如二甲氨基,C1-C4烷酰基氨基,如乙酰胺基,苯基-C1-C4烷基氨基,如苄基氨基,苯甲酰胺基或萘甲酰胺基;脲基,脒基;未被取代或被C1-C4烷基,C1-C4烷氧基,C1-C4亚烷基二氧基,C1-C4亚烷基(RCH=)二氧基,羧基,氨磺酰基,C1-C4烷氧羰基氨基,C1-C4烷酰基氧基,羟基,卤素和/或三氟甲基取代的苯基或萘基,如苯基,萘基,2-甲基苯基,3-甲氧基苯基,4-甲氧基苯基,3,4,5-三甲氧基苯基,3,4-亚甲基二氧基苯基,2-羧基苯基,3-羧基苯基,4-羧基苯基或8-羧基萘基,4-氨磺酰基苯基,4-叔丁氧羰基氨基苯基,2-叔丁氧羰基氨基苯基,2-乙酰氧基苯基,3,4-二羟基苯基,2-氟苯基,3-氟苯基,3-氟苯基,4-氟苯基,3,4-二氯苯基或3,5-双三氟甲基苯基;呋喃基,如2-呋喃基,C1-C4烷基呋喃基,如4-甲基呋喃-2-基,噻吩基,咪唑基,如咪唑-1-基或咪唑-4-基,(氧杂)噁唑啉基,如2,5-二氢-3-氧代-1,2-噁唑基,噻唑基,噻唑啉基(二氢噻唑基),如4,5-二氢噻唑基,羧基-C1-C4烷基噻唑基,如4-羧基甲基噻唑基,C1-C4烷氧羰基-C1-C4烷基噻唑基,如甲氧羰基-甲基噻唑基或乙氧羰基甲基噻唑基,四唑基,吡啶基,吡嗪基,吲哚基,如吲哚-3-基,喹啉基,如喹啉-4-基,苯并吖庚因基或羧基-C1-C4烷基-2,3,4,5-四氢-1H-1-苯并吖庚因基,如1-羧甲基-2,3,4,5-四氢-1H-1-苯并吖庚因基,R8是氢,C1-C4烷基,如甲基,乙基或异丙基,羟基-C1-C4烷基,如2-羟乙基,C1-C4烷氧基-C1-C4烷基,如2-甲氧基乙基,羟基-C1-C4烷氧基-C1-C4烷基,如2-(2-羟基乙氧基)乙基,苯基-C1-C4烷基,如苄基,吡啶基-C1-C4烷基,如吡啶基甲基,C1-C4烷酰基,如乙酰基,苯基-C1-C4烷酰基,如苯基乙酰基,C1-C4烷氧羰基,如叔丁氧羰基,或苯基-C1-C4烷氧羰基,如苄氧羰基,或R7和R8与X和连接R8和X的氮原子一起形成吡咯烷子基,羧基吡咯烷子基,如2-羧基吡咯烷子基,羟基吡咯烷子基,如3-羟基吡咯烷子基,羟基-C1-C4烷基吡咯烷子基,如2-羟甲基吡咯烷子基,一-或二-氧杂吡咯烷子基,如2-氧杂吡咯烷子基或2,5-二氧杂吡咯烷子基,C1-C4烷基(氧杂)吡咯烷子基,如2-甲基-5-氧杂-吡咯烷子基,羟基-C1-C4烷基(氧杂)吡咯烷子基,如2-羟甲基-5-氧杂-吡咯烷子基,羧基(氧杂)吡咯烷子基,如5-羧基-2-氧杂-吡咯烷子基,2-羧基-4-羟基-吡咯烷子基或2-羧基-3-羟基-吡咯烷子基,2-氧杂咪唑烷子基,如2-氧杂-3-苯基-咪唑烷子基,四氢噻唑基,如四氢噻唑-1-基,哌啶子基,C1-C4烷基哌啶子基,如4-甲基哌啶子基,3-甲基哌啶子基或4-丁基哌啶子基,二-C1-C4烷基哌啶子基,如2,6-二甲基哌啶子基,羧基哌啶子基,如2-羧基哌啶子基,3-羧基哌啶子基或4-羧基哌啶子基,C1-C4烷氧羰基哌啶子基,如2-乙氧羰基哌啶子基或4-乙氧羰基哌啶子基,苯基氨基甲酰基哌啶子基,如2-苯基氨基甲酰基哌啶子基,3-苯基氨基甲酰基哌啶子基或4-苯基氨基甲酰基哌啶子基,氧杂哌啶子基,如4-氧杂哌啶子基,二氧杂哌啶子基,氧杂(苯基-C1-C4烷基)哌啶子基,如2-苄基-4-氧杂-哌啶子基,氧杂(苯基)哌啶子基,如2-氧杂-3-苯基-哌啶子基或2-氧杂-5-苯基-哌啶子基,羟基哌啶子基,如3-羟基哌啶子基或4-羟基哌啶子基,羟基(苯基-C1-C4烷基)哌啶子基,如2-苄基-4-羟基-哌啶子基,羧基(羟基)哌啶子基,如2-羧基-4-羟基-哌啶子基,二-C1-C4烷基氨基哌啶子基,如4-二甲氨基哌啶子基,C1-C4烷酰胺基哌啶子基,如4-乙酰胺基哌啶子基,C1-C4烷酰胺基(苯基-C1-C4烷基)哌啶子基,如4-乙酰胺基-2-苄基-哌啶子基,C1-C4烷酰胺基(苯基)哌啶子基,如4-乙酰胺基-2-苯基-哌啶子基,苯基哌啶子基,如4-苯基哌啶子基,C1-C4烷氧基哌啶子基,如4-甲氧基哌啶子基,C1-C4烷氧基(C1-C4烷基)哌啶子基,如4-甲氧基-4-甲基-哌啶子基,二-C1-C4烷氧基哌啶子基,如4,4-二甲氧基哌啶子基,二-C1-C4烷氧基(苯基-C1-C4烷基)哌啶子基,如2-苄基-4,4-二甲氧基哌啶子基,C1-C4亚烷基二氧基哌啶子基,如4-亚乙基二氧基哌啶子基,羟基-C1-C4烷基哌啶子基,如2-羟甲基哌啶子基,4-羟甲基哌啶子基,2-(2-羟乙基)哌啶子基或4-(1-羟甲基)哌啶子基,未取代的或卤化的苯甲酰基哌啶子基,如4-(4-氟苯甲酰基)哌啶子基,C1-C4烷酰基哌啶子基,如4-乙酰基哌啶子基,氧杂-咪唑烷子基哌啶子基,如4-(2-氧杂咪唑烷子基)哌啶子基,高哌啶子基,氧杂-高哌啶子基,如2-氧杂高哌啶子基,氮杂双环壬基,如1-氮杂双环壬基,哌嗪子基,C1-C4烷基哌嗪子基,如4-甲基哌嗪子基,氧杂哌嗪子基,如3-氧杂哌嗪子基,二氧杂哌嗪子基,如3,5-二氧杂哌嗪子基,未取代或低级烷氧基化的苯基哌嗪子基,如4-(4-甲氧基苯基)哌嗪子基,吗啉代,二-C1-C4烷基吗啉代,如3,5-二甲基吗啉代,硫杂吗啉代,苯基,环己-1,3-二烯-5-基,羟基苯基,如4-羟基苯基,C1-C4烷氧基苯基,如3-甲氧基苯基,羧基苯基,如3-羧基苯基,卤代苯基,如2-氟苯基,3-氟苯基或4-氟苯基,三氟甲基苯基,双三氟甲基苯基,如3,5-双三氟甲基苯基,萘基或四氢萘基,如1,2,3,4-四氢萘基,硝基苯并咪唑基,如5-硝基苯并咪唑-1-基或6-硝基苯并咪唑-1-基,四氢喹啉基,如1,2,3,4-四氢喹啉-1-基,未取代或氧杂取代的四氢异喹啉基,如1,2,3,4-四氢异喹啉-2-基或1-氧杂-1,2,3,4-四氢异喹啉-2-基,或四氢苯并吖庚因基,如2,3,4,5-四氢-1H-1-苯并吖庚因-1-基,R9是低级烷基,或R7,R8和R9与X和连接R8,R9和X的氮原子一起形成一个未被取代或被氨基,C1-C4烷基氨基或二-C1-C4烷基氨基取代的吡啶鎓基团,且A-是氢卤酸的阴离子,alk是C1-C4亚烷基或C1-C4亚烷基(RCH=),如亚甲基,亚乙基或亚乙基(CH3CH=),及X(除非与R7,R8和连接R8和X的氮原子一起,或与连接R8,R9和X的氮原子一起,它构成上述环体系之一部分)是直键,C1-C4亚烷基,如亚乙基,亚丙基或亚丁基,C1-C4亚烷基(RCH=),如亚甲基,亚乙基(CH3CH=),异亚丙基,异亚丁基或二甲基亚丙基,C1-C4亚烯基,如1,2-戊-4-亚烯基,包括羰基的氧代-C1-C4亚烷基,如羰基,氧代亚乙基,1,3-(1-氧代)亚丙基或1,4-(1-氧代)亚丁基,二氧-C1-C4亚烷基,如乙二酸酰基,氧代-C1-C4亚烯基,如1-氧代丙-2-亚烯基,羟基-C1-C4亚烷基(RCH=),如2-羟基亚乙基(CH3CH=)或2-羟基亚丙基(CH3CH2CH=),氧代(羟基)-C1-C4亚烷基,如1-氧代-2-羟基-亚乙基,氨基-C1-C4亚烷基,如氨基亚乙基,氨基-C1-C4亚烷基(RCH=),如5-氨基亚戊基(CH3CH2CH2CH2CH=),羧基-C1-C4亚烷基,如1-羧基亚乙基或1,3-(1-羧基)亚丙基,羧基-C1-C4亚烷基(RCH=),如3-羧基亚丙基(CH3CH2CH=),C1-C4烷氧羰基-C1-C4亚烷基(RCH=),如乙氧羰基亚甲基,C1-C4烷氧羰基-C1-C4亚烷基,如1,3-(1-叔丁氧羰基)亚丙基,ω-氮杂-α-氧代-C1-C4亚烷基,如1,3-(1-氧代-3-氮杂)亚丙基,或ω-氮杂-α-氧代-C1-C4亚烯基,如1,3-(3-氮杂-1-氧代)丙-2-亚烯基,3-7员亚环烷基(RCH=),如亚环丙基(CH3CH2CH=),或未被取代或被卤素和/或三氟甲基取代的苯基-C1-C4亚烷基(RCH=)或苯基-C1-C4亚烷基,如2-苯基亚乙基(CH3CH=),1,2-(1-苯基)亚乙基,1,2-[1-(4-氯苯基)亚乙基或1,3-(3-苯基)亚丙基。
在每一种情况中,本发明尤其涉及上述式I化合物及其盐,其中R1是式-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-N+(R8)(R9)-X-R7A-(Id),-alk-O-X-R7(Ie)或-alk-S-X-R7(If)基团,而R2是R5基团,其中R3,R4,R5,R6,R7,R8,R9,alk和X分别定义如上,条件是在R1是式Ic基团,R2和R3分别是氟,氯,溴,甲基,乙基或三氟甲基,及R4是氢的式I化合物中,如果alk是亚甲基,亚乙基(CH3CH=)或亚丙基(CH3CH2CH=),则基团-N(R8)-X-R7不是通过氮原子连接的5员一-,二-,三-或四-氮杂杂芳基,而是任意苯并稠合和/或被有至多6(包括6)个碳原子的烷基取代的,或在ω位被式-N(Ra)-Rb取代的基团,其中Ra和Rb分别为氢,烷基,环烷基,苯基-低级烷基或吡啶基-低级烷基,或与连接它们的氮原子一起构成吡咯烷子基,哌啶子基,哌嗪子基,N’-低级烷基哌嗪子基,吗啉代或吖庚因子基。
本发明优选这样的式I化合物及其盐,其中基团R1是-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic)或-alk-N+(R8)(R9)-X-R7A-(Id),而R2是R5基团,R3,R4和R5分别是氢,C1-C4烷基,如甲基或乙基,原子序数不超过35(包括35)的卤素,如氯,氟或溴,三氟甲基,氰基或硝基,R6是氨基,C1-C4烷基氨基,C1-C4烷酰基氨基,N-C1-C4烷基-N-C1-C4烷酰基-氨基或二-C1-C4烷基氨基,R7是氢,烷基,如乙基,羟基-C1-C4烷基,如2-羟乙基,多卤代-C1-C4烷基,如三氟甲基,3-6员环烷基,如环丙基,3-6员氮氧杂环烷基,如吗啉代,羧基,C1-C4烷氧羰基,如甲氧羰基,乙氧羰基或叔丁氧羰基,苯基-C1-C4烷氧羰基,如苄氧羰基,氨基甲酰基,苯基氨基甲酰基,C1-C4烷磺酰基,如甲磺酰基,氨基,吗啉代,苯甲酰胺基;未被取代或被羧基,氨磺酰基,C1-C4烷氧基,C1-C4烷酰氧基,卤素和/或三氟甲基取代的苯基,如苯基,3-甲基苯基,3-羧基苯基,2-氟苯基,3-氟苯基,4-氟苯基,3,5-双三氟甲基苯基;呋喃基,噻吩基,噻唑基,噻唑啉基(二氢噻唑基),如4,5-二氢噻唑基,羧基-C1-C4烷基噻唑基,如4-羧基甲基噻唑基,C1-C4烷氧羰基-C1-C4烷基噻唑基,如4-甲氧羰基-甲基噻唑基或4-乙氧羰基甲基噻唑基,或吡啶基,R8是氢,C1-C4烷基,如甲基或乙基,羟基-C1-C4烷基,如2-羟乙基,苯基-C1-C4烷基,如苄基,或吡啶基-C1-C4烷基,如吡啶基甲基,或R7和R8与X和连接R8和X的氮原子一起形成吡咯烷子基,羧基吡咯烷子基,如2-羧基吡咯烷子基,羟基吡咯烷子基,如3-羟基吡咯烷子基,四氢噻唑基,如四氢噻唑-1-基,哌啶子基,C1-C4烷基哌啶子基,如4-甲基哌啶子基,二-C1-C4烷基哌啶子基,如2,6-二甲基哌啶子基,羧基哌啶子基,如2-羧基哌啶子基,3-羧基哌啶子基或4-羧基哌啶子基,C1-C4烷氧羰基哌啶子基,如2-乙氧羰基哌啶子基或4-乙氧羰基哌啶子基,苯基氨基甲酰基哌啶子基,如2-苯基氨基甲酰基哌啶子基,3-苯基氨基甲酰基哌啶子基或4-苯基氨基甲酰基哌啶子基,氧杂哌啶子基,如4-氧杂哌啶子基,二-C1-C4烷基氨基哌啶子基,如4-二甲氨基哌啶子基,羟基-C1-C4烷基哌啶子基,如2-(2-羟乙基)哌啶子基,高哌啶子基,氮杂双环壬基,如1-氮杂双环壬基,哌嗪子基,C1-C4烷基哌嗪子基,如4-甲基哌嗪子基,氧杂哌嗪子基,如3-氧杂哌嗪子基,二氧杂哌嗪子基,如3,5-二氧杂哌嗪子基,未取代或低级烷氧基化的苯基哌嗪子基,如4-(4-甲氧基苯基)哌嗪子基,吗啉代,硫杂吗啉代,苯基,环己-1,3-二烯-5-基,羟基苯基,如4-羟基苯基,C1-C4烷氧基苯基,如3-甲氧基苯基,羧基苯基,如3-羧基苯基,卤代苯基,如2-氟苯基,3-氟苯基或4-氟苯基,三氟甲基苯基,双三氟甲基苯基,如3,5-双三氟甲基苯基,硝基苯并咪唑基,如5-硝基苯并咪唑-1-基或6-硝基苯并咪唑-1-基,四氢喹啉基,如1,2,3,4-四氢喹-1-啉-1-基,或未取代或氧杂取代的四氢异喹啉基,如1,2,3,4-四氢异喹-1-啉-1-基,R9是低级烷基,或R7,R8和R9与X和连接R8,R9和X的氮原子一起形成一个未取代或氨基取代的吡啶鎓基团,且A-是氢卤酸的阴离子,alk是C1-C4亚烷基或C1-C4亚烷基(RCH=),如亚甲基,及X(除非与R7,R8和连接R8和X的氮原子一起,或与连接R8,R9和X的氮原子一起,它构成上述环体系之一部分)是直键,C1-C7亚烷基,如亚甲基,亚乙基,亚丙基或亚丁基,C1-C4亚烷基(RCH=),如亚甲基,亚乙基(CH3CH=),异亚丙基(CH3CH2CH=)或2,2-二甲基亚丙基(CH3CH2CH=),包括羰基的氧代-C1-C4亚烷基,如羰基,氧代亚乙基,1,3-(1-氧代)亚丙基或1,4-(1-氧代)亚丁基,氧代-C1-C4亚烯基,如1-氧代丙-2-亚烯基,氨基-C1-C4亚烷基(RCH=),如5-氨基亚戊基(CH3CH2CH2CH2CH=),羧基-C1-C4亚烷基(RCH=),如3-羧基亚丙基(CH3CH2CH=),C1-C4烷氧羰基-C1-C4亚烷基(RCH=),ω-氮杂-α-氧代-C1-C4亚烷基,如1,3-(1-氧代-3-氮杂)亚丙基,或ω-氮杂-α-氧代-C1-C4亚烯基,如1,3-(3-氮杂-1-氧代)丙-2-亚烯基,或未被取代或被卤素和/或三氟甲基取代的苯基-C1-C4亚烷基(RCH=),如2-苯基亚乙基(CH3CH=)。
本发明尤其涉及这样的式I化合物及其盐,其中R1是式-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic)或-alk-N+(R8)(R9)-X-R7A-(Id)基团,而R2是R5基团,R3和R4分别是氢,C1-C4烷基,如甲基或乙基,原子序数不超过35(包括35)的卤素,如氯,氟或溴,或硝基,R5是氢,R7是氢,烷基,如乙基,多卤代-C1-C4烷基,如三氟甲基,3-6员环烷基,如环丙基,3-6员氮氧杂环烷基,如吗啉代,羧基,C1-C4烷氧羰基,如甲氧羰基或乙氧羰基;未被取代或被羧基,氨磺酰基,C1-C4烷氧基,卤素和/或三氟甲基取代的苯基,如苯基或3-甲基苯基;呋喃基,如2-呋喃基,噻唑啉基(二氢噻唑基),如4,5-二氢噻唑基,羧基-C1-C4烷基噻唑基,如4-羧基甲基噻唑基,或C1-C4烷氧羰基-C1-C4烷基噻唑基,如4-甲氧羰基-甲基噻唑基或4-乙氧羰基甲基噻唑基,R8是氢,C1-C4烷基,如甲基或乙基,或吡啶基-C1-C4烷基,如吡啶基甲基,或R7和R8与X和连接R8和X的氮原子一起形成吡咯烷子基,哌啶子基,羧基哌啶子基,如3-羧基哌啶子基或4-羧基哌啶子基,C1-C4烷氧羰基哌啶子基,如2-乙氧羰基哌啶子基或4-乙氧羰基哌啶子基,氧杂哌啶子基,如4-氧杂哌啶子基,高哌啶子基,氮杂双环壬基,如1-氮杂双环壬基,哌嗪子基,C1-C4烷基哌嗪子基,如4-甲基哌嗪子基,未取代或低级烷氧基化的苯基哌嗪子基,如4-(4-甲氧基苯基)哌嗪子基,吗啉代或硫杂吗啉代,R9是低级烷基,或R7,R8和R9与X和连接R8,R9和X的氮原子一起形成一个未取代或氨基取代的吡啶鎓基团,且A-是氢卤酸的阴离子,alk是C1-C4亚烷基或C1-C4亚烷基(RCH=),如亚甲基,及X(除非与R7,R8和连接R8和X的氮原子一起,或与连接R8,R9和X的氮原子一起,它构成上述环体系之一部分)是直键,C1-C7亚烷基,如亚甲基,亚乙基,亚丙基或亚丁基,C1-C4亚烷基(RCH=),如亚甲基,亚乙基(CH3CH=),异亚丙基或2,2-二甲基亚丙基(CH3CH2CH=),包括羰基的氧代-C1-C4亚烷基,如羰基,氧代亚乙基或1,3-(1-氧代)亚丙基,氨基-C1-C4亚烷基(RCH=),如5-氨基亚戊基(CH3CH2CH2CH2CH=),羧基-C1-C4亚烷基(RCH=),如3-羧基亚丙基(CH3CH2CH=),或未被取代或被卤素和/或三氟甲基取代的苯基-C1-C4亚烷基(RCH=),如2-苯基亚乙基(CH3CH=)。
例如,本发明尤其涉及这样的式I化合物及其盐,其中R1是式-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic),-alk-O-X2-R7(Ie)或-alk-S-X2-R7(If)基团,R2是氢,R3和R4分别是原子序数不超过35(包括35)的卤素,如溴,或硝基,R6是氨基,R7是羧基,苯基-C1-C4烷氧羰基,如苄氧羰基;未被取代或被C1-C4烷基如甲基,C1-C4烷氧基如甲氧基,羟基,原子序数不超过35(包括35)的卤素,如氟,氯或溴,硝基,羧基,C1-C4烷氧羰基,如甲氧基-或乙氧基-羰基,苯基,苯氧基和/或三氟甲基取代的苯基氨基甲酰基;或四唑基,R8是氢,或与X和连接R8和X的氮原子一起形成亚哌啶基(piperidinylene),alk是亚甲基,及X是C1-C4亚烷基(RCH=),如亚甲基,或在式Ic中是羰基,氨基-C1-C4亚烷基(RCH=),如5-氨基亚戊基(CH3CH2CH2CH2CH=),羧基-C1-C4亚烷基(RCH=),如4-羧基亚丁基(CH3CH2CH2CH=),或与N(R8)基团形成由α-碳原子连接的ω-氮杂-α-氧代-C3-C5亚烷基,如1,3-(3-氮杂-1-氧代)亚丙基,或与R8和连接R8和X的氮原子一起形成亚哌啶基。
本发明优选这样的式I化合物及其盐,其中R1是式-CH(R6)-alk-R7(Ia),-alk-CH(R6)-R7(Ib),-alk-N(R8)-X-R7(Ic)或-alk-N+(R8)(R9)-X-R7A-(Id)基团,而R2是R5基团,R3和R4分别是氢,C1-C4烷基,如甲基或乙基,原子序数不超过35(包括35)的卤素,如氯,氟或溴,或硝基,R5是氢,R7是氢,烷基,如乙基,多卤代-C1-C4烷基,如三氟甲基,3-6员环烷基,如环丙基,3-6员氮氧杂环烷基,如吗啉代,羧基,C1-C4烷氧羰基,如甲氧羰基或乙氧羰基;未被取代或被羧基,氨磺酰基,C1-C4烷氧基,卤素和/或三氟甲基取代的苯基,如苯基或3-甲基苯基;呋喃基,如2-呋喃基,噻唑啉基(二氢噻唑基),如4,5-二氢噻唑基,羧基-C1-C4烷基噻唑基,如4-羧基甲基噻唑基,或C1-C4烷氧羰基-C1-C4烷基噻唑基,如4-甲氧羰基-甲基噻唑基或4-乙氧羰基甲基噻唑基,R8是氢,C1-C4烷基,如甲基或乙基,或吡啶基-C1-C4烷基,如吡啶基甲基,或R7和R8与X和连接R8和X的氮原子一起形成吡咯烷子基,哌啶子基,羧基哌啶子基,如3-羧基哌啶子基或4-羧基哌啶子基,C1-C4烷氧羰基哌啶子基,如2-乙氧羰基哌啶子基或4-乙氧羰基哌啶子基,氧杂哌啶子基,如4-氧杂哌啶子基,高哌啶子基,氮杂双环壬基,如1-氮杂双环壬基,哌嗪子基,C1-C4烷基哌嗪子基,如4-甲基哌嗪子基,未取代或低级烷氧基化的苯基哌嗪子基,如4-(4-甲氧基苯基)哌嗪子基,吗啉代或硫杂吗啉代,alk是C1-C4亚烷基或C1-C4亚烷基(RCH=),如亚甲基,及X(除非与R7,R8和连接R8和X的氮原子一起,它构成上述环体系之一部分)是直键,C1-C7亚烷基,如亚甲基,亚乙基,亚丙基或亚丁基,C1-C4亚烷基(RCH=),如亚甲基,亚乙基(CH3CH=),异亚丙基(CH3CH2CH=)或2,2-二甲基亚丙基(CH3CH2CH=),包括羰基的氧代-C1-C4亚烷基,如羰基,氧代亚乙基,1,3-(1-氧代)亚丙基或1,4-(1-氧代)亚丁基,氧代-C1-C4亚烯基,如1-氧代丙-2-亚烯基,氨基-C1-C4亚烷基(RCH=),如5-氨基亚戊基(CH3CH2CH2CH2CH=),羧基-C1-C4亚烷基(RCH=),如3-羧基亚丙基(CH3CH2CH=),C1-C4烷氧羰基-C1-C4亚烷基(RCH=),ω-氮杂-α-氧代-C1-C4亚烷基,如1,3-(1-氧代-3-氮杂)亚丙基,或ω-氮杂-α-氧代-C1-C4亚烯基,如1,3-(3-氮杂-1-氧代)丙烯基-2-亚基,或未被取代或被卤素和/或三氟甲基取代的苯基-C1-C4亚烷基(RCH=),如2-苯基亚乙基(CH3CH=)。
另一方面,例如,本发明优选这样的式I化合物及其盐,其中R1是式-alk-N(R8)-X-R7(Ic)基团,R2是氢,R3和R4分别是原子序数不超过35(包括35)的卤素,如溴,或硝基,R6是氨基,R7是羧基,R8是氢,或与X和连接R8和X的氮原子一起形成亚哌啶基,alk是亚甲基,及X是C1-C4亚烷基(RCH=),如亚甲基,羰基,或与N(R8)基团形成ω-氮杂-α-氧代-C3-C5亚烷基,如1,3-(3-氮杂-1-氧代)亚丙基,由α-碳原子连接,或与R8和连接R8和X的氮原子一起形成亚哌啶基。
另一方面,本发明优选这样的式I化合物及其盐,其中R1是式-alk-N(R8)-X-R7(Ib)基团,R2,R3,R4和R5分别是氢,C1-C4烷基,如甲基或乙基,原子序数不超过35(包括35)的卤素,如氯,氟或溴,氰基或硝基,R7是未被取代或被C1-C4烷基如甲基,C1-C4烷氧基如甲氧基,羧基,C1-C4烷氧羰基如甲氧羰基,氨基甲酰基,氰基,硝基,卤素和/或三氟甲基取代的苯基,呋喃基,噻吩基或吡啶基,或未被取代的3-8员环烷基,如环丙基,C1-C7烷基,如甲基,乙基,丙基,异丙基,仲丁基或叔丁基,氨基-C1-C4烷基,如氨基甲基,或多卤代-C1-C4烷基,如三氟甲基,R8是氢,alk是亚甲基,及X是羰基。
本发明更优选这样的式I化合物及其盐,其中R2是R5基团,R1是式-alk-N(R8)-X-R7(Ic)或-alk-N+(R8)(R9)-X-R7A-(Id)基团,R3和R4分别是氢,C1-C4烷基,如甲基或乙基,原子序数不超过35(包括35)的卤素,如氯,氟或溴,或硝基,R5是氢,R7是3-6员环烷基,如环丙基,3-6员氮氧杂环烷基,如吗啉代,羧基,C1-C4烷氧羰基,如甲氧羰基或乙氧羰基,噻唑啉基(二氢噻唑基),如4,5-二氢噻唑基,或C1-C4烷氧羰基-C1-C4烷基噻唑基,如4-甲氧羰基-甲基噻唑基或4-乙氧羰基甲基噻唑基,R8是氢或C1-C4烷基,如甲基或乙基,或R7和R8与X和连接R8和X的氮原子一起形成吡咯烷子基,哌啶子基,羧基哌啶子基,如4-羧基哌啶子基,C1-C4烷氧羰基哌啶子基,如4-乙氧羰基哌啶子基,氧杂哌啶子基,如4-氧杂哌啶子基,或高哌啶子基,alk是亚甲基,及X(除非与R7,R8和连接R8和X的氮原子一起,它构成上述环体系之一部分)是直键,C1-C7亚烷基,如亚甲基,亚乙基,亚丙基或亚丁基,氨基-C1-C4亚烷基(RCH=),如5-氨基亚戊基(CH3CH2CH2CH2CH=),或羧基-C1-C4亚烷基(RCH=),如3-羧基亚丙基(CH3CH2CH=)。
本发明尤其涉及实施例提到的式I化合物及其盐,特别是其可药用盐。
制备本发明式I化合物的方法如下:a)在式II化合物中其中基团R’和R”相同或不同,分别为羟基保护基,基团R’1和R”2之一是R5,另一个是-CH(R’6)-alk-R7(IIa),-alk-CH(R’6)-R’7(IIb),-alk-N(R’8)-X-R’7(IIc),-alk-N+(R’8)(R9)-X-R’7A-(IId),-alk-O-X-R’7(IIe)或-alk-S-X-R’7(IIf),其中R’6是基团R6或保护的氨基,R’7是基团R7,保护的羧基或保护的氨基甲酰基,及R’8是基团R8或氨基保护基,羟基保护基R’和/或R”及可能存在的氨基-保护基R’8可以被除去,羧基或氨基甲酰基(如果存在)可从保护的羧基R’7或保护的氨基甲酰基R’7脱离,和/或b)为了制备基团R1和R2之一是式Ic,Ie或If基团的式I化合物及其盐,将式III和IV化合物缩合,和Y2-X-R’7(IV),其中基团R”1和R”2之一是基团R5,另一个是式-alk-Y1(IIIa),基团Y1和Y2之一是羟基,巯基或H-N(R’8)基团,另一个是可以除去从而形成一个键的基团,R’7是基团R7,保护的羧基或保护的氨基甲酰基,及R’8是基团R8或氨基保护基,除去可能存在的氨基保护基R’8,而且如果存在,羧基或氨基甲酰基可从保护的羧基R’7或保护的氨基甲酰基R’7游离,或c)为了制备基团R1和R2之一是基团R5,另一个是式-alk-CH(R6)-R7(Ib)的式I化合物,其中R6是氨基,R7是羧基,将式II化合物其中基团R”1和R”2之一是基团R5,另一个是式-alk-C(R’7)(R’6)-R’7(IIa’),R’和R”相同或不同,分别是羟基保护基,R’6是保护的氨基,R’7是彼此相同或不同的保护的羧基,进行酸处理,如果需要,将所得化合物转化成不同的式I化合物,将根据本方法得到的异构体混合物分离,以及将分离得到优选异构体和/或将根据本方法得到的游离化合物转化成盐,或将根据本方法得到的盐转化成对应的游离化合物。
适于用作羟基保护基的R’和R”是,例如,常用于临时保护内酰胺基的羟基保护基,尤其是形成酯的基团如低级烷基,优选甲基,和三-低级烷基甲硅烷基,如三甲基甲硅烷基。
氨基保护基R’8是,例如,酰基,而不是R”8,如从芳族羧酸或从羧酸的芳族半酯衍生的酰基,如未取代或取代的苯甲酰基,或未取代或取代的苯基羰基如苯氧基羰基。
保护的羧基是,例如,以酯形式而不是以酯化形式保护的羧基R7,以及,例如,是以未取代或取代的苯基酯形式或以三-低级烷基甲硅烷基酯如三甲基甲硅烷基酯形式保护的基团。保护的氨基甲酰基是,例如,以苯邻二甲酰亚胺形式保护的基团。
根据上述
方法变型a)从基团R’7和/或R’8中除去所说保护基R’和/或R”或游离保护基是用常规方法进行,例如,经过酸处理,如用含约20-40%的氢溴酸的乙酸处理,或进行适当的酸性水解,如用约1N-4N的盐酸和乙酸或四氢呋喃/乙醇混合物处理。
例如,其中alk是1,1-低级亚烷基(RCH=)的式II起始原料的制备方法如下:在相应的式V化合物中,其中基团R1和R2之一是低级烷基,如尤其是甲基,用常规方法,如在钯或阮内镍存在下通过催化氢化反应将硝基还原成氨基;将所得亚苯基-1,2-二胺在酸性条件下,如在盐酸存在下与草酸缩合,生成相应的式VI喹啉二酮;通过与可产生卤素Hal的卤化剂反应将该化合物转化成相应的式VII 2,3-二卤代喹喔啉;采用常规方法,例如,通过与碱金属-低级醇盐如甲醇钠反应,可将化合物中基团Hal用保护的羟基-OR’或-OR”如低级烷氧基,尤其是甲氧基取代;所得式VIII化合物用可引入卤素Y1的卤化剂,如N-溴琥珀酰亚胺,在氮杂-异丁腈存在下将其侧链卤化,形成相应的式VIII化合物,其中基团R1和R2之一是alk-Y1,另一个是基团R5,其中Y1是卤素,特别是溴,且R’和R”是羟基保护基。
然后,该化合物可以进一步与式CH2(R’6)-R’7(VIIIa),H-N(R’8)-X-R’7(VIIIb),HO-X-R’7(VIIIc)或HS-X-R’7(VIIId)反应,其中R’6是被二价芳脂族基团如亚苄基或尤其是二苯甲基保护的氨基,R’7是基团R7,保护的羧基或保护的氨基甲酰基,及R’8是是基团R8或氨基保护基。
本方法尤其适用于制备这样的式II化合物,其中R’1和R’2之一是基团R5,另一个是R6是氨基的式-alk-CH(R6)-R’7(II’b)基团,R’7是R7而不是氢,X在α位没有氧基且,例如,X是低级亚烷基或低级亚烷基(RCH=),R8是氢或脂族或芳脂族基团,或R’7和R’8与X和连接R’8和X的氮原子一起形成一个未取代或取代的一-或二-氮杂环烷基,氮氧杂环烷基,氮硫杂环烷基,或通过氮原子连接的任意氧化的硫杂环烷基或R’7是R7的式-alk-S-X-R’7(IIf)基团。
为了制备R’1和R’2之一是式-alk-N(R’8)-X-R’7(IIc;R8=氢)基团,另一个是基团R5的式II化合物,可将式IX化合物其中基团R’和R”是相同或不同的羟基保护基,基团R1a和R2a之一是基团R5,另一个是低级烷酰基如乙酰基或尤其是甲酰基,在还原条件下,例如,在二-氢化轻金属如硼氢碱金属存在下与式如H-N(R’8)-X-R’7的胺反应。
其中基团R1a和R2a之一是基团R5,另一个是其中R7是羧基且alk优选亚甲基的式-CH(R’6)-alk-R’7(IIa)基团的式II化合物,可以通过,例如,在三氟化硼醚合物存在下,使其中基团R1a和R2a之一是基团R5,另一个是甲酰基的式IX醛与低级烷基氨基甲酸酯和如H-CH=CH-alk-Si(低级烷基)3的ω-三-低级烷基甲硅烷基-低级烯烃反应,将甲酰基转化成式-CH(R’6)-alk-CH=CH2(II’a)基团,并且用常规方法,例如用碘化钠/氧化钌,在如此得到的中间体中氧化末端的乙烯基。
其中基团R1a和R2a之一是基团R5,另一个是甲酰基的式IX醛可以优选在双(三苯膦)氯化钯(II)和氯化锂存在下,通过其中基团R1和R2之一是卤素,另一个是基团R5的卤素化合物VIII与乙烯基-三-低级烷基锡烷如乙烯基-三丁基-锡烷反应,形成相应的其中基团R1和R2之一是乙烯基,另一个是基团R5的式VIII化合物,然后在-80--40℃用臭氧/氧氧化,接着与三苯膦反应得到。
另一种制备其中R1a是甲酰基,R3是氢或硝基及R2a和R4是氢的式IX化合物的方法是:在40-100℃,在低级链烷醇碱金属盐存在下,例如在沸腾的甲醇/甲醇钠中,用2-硝基丙烷的低级链烷醇处理R1是式-alk-Y1基团,R2,R3和R4是氢的式VIII化合物,其中Y1是卤素,如果需要,硝化所得产物,优选用硝酸,硫酸和三氟乙酸酐的三氟乙酸处理。
其中基团R1a和R2a之一是基团R5,另一个是低级烷酰基如乙酰基的式IX酮可以在钯催化剂如双(三苯膦)氯化钯(II)和氯化锂存在下,优选在加热着的二甲基甲酰胺中通过其中基团R1和R2之一是卤素如溴,另一个是基团R5的卤素化合物VIII与1-低级烷氧基-低级烯基-三-低级烷基-锡烷反应,酸性处理后得到相应的其中基团R1a和R2a之一是低级烷酰基,另一个是基团R5的式IX化合物。
其中基团R1和R2之一是式-alk-Y1基团,其中Y1是卤素,另一个是基团R5的卤素化合物VIII也可用作制备其中基团R’1和R’2之一是基团R5,另一个是其中R’7是基团R7且R’8是氢的式-alk-N(R’8)-X-R’7(IIc)基团的式II化合物的有利方法的起始原料。根据此方法,式VIII卤素化合物被用常规方法,例如,用链烷醇碱金属盐如甲醇钠处理,转化成相应的其中基团R1和R2之一是甲酰基的化合物VIII,然后在还原条件下,例如,在硼氢化钠存在下,进一步与式-H-N(R’8)-X-R’7(VIIIb)化合物反应。
为了制备其中基团R’1和R’2之一是基团R5,另一个是其中R’7是基团R7而不是氢,X在α位有一个氧基并且是,例如,氧代-低级亚烷基或羰基,及R8是氢的式-alk-N(R’8)-X-R’7(IIc)基团的式II化合物,可在其中基团R1和R2之一是式-alk-Y1基团,其中Y1是卤素,另一个是基团R5的化合物VIII中,采用常规方法,例如,通过与碱金属叠氮化物或叠氮化铵,如叠氮化钠,优选在二甲基甲酰胺中,将卤素Y1转化成叠氮基,然后采用常规方法,例如,通过用三苯膦的水处理,将叠氮基还原成氨基,并将所得其中基团R1和R2之一是式-alk-Y1基团,其中Y1是氨基,另一个是基团R5的化合物VIII与式HO-X-R7(VIIIe)或其反应衍生物如酰氯,例如Hal-X-R7(VIIIe1),酐,例如R7-X-O-X-R7(VIIIe2),磺酸酐如甲磺酸酐,芳香族或芳脂族异氰酸酯,例如ONC-R7(VIIIe3),或脂族二羧酸酐,例如琥珀酸酐反应。
从其中基团R1和R2之一是式-alk-Y1基团,其中Y1是氨基,另一个是基团R5的式VIII胺化合物开始也可以制备其中基团R’1和R’2之一是基团R5,另一个是其中R’7是酯化膦酰基R7如二-低级烷基膦酰基,X是亚甲基及R8是氢的式-alk-N(R’8)-X-R’7(IIc)基团的式II化合物:首先,用甲醛处理,例如在乙醇中用甲醛水溶液处理,然后,在卤代甲硅烷如三-低级烷基-氯甲硅烷存在下,将所得三聚中间体与磷酸二酯如二-低级烷基亚磷酸酯反应。
为了制备其中基团R’1和R’2之一是基团R5,另一个是式-alk-O-X-R’7(IIe)基团的式II化合物,可用与上述方法类似的方法,以其中基团R1和R2之一是式-alk-Y1基团,其中Y1是卤素,另一个是基团R5的式VIII化合物为起始原料,将-alk-Y1基团水解成相应的-alk-OH基团,然后将反应产物与其中Hal是卤素,R’7是基团R7,保护的羧基或保护的氨基甲酰基的式-Hal-X-R’7(VIIIg)化合物反应。
其中基团R’1和R’2之一,尤其是R’1为式-alk-N(R8)-X-R’7(IIc)基团,其中alk是低级亚烷基(RCH=),R8是氢且X和R’7定义如上,另一个是基团R5的式II化合物,也可用以下方法制备:在钯催化剂存在下,优选在二甲基甲酰胺中加热,将相应的其中基团R1和R2之一是卤素如溴,另一个是基团R5的式VIII化合物与1-低级烷氧基-低级烯基-三-低级烷基锡烷,优选在钯催化剂如双(三苯膦)氯化钯(II)和氯化锂存在下反应,酸处理后得到相应的其中基团R1和R2之一是低级烷酰基,另一个是基团R5的式VIII化合物;将所得化合物与式H2N-X-R’7化合物缩合,并用常规方法,例如用硼氢化钠,将所得其中基团R1和R2之一是-alk’=N-X-R’7,其中alk’是低级亚烯基,另一个是基团R5的式VIII化合物中的外环双键还原成单键。该方法的变化形式尤其适用于制备其中基团R’1和R’2之一,尤其是R’1为式-alk-N(R’8)-X-R’7(IIc)基团,其中alk是亚乙基(CH3CH=),X是低级亚烷基或低级亚烷基(RCH=)或直键,及R’8是氢,另一个是基团R5的式II化合物,即通过将上述式VIII化合物与1-乙氧基乙烯基-三丁基-锡烷反应生成相应的其中基团R1和R2之一是乙酰基,另一个是基团R5的式VIII化合物制成。
用类似的方法,经过下列反应也可以得到其中基团R’1和R’2之一,尤其是R’1为式-alk-N(R’8)-X-R’7(IIc)和-alk-O-X-R’7(IIc)基团,其中alk是亚乙基,R’8是氢,及R’7和X定义如上(,及另一个是基团R5)的式II化合物:优选在双(三苯膦)氯化钯(II)和氯化锂存在下,将上述其中基团R1和R2之一是卤素如溴,另一个是基团R5的卤素化合物VIII与乙烯基-三-低级烷基锡烷反应,生成相应的其中基团R1和R2之一是乙烯基,另一个是基团R5的式VIII化合物;经过硼氢化反应然后氧化将该化合物转化成其中基团R1和R2之一是羟乙基,另一个是基团R5的式VIII化合物,如果需要,先与甲磺酰氯反应,然后与碱金属叠氮化物反应,最后与三苯膦反应,将2-羟乙基转化成2-氨基乙基,如果需要,通过还原胺反应用式-N(R’8)-X-R’7基团取代氨基。
除非另有说明,式VIII化合物的上述反应采用常规方法进行,优选在惰性有机溶剂如四氢呋喃,二噁烷或二甲基甲酰胺,或两相系统如苯/水或甲苯/水中,如果需要,在碱性缩合剂如脂肪叔胺,例如三乙胺,或芳族叔氮碱,例如吡啶,脂族或芳脂族季铵盐,例如四甲基硫酸氢铵,或金属碱,例如碱金属氢氧化物,碱金属碳酸盐或氨基碱金属,如氢氧化钠或氢氧化钾,碳酸钠或碳酸钾,或氨基钠或氨基钾,以及任选其它赋形剂,如N-(3-二甲氨基丙基)-N’-乙基-碳化二亚胺盐酸盐/1-羟基苯并三唑存在下,如果需要,在约25-120℃,优选50-120℃范围内加热反应。
根据方法变型b)可以被除去而形成一个键的基团有,例如,在其中Y1是H-N(R8)基团或羟基与其中X在相对于Y2的α位有一个氧基,或是游离的或酯化的羟基,如羟基,低级烷氧基,苄氧基,任意硝化的苯氧基或式-O-X-R’7基团,如由羧酸酐或磺酸酐衍生的基团Y2的反应中,反应的酯化羟基,如被无机酸或磺酸,尤其是卤原子如氯,溴或碘酯化的羟基,或被脂族或未取代或取代的芳族磺酸,例如低级烷磺酰氧基如甲磺酰氧基,或未取代或取代的苯磺酰氧基如苯磺酰氧基,溴苯磺酰氧基或甲苯磺酰氧基酯化的羟基。含有这些基团的式IV化合物有,例如,其中X是低级亚烷基,低级亚烯基,低级亚烷基(RCH=),羰基氨基-低级亚烷基(RCH=),氨基甲酰基低级亚烷基(RCH=)或低级烷氧羰基-低级亚烷基(RCH=)的式HOOC-X-R7(IVa)羧酸,其中X是低级亚烷基,低级亚烷基(RCH=),羰基或一个键的式Hal-C(=O)-X-R’7(IVb)羧酰卤,其中X是低级亚烷基,低级亚烷基(RCH=)或一个键的式R’7-X-C(=O)-O-C(=O)-X-R7(IVc)羧酸酐,式Hal-S(O2)-X-R7(IVd)磺酰卤,式R7-S(O2)-O-S(O2)-R7(IVe)磺酸酐,以及二羧酸酐如琥珀酸酐。
方法变型b)中式III化合物与式IV化合物的反应采用常规方法进行,优选在惰性有机溶剂如四氢呋喃,二噁烷或二甲基甲酰胺,或两相系统如苯/水或甲苯/水中,如果需要,在碱性缩合剂如脂肪叔胺,例如三乙胺,或芳族叔氮碱,例如吡啶,脂族或芳脂族季铵盐,例如四甲基硫酸氢铵,或金属碱,例如碱金属氢氧化物,碱金属碳酸盐或氨基碱金属,如氢氧化钠或氢氧化钾,碳酸钠或碳酸钾,或氨基钠或氨基钾,以及任选其它赋形剂,如N-(3-二甲氨基丙基)-N’-乙基-碳化二亚胺盐酸盐/1-羟基苯并三唑存在下,如果需要,在约25-120℃,优选50-120℃范围内加热进行反应。
例如,在本发明优选实例中,其中Y1是羟基的式III化合物是在脂族季铵盐如四乙基磷酸氢铵存在下,在两相系统如苯/水中与Y2是卤素如溴的式IV化合物反应。
在本发明另一个优选实例中,例如,其中Y1是氨基的式III化合物在脂族叔胺如三乙胺,N-(3-二甲氨基丙基)-N’-乙基-碳化二亚胺盐酸盐和1-羟基苯并三唑存在下,与-C(O)-X-基团是α-氧代-低级亚烷基,ω-氮杂-α-氧代-低级亚烷基或ω-氮杂-α-氧代-低级亚烯基的式HOOC-X-R7(IVa)化合物反应,或与其中X是低级亚烷基,低级亚烷基(RCH=)或一个键的式R’7-X-C(=O)-O-C(=O)-X-R7(IVc)羧酸酐反应。
起始原料式III化合物可以用目前已知的方法制备,例如,在氮杂-异丁腈存在下,用可以产生卤素Y1的卤化剂如N-溴-琥珀酰亚胺卤化式VIII化合物,形成相应的其中基团R1和R2之一是式-alk-Y1基团,其中Y1是卤素(优选溴),另一个是基团R5的式VIII化合物,R’和R”是羟基保护基,并除去羟基保护基R’和R”,或如果需要,用常规方法,例如碱性水解,在碳酸钾存在下将所得其中基团R1和R2之一是式-alk-Y1基团,其中Y1是卤素,另一个是基团R5的式VIII化合物转变成相应的Y1是羟基的式III化合物,或者在二甲基甲酰胺中与碱金属叠氮化物如叠氮化钠反应,然后与三苯膦的四氢呋喃反应,并在各种情况下除去羟基保护基R’和R”,将其转化成Y1是氨基的式III化合物。
方法变型c)中的基团R”1和R”2之一是基团R5,另一个是式-alk-C(R’7)(R’6)-R’7(II’a)基团的式II化合物中的保护的氨基R’6是,例如,上述
方法变型a)的氨基保护基中的一个保护的氨基,例如低级烷酰基氨基或低级烷氧羰基氨基。保护的羧基R’7是,例如,酯化的羧基如低级烷氧羰基或三-低级烷基甲硅烷氧基羰基,未取代或取代的苯基-低级烷氧羰基或苯氧羰基。在酸性处理时保护的羧基R’7被水解成羧基,它们其中之一被脱羧基化,而且,氨基保护基R’6和如果存在的羟基保护基R’和/或R”被除去。
方法变型c)的起始原料可以采用常规方法,例如,通过其中基团R”1和R”2之一是式-alk-Y1基团且Y1是反应的酯化羟基如卤素或上述磺酰氧基之一的式VIII化合物与式H-C(R’6)(R’7)-R’7的氨基丙二酸衍生物反应制备。
可用常规方法将本方法得到的化合物转变成不同的式I化合物。
例如,可采用常规方法引入脂族,芳脂族或脂环族基团,如低级烷基,或从脂族或芳脂族羧酸,或从脂族或芳脂族半酯,或从碳酸或脂族或芳脂族磺酸的脂族,芳脂族或芳香族半酯,或从磷酸,或从磷酸酯衍生的酰基,如低级烷酰基,低级烷磺酰基,或低级烷-,低级烯-或低级炔-二羧酸的酰基,如低级烷基富马酰基,例如,通过与低级烷基化剂如低级烷基卤化物,或反应性低级链烷酸衍生物如低级烷酰氯或低级链烷酸腈,低级烷磺酸酐或低级烷磺酰氯,或低级烷-,低级烯-或低级炔-二羧酸二-低级烷基酯,如富马酸低级烷基酯,如果需要,在常规碱性缩合剂存在下反应。特别是在R1和R2之一是式Ic基团且R8是氢的式I化合物中,可以不引入氢而引入其它基团。
而且,在R1和R2之一是式Ic,Id或If基团,其中X是一个键,R7和/或R8是氢的式I化合物中,氢原子R7和/或R8可用常规方法用非氢R7和/或R8置换。
而且,含有酯化或氨化羧基的式I化合物可用常规方法水解,生成对应的羧酸。反之,含有游离羧基的式I化合物可用常规方法酯化或氨化。
而且,所得式I化合物中的氰基可用常规方法如与腙酸反应将其转化成四唑基。
可用目前已知的方法,例如,通过用碱如碱金属氢氧化物,金属碳酸盐或金属碳酸氢盐,或用本文开始时提到的其它形成盐的碱,或用酸如无机酸,例如用盐酸,或用本文开始时提到的其它形成盐的酸处理,将所得盐转化成游离化合物。
可用目前已知的方法将所得盐转化成不同的盐,例如,在其中形成的无机盐不溶解并因此可从反应平衡中除去的适当溶剂中,通过用不同酸的适当金属盐,如钠盐,钡盐或银盐处理,形成酸加成盐,以及采用使游离酸游离的办法处理碱性盐,然后再将其转化成盐。
也可以水合物形式得到式I化合物,包括它们的盐,或可以包括用于结晶过程的溶剂。
从新化合物的游离形式与其盐形式的密切关系来看,上文和下文中关于游离化合物及其盐的任何论述均应理解为还包括对应的盐和游离化合物,而且,均认为是合理和有利的。
可用基于结构间物理化学差别的已知方法如色谱和/或分级结晶法将非对映体混合物和外消旋体混合物分离成纯非对映体或外消旋体。
也可根据已知方法将所得外消旋体溶解于光学对映体,例如,从光学活性溶剂中重结晶,添加微生物或所得非对映体和外消旋体混合物与光学活性辅助化合物,例如,取决于式I化合物中的酸性,碱性或调节功能团,与光学活性酸,碱或光学活性醇反应,形成非对映体盐或功能团衍生物如酯,然后将其分离成非对映体,这些非对映体可用适当的常规方法游离出所要的对映体。适用于这一目的的碱,酸和醇有,例如,光学活性的生物碱,如马钱子碱,辛可宁或番木鳖碱,或D-或L-(1-苯基)乙胺,3-甲基哌啶,麻黄碱,苯异丙胺和类似的可合成碱,光学活性羧酸或磺酸,如奎尼酸,D-或L-酒石酸,D-或L-二-邻甲苯基酒石酸,D-或L-苹果酸,D-或L-扁桃酸,或D-或L-樟脑磺酸,以及光学活性醇,如冰片或D-或L-(1-苯基)乙醇。
本发明还涉及一些方法,根据这些方法在本方法任何阶段得到中间体化合物将在剩下的步骤中被作为起始原料使用,而且,起始原料是以盐的形式,尤其是反应条件下形成的盐的形式使用。
本发明还涉及新的起始原料,这些原料已被开发具体用于本发明化合物的制备,尤其涉及能生成在本文开始时所述的优选式I化合物的起始原料,以及制备它们和将它们用作中间体的方法。
本申请尤其涉及式IX化合物及其盐,其中基团R’和R”是相同或不同的羟基保护基,基团R1a和R2a之一是R5基团,另一个是低级烷酰基如尤其是甲酰基或乙酰基,或-CH(R’6)-alk-R7(IIa),-alk-CH(R’6)-R’7(IIb),-alk-N(R’8)-X-R’7(IIc),-alk-N+(R’8)(R9)-X-R’7A-(IId),-alk-O-X-R’7(IIe),-alk-S-X-R’7(IIIa)或-alk-Y1(IIIa),其中Y1是羟基,反应的酯化羟基,巯基或式-N(R’8)-H基团,R’7是基团R7而不是氢,或是保护的羧基或保护的氨基甲酰基,R’8是基团R8或氨基保护基,R3,R4,R5,R6,R7,R8,alk和X如同对式I化合物的定义,更具体地是对优选的式I化合物的定义,条件是,在R1a是低级烷酰基或式IIc,IIe或IIIa基团的式I化合物中,如果R2a和R3分别是氟,氯,溴,甲基,乙基或三氟甲基且R4是氢,则低级烷酰基R1a不是甲酰基或基团IIc不是由氮原子连接5员一-,二-,三-或四-氮杂芳基,而是任意由有至多6(包括6)个碳原子的烷基苯并稠合和/或取代的,或在ω-位被式-N(Ra)-Rb基团取代的基团,其中Ra和Rb分别是氢,烷基,环烷基,苯基-低级烷基或吡啶基-低级烷基,或与连接它们的氮原子一起形成吡咯烷子基,哌啶子基,哌嗪子基,N’-低级烷基哌嗪子基,吗啉代或吖庚因子基,或者基团IIe或IIIa不是羟甲基,1-羟乙基或1-羟丙基,或基团IIIa不是卤代甲基,1-卤代乙基和1-卤代丙基。
本发明优选这样的式IX化合物及其盐,其中基团R’和R”是相同或不同的羟基保护基,基团R1a和R2a之一是R5基团,另一个是低级烷酰基如尤其是甲酰基或乙酰基,或式-alk-N(R’8)-X-R’7(IIc),-alk-N+(R’8)(R9)-X-R’7A-(IId),-alk-O-X-R’7(IIe),-alk-S-X-R’7(IIf)或-alk-Y1(IIIa)基团,其中Y1是羟基,卤素,低级烷磺酰氧基,磺酰氧基或式-N(R’8)-H基团,R’7是基团R7,保护的羧基或保护的氨基甲酰基,R’8是基团R8或氨基保护基,R2a是R5基团,R3,R4和R5分别是氢,C1-C4烷基,原子序数不超过35(包括35)的卤素,氰基或硝基,R6是氨基,R7是羧基,C1-C4烷氧羰基;未被取代或被C1-C4烷基如甲基,C1-C4烷氧基,羟基,原子序数不超过35(包括35)的卤素和/或三氟甲基取代的苯基-C1-C4烷氧羰基;氨基甲酰基,未被取代或被C1-C4烷基,C1-C4烷氧基,羟基,原子序数不超过35(包括35)的卤素,硝基,羧基,C1-C4烷氧羰基,苯基,苯氧基和/或三氟甲基取代的苯基氨基甲酰基;四唑基或膦酰基,R8是氢,或与X和连接R8和X的氮原子一起形成亚吡咯烷基,亚哌啶基或亚哌嗪基,alk是C1-C4亚烷基,及X是羰基,C1-C4亚烷基,C1-C4亚烷基(RCH=),氨基-C1-C4亚烷基(RCH=),羧基-C1-C4亚烷基(RCH=),或与N(R8)基团通过α-碳原子连接成ω-氮杂-α-氧代-C3-C5亚烷基或ω-氮杂-α-氧代-C3-C5亚烯基,苯基-C1-C4亚烷基(RCH=),如2-苯基亚乙基(CH3CH=),或在式Ic中与R8和连接R8和X的氮原子一起形成亚吡咯烷基,亚哌啶基或亚哌嗪基。
本发明优选这样的式IX化合物及其盐,其中基团R’和R”是相同或不同的低级烷基,基团R1a是式(IIIa)基团,其中Y1是羟基,卤素或式-N(R’8)-H基团,其中R’8是基团R8,R2a是R5基团,R3,R4和R5分别是氢,C1-C4烷基,原子序数不超过35(包括35)的卤素,氰基或硝基,及alk是C1-C4亚烷基。
本发明还涉及含有作为活性成分的本发明化合物或其可药用盐的药物组合物,以及制备药物组合物的方法。
含有本发明化合物或其可药用盐的本发明药物组合物可以给温血动物肠道内,如口服和直肠给药,以及胃肠外给药。该组合物可以仅含有药物活性成分本身,或除此之外还含有可药用载体。活性成分的日剂量取决于给药对象的年龄,病情和给药方式。
新的药物组合物含有,例如,约10-80%,优选20-60%活性成分。以肠道内或胃肠外形式给药的本发明药物组合物是,例如,单位剂型,如锭剂,片剂,胶囊剂或栓剂,也可以是安瓿。可用目前已知的方法,例如,采用常用的混合,粒化,成型,溶解或冻干方法制备它们。例如,将活性成分与固体载体,任选是否粒化所得混合物,然后处理混合物或颗粒,如果需要或必要,添加适当赋形剂,形成片剂或锭剂芯,制成用于口服给药的药物组合物。
适当的载体具体有填充剂,如糖类,例如乳糖,蔗糖,甘露糖醇或山梨糖醇,纤维素制品和/或磷酸钙,例如磷酸三钙或磷酸氢钙,以及粘合剂,例如,用玉米,小麦,稻米或马铃薯淀粉制成的浆糊,明胶,黄蓍胶,甲基纤维素和/或聚乙烯吡咯烷酮,如果需要,还要加入崩解剂,如上述淀粉和羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂,藻酸或其盐如藻酸钠。赋形剂具体有流动剂,流动调节剂和润滑剂,例如,硅酸,滑石,硬脂酸或其盐如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。锭剂芯可用适当的(任选肠内)包衣制成,尤其可用含有阿拉伯胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛的糖浆溶液,或在适当有机溶剂或溶剂混合物中的包衣溶液制成,或者,为了制备肠内包衣,可用适当的纤维素制品如邻苯二甲酸乙酰基纤维素或邻苯二甲酸羟丙基甲基纤维素制成。可以在片剂或锭剂包衣中加入染色剂或色素,例如,为了识别目的或指出不同剂量的活性成分。
其它可口服给药的药物组合物有硬明胶胶囊和含有明胶和增稠剂如甘油或山梨糖醇的软密封胶囊。硬明胶胶囊中可以含有颗粒状活性成分,以及填充剂如乳糖,粘合剂如淀粉,和/或润滑剂(glidant)如滑石或硬脂酸镁,如果需要,还可加入稳定剂。在软胶囊中优选将活性成分溶解于或悬浮于适当液体如脂油,石蜡或液体聚乙二醇,也可以添加稳定剂
可直肠给药的适当药物组合物有,例如,活性成分与栓剂基础材料结合构成的栓剂。适当的栓剂基础材料有,例如,天然或合成的甘油三酯,石蜡烃,聚乙二醇或高级醇。也可以使用由活性成分与基础材料结合形成的明胶直肠胶囊。适当的基础材料有,例如,液体甘油三酯,聚乙二醇或石蜡烃。
对于胃肠外给药,可使用适当的,尤其是可溶于水的活性成分如可溶于水的盐的水溶液,以及活性成分的悬浮液,如相应的可注射油性悬浮液,可使用适当的亲油溶剂或载体,如脂油,例如芝麻油,或合成的脂肪酸酯,例如油酸乙酯或甘油三酯,或含有增加粘性的物质如羧甲基纤维素钠,山梨糖醇和/或葡聚糖的可注射水性悬浮液,并任意添加稳定剂。
所用活性成分的剂量由温血动物的种类,年龄和病情以及给药方式决定。在正常情况下对体重约75kg的患者的口服给药的日剂量约为10-500mg。
下列实施例用来说明本发明;温度均用摄氏度表示,压力用mbar表示。实施例1:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-甘氨酸氢溴酸盐
将380mg(0.921mmol)N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)甘氨酸叔丁酯溶解于6mL约25%溴化氢的乙酸溶液,并将溶液在70℃搅拌2小时。将混合物冷却到20℃并用乙醚稀释。滤出固体用乙醚洗涤。高真空干燥之后得到标题化合物,为白色粉末。1H-NMR(250MHz,DMSO-D6+5%D2O)δ=7.42,7.37(2d,2H),4.32(s,2H),3.91(s,2H).MS:328.2(M+H)+.M.p.=281℃(分解)
起始原料,例如,可制备如下:a)
5-溴-2,3-二氨基-甲苯
在约27℃将15g(64.9mmol)4-溴-2-甲基-6-硝基-苯胺的300mL乙醇溶液在1.5g阮内镍存在下氢化4小时。然后过滤反应混合物并蒸发浓缩,得到标题化合物为棕色油。1H-NMR(250MHz,CDCl3)δ=6.76,6.73(2d,2H),3.22(s,2NH2), 2.14(s,Me).b)
7-溴-5-甲基-1,4-二氢喹喔啉-2,3-二酮
将13.05g(64.9mmol)5-溴-2,3-二氨基-甲苯和6.42g(1.1当量)草酸在2N盐酸中回流搅拌16小时。冷却混合物,滤出固体并用水洗涤,得到标题化合物为棕色固体。1H-NMR(250MHz,DMSO)δ=11.98,11.32(2s,2NH),7.13(s,2H),2.33(s,Me).c)
7-溴-2,3-二氯-5-甲基-喹喔啉
将17g(66.6mmol)7-溴-5-甲基-1,4-二氢-喹喔啉-2,3-二酮在80mL氯氧化磷中搅拌,在回流温度搅拌5小时,然后在20℃搅拌40小时。蒸发浓缩混合物并高真空干燥。在剩余物中小心加入饱和碳酸钾溶液,然后滤出固体并用水洗涤,得到标题化合物为棕色固体。
1H-NMR(250MHz,DMSO)δ=8.16,7.99(2d,2H),2.63(s,Me).d)
7-溴-5-甲基-2,3-二甲氧基-喹喔啉
将2.97g(129.5mmol)钠溶解于100mL甲醇。将该溶液加到18.9g(64.7mmol)7-溴-5-甲基-2,3-二氯-喹喔啉的60mL甲醇中,并将混合物加热回流20小时。冷却混合物并加入15mL水。滤出固体并用甲醇和水洗涤,得到标题化合物为米色固体。
1H-NMR(250MHz,DMSO)δ=7.73,7.58(2d,2H),4.05,4.03(2s,2Me),2.58(s,Me).e)
7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉
将15g(53mmol)7-溴-5-甲基-2,3-二甲氧基-喹喔啉,9.9g(1.05当量)N-溴琥珀酰亚胺和0.87g(0.1当量)偶氮-异丁腈溶解于100mL四氯化碳,并将溶液回流搅拌24小时。滤出固体,滤液用二氯甲烷稀释,然后用水和盐水各洗涤一次。有机相用硫酸镁干燥并蒸发浓缩。剩余物从乙酸乙酯和己烷重结晶,得到标题化合物为浅橙色晶体。1H-NMR(250MHz,CDCl3)δ=7.90,7.68(2d,2H),4.95(s,2H),4.20,4.13(2s,2Me).f)
N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-甘氨酸叔丁 酯
将850mg(2.35mmol)7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉,0.982mL三乙胺和719mg甘氨酸叔丁酯盐酸盐溶解于15mL乙腈,并将溶液回流搅拌18小时。蒸发浓缩混合物,将剩余物溶解于乙醚并用5%碳酸钠水溶液和盐水洗涤。合并有机相,用硫酸镁干燥并蒸发浓缩。剩余物经硅胶色谱纯化,用乙酸乙酯和石油醚(1∶2)洗脱,得到标题化合物为黄色油。1H-NMR(250MHz,CDCl3)δ=7.88,7.57(2d,2H),4.20(s,2H),4.15,4.12(2s,2Me),3.32(s,2H),1.42(s,9H).实施例2:
下列化合物可用类似实施例1的方法制备:N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-β-氨基丙酸氢溴酸盐,m.p.=271℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-谷氨酸氢溴酸盐,m.p.=220℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-苯基丙氨酸氢溴酸盐,m.p.=249℃(分解);α-N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-赖氨酸二氢溴酸盐,m.p.=256℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-2-羧酸乙酯氢溴酸盐,m.p.=240℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸乙酯氢溴酸盐,m.p.>250℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-3-羧酸乙酯氢溴酸盐,m.p.>260℃。实施例3:
下列化合物可用类似实施例1的方法制备,但起始原料要用7-溴-5-溴甲基-2,3-二甲氧基-8-硝基-喹喔啉代替7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉:7-溴-5-(5-硝基-苯并咪唑-1-基甲基)-1,4-二氢-喹喔啉-2,3-二酮氢溴酸盐,m.p.=246℃(分解);7-溴-5-(6-硝基-苯并咪唑-1-基甲基)-1,4-二氢-喹喔啉-2,3-二酮氢溴酸盐,m.p.=278℃(分解);N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-二甲氨基哌啶二氢溴酸盐,m.p.=209℃(分解);N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3,4-四氢喹啉氢溴酸盐,m.p.=213℃(分解);N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-β-氨基丙酸氢溴酸盐,m.p.=254℃(分解);α-N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-赖氨酸二氢溴酸盐,m.p.=180℃(分解);N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-苯基丙氨酸二氢溴酸盐,m.p.=218℃(分解);N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酸氢溴酸盐,m.p.=238℃(分解);N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸乙酯氢溴酸盐,m.p.=260℃(分解)。
起始原料,例如,可制备如下:a)
7-溴-5-溴甲基-2,3-二甲氧基-8-硝基-喹喔啉
将20mL硫酸冷却到0℃,然后加入5g(13.8mmol)7-溴-5-甲基-2,3-二甲氧基-喹喔啉。15分钟后再加入1.46g(1.05当量)硝酸钾,并将混合物在20℃搅拌15小时。将混合物倒入冰中,滤出固体并用水洗涤,得到标题化合物为米色固体。1H-NMR(250MHz,DMSO-D6)δ=8.14(s,H),5.09(s,2H),4.12,3.99(2s,2Me).实施例4:
下列化合物可用类似实施例1的方法制备,但起始原料要用5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉代替7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉:N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸乙酯氢溴酸盐,m.p.=287℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-β-氨基丙酸氢溴酸盐,m.p.=241℃(分解);α-N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(D)-赖氨酸二氢溴酸盐,m.p.=185℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酸氢溴酸盐,m.p.=271℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-谷氨酸氢溴酸盐,m.p.=143℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-苯基丙氨酸氢溴酸盐,m.p.=204℃(分解);α-N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-赖氨酸二氢溴酸盐,m.p.=150℃(分解)。
起始原料,5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉,可制备如下:a1)
5-溴甲基-2,3-二甲氧基-喹喔啉
用类似实施例1c,1d和1e所述方法,以5-甲基-2,3-二氧-1,2,3,4-四氢喹喔啉(CAS登录号61875-33-0)为起始原料,可制备标题化合物。b1)
5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉
将25mL硫酸冷却到0℃,然后加入9.5g(33.55mmol)5-溴甲基-2,3-二甲氧基-喹喔啉。10分钟后再加入3.39mL(1当量)硝酸异丙酯,并将混合物在0℃搅拌1小时。将混合物倒入冰中,滤出固体并用水洗涤,得到标题化合物为米色固体。1H-NMR(250MHz,DMSO-D6)δ8.62,8.40(2d,2H),5.02(s,2H),4.27,4.19(2s,2Me).
5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉可制备如下:a2)
5-甲基-7-硝基-喹喔啉-2,3-二酮
将9.3g(55.63mmol)2,3-二氨基-5-硝基-甲苯和14g草酸的93mL6N HCl的混合物加热回流30分钟,然后在室温搅拌过夜使反应完成。滤出悬浮物并用水洗涤,然后将其溶解于250mL 2N NaOH,并加热回流直至变成均匀溶液。冷却后将混合物酸化至pH3,然后滤出所得5-甲基-7-硝基-喹喔啉-2,3-二酮。b2)
2,3-二氯-5-甲基-7-硝基-喹喔啉
将62mL POCl3加到根据上述a2)得到的5-甲基-7-硝基-喹喔啉-2,3-二酮中,并将混合物加热回流18小时。减压除去过量POCl3,剩余物用10%碳酸钠水溶液中和,然后过滤,干燥。c2)
2,3-二甲氧基-5-甲基-7-硝基-喹喔啉
将根据上述a1)得到的粗2,3-二氯-5-甲基-7-硝基-喹喔啉溶解于1.24g(27mmol)钠的140mL甲醇溶液中,并加热沸腾4小时。冷却后,用旋转蒸发器浓缩混合物,2N HCl中和,乙酸乙酯萃取,硫酸钠干燥,过滤并再用旋转蒸发器浓缩。经硅胶过滤和二氯甲烷洗脱,得到标题化合物为黄色晶体。m.p.:167-168℃,TLC:己烷/乙酸乙酯9/1:Rf=0.40。d2)
5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉
将0.249g(1.0mmol)2,3-二甲氧基-5-甲基-7-硝基-喹喔啉,0.178g(1mmol)N-溴琥珀酰亚胺和0.016g(0.1mmol)偶氮异丁腈的3mLCCl4悬浮液加热回流20小时。反应混合物用水和盐水洗涤,并用旋转蒸发器浓缩。从乙酸乙酯结晶后得到标题化合物。TLC:己烷/乙酸乙酯6/1:Rf=0.63。
1H-NMR(CDCl3):δ8.64(d,J=3,1H),8.41(d,J=3,1H),5.02(s,2H),4.27(s,3H),4.20(s,3H).实施例5:
下列化合物可用类似实施例1的方法制备,但起始原料要用6-甲基-7-硝基-1,4-二氢喹喔啉-2,3-二酮代替7-溴-5-甲基-1,4-二氢喹喔啉-2,3-二酮:N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-6-基甲基)-β-氨基丙酸氢溴酸盐,m.p.=305℃(分解);α-N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-6-基甲基)-(L)-赖氨酸二氢溴酸盐,m.p.=230℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-6-基甲基)-(L)-苯基丙氨酸氢溴酸盐,m.p.=228℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-6-基甲基)-(L)-谷氨酸氢溴酸盐,m.p.=235℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酸氢溴酸盐,m.p.=270℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-6-基甲基)-哌啶-4-羧酸盐酸盐,m.p.=255℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-6-基甲基)-哌啶-4-羧酸乙酯,m.p.=288-289℃(分解)。实施例6:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-哌啶-4-羧酸
在20℃将1.28g(3.12mmol)N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸乙酯氢溴酸盐(实施例2)在12mL 2N氢氧化钠溶液中搅拌16小时。用2N盐酸酸化混合物。滤出所得固体并用水和乙醚洗涤,得到标题化合物为白色固体。1H-NMR(250MHz,DMSO-D6+10%D2O)δ7.45,7.38(2d,2H),4.46(s,2H),3.4(m,2H),3.0(m,2H),2.05(m,2H),1.9(m,H),1.7(m,H).MS:381(M1).M.p.>300℃.实施例7:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-哌啶-4-羧酸苯基酰胺
在20℃将382mg(1mmol)N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸(实施例6),186mg(2当量)苯胺,480mg(2.5当量)N-(3-二甲氨基丙基)-N’-乙基碳化二亚胺盐酸盐和384mg(2.5当量)1-羟基-苯并三唑在无水二甲基甲酰胺中搅拌48小时。将混合物倒入水中,用100mL二氯甲烷萃取三次。合并有机相并蒸发浓缩。将剩余物溶解于30mL二氯甲烷,并将溶液搅拌30分钟。滤出白色固体,用二氯甲烷洗涤并干燥。1H-NMR(250MHz,DMSO-D6)12.0,11.8(2s,2NH),9.9(s,NH),7.6(d,2H),7.30-7.15(m,4H),7.01(t,H),3.77(s,2H),2.95(m,2H),2.38(m,1H),2.05(m,2H),1.85-1.60(m,4H).MS:456(M1).M.p.>250℃.实施例8:
下列化合物可用类似实施例6和7的方法制备:N-(7-溴-2,3-二氧-8-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸盐酸盐,m.p.=278℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-羧酸盐酸盐,m.p.=294℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-2-羧酸盐酸盐,m.p.=225-240℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-3-羧酸,m.p.>250℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-3-羧酸苯基酰胺盐酸盐,m.p.>260℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-2-羧酸苯基酰胺。实施例9:
5-氨基甲基-7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉盐 酸盐
将150mg(0.5mmol)5-氨基甲基-7-溴-2,3-二甲氧基-1,2,3,4-四氢喹喔啉溶解于3mL乙酸和3mL 48%溴化氢的乙酸溶液。在20℃18小时后用乙醚稀释混合物,滤出固体并用乙醚洗涤。1H-NMR(250MHz,DMSO-D6)δ12.15,11.75(2s,2NH),8.10(br,NH2),7.42,7.35(2d,2H),4.28,4.20(m,2H).M.p.>250℃.
起始原料,例如,可制备如下:a)
5-叠氮基甲基-7-溴-2,3-二甲氧基-1,2,3,4-四氢喹喔啉
在20℃将743mg(2当量)叠氮化钠加到2.07g(5.72mmol)7-溴-5-溴甲基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉的25mL二甲基甲酰胺中。3小时后将混合物倒入水中,用乙醚萃取,用水和盐水洗涤,硫酸镁干燥。蒸发浓缩溶剂。1H-NMR(250MHz,CDCl3)δ7.92,7.58(2d,2H),4.80(s,2H),4.18,4.13(2s,2Me).b)
5-氨基甲基-7-溴-2,3-二甲氧基-1,2,3,4-四氢喹喔啉
将4.47gg(13.8mmol)5-叠氮基甲基-7-溴-2,3-二甲氧基-1,2,3,4-四氢喹喔啉溶解于35mL四氢呋喃,并加入3.98g(1.1当量)三苯膦。在20℃搅拌混合物4小时,加入746mg水并继续搅拌混合物3小时。滤出固体,滤液用乙酸乙酯和碳酸钠溶液萃取。合并有机相,用盐水洗涤,硫酸镁干燥及蒸发浓缩。剩余物经硅胶色谱纯化,用乙酸乙酯/石油醚1∶1洗脱。1H-NMR(250MHz,CDCl3)δ7.85,7.53(2d,2H),4.22(s,2H),4.12(s,2Me).实施例10:
3-[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-氨基甲酰基]丙烯酸乙酯
在20℃将351mg(1mmol)5-氨基甲基-7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉盐酸盐,217mg(1.5当量)富马酸一乙基酯,0.210mL三乙胺,383mg(2当量)N-(3-二甲氨基丙基)-N’-乙基-碳化二亚胺盐酸盐和270mg(2当量)1-羟基-苯并三唑在无水二甲基甲酰胺中搅拌18小时。将混合物倒入700mL水和3mL 1N盐酸中,并搅拌15分钟。滤出固体,用水洗涤并干燥。1H-NMR(250MHz,DMSO-D6)δ12.0,11.4(2s,2NH),9.18(t,NH),7.23,7.18(2d,2H),7.05,6.64(2d,2H),4.50(d,2H),4.18(q,2H),1.24(t,3H).MS:395(M+).M.p.=288-293℃.实施例11:
3-[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-氨基甲酰基]丙烯酸
将144mg(0.36mmol)3-[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基甲酰基]丙烯酸乙酯和76mg氢氧化锂水合物溶解于18mL四氢呋喃/水(2∶1),并将溶液搅拌18小时。加入50mL水,蒸发浓缩四氢呋喃,用1N盐酸酸化溶液。滤出固体,用水洗涤并干燥。1H-NMR(250MHz,DMSO-D6)δ12.9(COOH),12.05,11.38(2s,2NH),9.17(t,NH),7.24,7.18(2d,2H),6.98,6.60(2d,2H),4.50(d,2H).MS:367(M+).M.p.>250℃.实施例12:
3-[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-氨基甲酰基]丙烯酸苯基酰胺
用类似实施例7所述方法制备标题化合物,但起始原料用3-[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基甲酰基]丙烯酸代替N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)哌啶-3-羧酸氢溴酸盐。m.p.>250℃。实施例13:
用类似实施例9-12所述方法制备下列化合物:N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-(3-苯基-脲基)-乙酰胺,m.p.>300℃;{[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基甲酰基]-甲基}-氨基甲酸叔丁酯,m.p.=238-242℃(分解);{[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基甲酰基]-甲基}-氨基甲酸苄酯,m.p.=225-230℃(分解)。实施例14:
7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙 酸
将1.14g(3.81mmol)7-溴-5-羟甲基-2,3-二甲氧基-喹喔啉,840mL(1.5当量)溴乙酸叔丁酯和65mg(0.05当量)四丁基硫酸氢铵在40mL苯和4mL 50%氢氧化钠溶液中搅拌18小时。将100mL水和100mL乙醚加到混合物中,分离出有机相,用乙醚萃取水相一次以上。合并有机相,用盐水洗涤,硫酸镁干燥并蒸发浓缩。将剩余物溶解于30mL乙酸和10mL2N盐酸,并加热回流2小时,然后冷却到20℃。加入200mL水,滤出固体,用水洗涤并干燥。1H-NMR(250MHz,DMSO-D6)12.0,11.45(2s,2NH),7.30,7.28(2d,2H),4.62(s,2H),4.19(s,2H).MS:328(M+).M.p.>250℃.
起始原料可,例如,制备如下:a)
7-溴-5-羟甲基-2,3-二甲氧基-喹喔啉
在20℃将11.5g(31.85mmol)7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉悬浮于100mL二噁烷。加入16.4g(164mmol)碳酸钙的100mL水,然后将混合物加热回流24小时。蒸发浓缩二噁烷并加入300mL二氯甲烷。滤出固体,用盐水洗涤有机相并蒸发浓缩。剩余物经硅胶色谱纯化,用乙酸乙酯和己烷(1∶1)洗脱。1H-NMR(250MHz,DMSO-D6)7.78,7.68(2d,2H),5.40(t,OH),4.96(d,2H),4.02(s,2Me).实施例15:
7-溴-2,3-二氧-5-羟甲基-1,2,3,4-四氢喹喔啉
将450mg(1.5mmol)7-溴-5-羟甲基-2,3-二甲氧基-喹喔啉溶解于30mL乙酸和10mL 2N盐酸,并将溶液加热回流2小时,然后冷却到20℃。滤出固体,用水洗涤并干燥。1H-NMR(250MHz,DMSO-D6)7.28,7.19(2d,2H),5.5(br,OH),4.62(s,2H).MS:270(M).M.p.>250℃.实施例16:
7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙 酸乙酯
将450mg(1.37mmol)7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙酸悬浮于20mL乙醇,加入0.5mL硫酸,并将混合物在氮气中加热回流2小时。冷却到20℃后加入80mL乙醚。滤出固体,用乙醚洗涤并干燥。1H-NMR(250MHz,DMSO-D6)12.0,11.1(2s,2NH),7.28,7.26(2d,2H),4.63(s,2H),4.23(s,2H),4.20(q,2H),1.22(t,3H).MS:356(M).M.p.=250-252℃.实施例17:
(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧 基)-N-苯基-乙酰胺
用类似实施例7所述方法制备标题化合物,但起始原料用7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙酸代替N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-3-羧酸氢溴酸盐。m.p.>250℃。实施例18:
7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基磺胺 酰基(sulfanvl)乙酸乙酯
氮气下用10mL乙醇稀释1.5mL(4mmol)21%乙醇钠的乙醇溶液。在0℃加入601mg(5mmol)硫代乙醇酸乙酯,然后将混合物加热到20℃。1小时后加入1.09g(3mmol)7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉,10mL乙醇和10mL四氢呋喃。将混合物搅拌18小时,用2mL 2N盐酸酸化并蒸发浓缩。用乙酸乙酯和0.1N盐酸萃取剩余物。合并的有机相用10%碳酸钠溶液和盐水洗涤,硫酸镁干燥并蒸发浓缩。将剩余物溶解于20mL 33%溴化氢的乙酸溶液,所得溶液在130℃加热20分钟,然后冷却到约80℃。搅拌的同时加入20mL乙醇,然后将溶液放置在5℃18小时。滤出晶体,用冷乙醇洗涤并干燥。1H-NMR(250MHz,DMSO-D6)12.02,11.42(2s,2NH),7.22,7.15(2d,2H),4.0(m,4H),3.22(s,2H),1.18(t,Me).MS:372(M).M.p.=251-253℃.实施例19:
7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基磺胺 酰基乙酸
将500mg(1.34mmol)7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基磺胺酰基乙酸乙酯悬浮于20mL四氢呋喃和10mL水,并加入225mg(4当量)氢氧化锂水合物。将混合物在20℃搅拌48小时。蒸发浓缩四氢呋喃,加入60mL水,溶液用1N盐酸酸化。滤出固体,用水洗涤并干燥。1H-NMR(250MHz,DMSO-D6)12.7(br,COOH),12.03,11.48(2s,2NH),7.22,7.18(2d,2H),3.98(s,2H),3.17(s,2H).MS:344(M).M.p.>250℃.实施例20:
(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基磺 胺酰基)-N-苯基乙酰胺
用类似实施例7所述方法制备标题化合物,但起始原料用(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基磺胺酰基)乙酸代替N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-3-羧酸氢溴酸盐。1H-NMR(250MHz,DMSO-D6)12.02,11.52(2s,2NH),10.1(s,NH),7.58(d,2H),7.32(m,2H),7.28,7.20(2d,2H),7.08(t,1H),4.05(s,2H),3.22(s,2H).MS:419(M+).M.p.>250℃.实施例21:
2-氨基-3-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉 -5-基)-丙酸乙酯氢溴酸盐
将1.55g(3.26mmol)2-氨基-3-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-丙酸乙酯半草酸盐溶解于33%HBr的乙酸溶液,并将溶液在130℃加热1小时。滤出固体并用乙醚洗涤。干燥后得到标题化合物为白色粉末。1H-NMR(DMSO-D6)δ=12.1(s,NH),8.35(br),7.25,7.20(2d,2H),4.2-4.03(m,3H),3.25(m,2H),1.10(t,3H);MS(FAB):356(M+H+).M.p.>280℃.
起始原料可,例如,制备如下:a)
2-氨基-3-(7-溴-2,3-二甲氧基-喹喔啉-5-基)-丙酸 乙酯半草酸盐
在室温和氮气下将2.49g(18mmol)碳酸钾和1.6g(6mmol)N-二苯亚甲基-甘氨酸乙酯加到1.81g(5mmol)7-溴-5-溴甲基-2,3-二甲氧基-喹喔啉和193mg(0.6当量)四-正丁基溴化铵的10mL乙腈悬浮液中。将反应混合物回流搅拌20小时,然后冷却到室温。滤出固体并用乙腈洗涤。蒸发浓缩溶剂,剩余物用1.35g(15mmol)草酸的25mL丙酮和1mL水溶解。将溶液在室温搅拌18小时,滤出固体,用丙酮洗涤,悬浮于100mL水并搅拌10分钟。再滤出固体,用水和丙酮洗涤并干燥。1H-NMR(DMSO-D6)δ=7.87,7.58(2d,2H),4.33(t,1H),4.08,4.03(2s,2Me),3.98(q,2H),3.61,3.47(2dd,2H),0.94(t,3H).实施例22:
2-氨基-3-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉 -5-基)-丙酸盐酸盐
将368mg(5当量)氢氧化锂水合物加到767mg(1.75mmol)2-氨基-3-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-丙酸乙酯氢溴酸盐的60mL四氢呋喃/水(2∶1)。将反应混合物在室温搅拌72小时。蒸发浓缩四氢呋喃,用1N盐酸酸化溶液。滤出固体并用水洗涤并干燥。1H-NMR(D2O+NaOD)δ=6.88,6.66(2d,2H),3.19,2.92,2.45(3dd,3H);MS(FD):327(M+).M.p.>250℃.实施例23:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-草酰胺酸乙酯
将254mg(0.79mmol)N-(7-溴-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基甲基)-草酰胺酸乙酯溶解于6mL约25%溴化氢的乙酸溶液,并将溶液在室温搅拌16小时。用乙醚稀释混合物,滤出固体并用乙醚洗涤。高真空干燥后得到标题化合物为米色固体。1H-NMR(250MHz,DMSO-D6+5%D2O)δ=7.24,7.19(2d,2H),4.40(s,2H),4.23(q,2H),1.27(t,3H).M.p.=192℃(分解)
起始原料可,例如,制备如下:a)
N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-草酰胺酸乙 酯
将300mg(1mmol)5-氨基甲基-7-溴-2,3-二甲氧基喹喔啉盐酸盐悬浮于10mL THF,并将悬浮液冷却到0℃。加入0.183mL(1.3当量)三乙胺,然后用30分钟滴加0.123mL(1.1当量)草酸一乙基酯氯化物。在0℃搅拌2小时,然后在20℃搅拌16小时,并蒸发浓缩。剩余物在乙醚中搅拌,滤出固体,用水和乙醚洗涤并干燥。1H-NMR(250MHz,CDCl3)δ=8.12(t,NH),7.90,7.58(2d,2H),4.81(d,2H),4.32(q,2H),4.19,4.14(2s,2Me),1.38(t,3H).实施例24:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-丙酰胺酸甲酯
用类似实施例23所述方法制备标题化合物。m.p.>300℃。实施例25:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-草酰胺酸
用类似实施例21所述方法以N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-草酰胺酸为起始原料制备标题化合物。m.p.=265℃(分解)。
起始原料可,例如,制备如下:a)
N-(7-溴-2,3-二甲氧基喹喔啉-5-基甲基)-草酰胺酸
将276mg(1mmol)N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)草酰胺酸乙酯和150mg碳酸钾悬浮于2mL水和5mL甲醇。将混合物搅拌20小时,并用1N HCl酸化,滤出固体,用甲醇和乙醚洗涤并干燥。m.p.>300℃。实施例26:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-丙酰胺酸
用类似实施例25所述方法制备标题化合物。m.p.>300℃。实施例27:
呋喃-2-羧酸(7-溴-2.3-二氧-1,2,3,4-四氢喹喔啉 -5-基甲基)-酰胺
将310mg(0.79mmol)呋喃-2-羧酸(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-酰胺溶解于6mL约25%溴化氢的乙酸溶液,并将溶液在室温搅拌16小时。用乙醚稀释混合物,滤出固体,用乙醚洗涤。高真空干燥后得到标题化合物为米色固体。1H-NMR(250MHz,DMSO-D6)δ=12.01,11.42(2s,2NH),9.12(t,NH),7.91(d,1H),7.22(m,3H),6.68(t,1H),4.50(d,2H).MS(FAB):364(M+).M.p.=216℃(分解)
起始原料可,例如,制备如下:a)
呋喃-2-羧酸(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)- 酰胺
在20℃将300mg(1mmol)5-氨基甲基-7-溴-2,3-二甲氧基-喹喔啉盐酸盐,124mg(1.1当量)呋喃-2-羧酸,212mg(1.1当量)N-(3-二甲氨基丙基)-N’-乙基-碳化二亚胺盐酸盐和12.2mg(0.1当量)4-二甲氨基-吡啶在无水THF中搅拌20小时。将混合物倒在水上,滤出固体,用水和乙醚洗涤。高真空干燥后得到标题化合物为米色固体。1H-NMR(250MHz,CDCl3)δ=7.89(d,1H),7.62(d,1H),7.40(d,1H),7.29(t,NH),7.13(d,1H),6.49(t,1H),5.01(d,2H),4.20,4.14(2s,2Me).实施例28:
用类似实施例23或27所述方法制备下列化合物:环丙烷羧酸(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-酰胺,m.p.=250℃(分解);2-氨基-N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-乙酰胺氢溴酸盐,m.p.=293℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3,5-双三氟甲基苯甲酰胺,m.p.>300℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-苯甲酰胺,m.p.=210℃(分解)。实施例29:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-乙酰胺
将50mg(0.19mmol)5-氨基甲基-7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉盐酸盐悬浮于4mL N,N-二甲基甲酰胺,并在20℃与0.02mL(1.2当量)乙酐和0.059mL(2.2当量)三乙胺一起搅拌24小时。蒸发浓缩溶剂,将固体悬浮于乙醚,滤出固体,用甲醇和乙醚洗涤。高真空干燥后得到标题化合物为白色固体。1H-NMR(250MHz,DMSO-D6)δ=12.02,11.48(2NH),8.65(t,NH),7.22,7.18(2d,2H),4.35(d,2H),1.93(s,Me).MS(ESP)310(M+-1).M.p.>300℃.实施例30:用类似实施例29所述方法制备下列化合物:N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-三氟乙酰胺,m.p.>300℃。实施例31:
用类似实施例1-29所述方法制备下列化合物:N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-酪氨酸氢溴酸盐,m.p.=264℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-叔-亮氨酸氢溴酸盐,m.p.=208℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-脯氨酸氢溴酸盐,m.p.=279℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-丙氨酸氢溴酸盐,m.p.=229℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(D)-丙氨酸氢溴酸盐,m.p.=228℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-肌氨酸氢溴酸盐,m.p.=280℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-缬氨酸氢溴酸盐,m.p.=226℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-草酰胺酸甲酯;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-草酰胺酸,m.p.=255℃(分解);4-[(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基甲酰基]-丁酸甲酯,m.p.>250℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-苄基-甘氨酸乙酯氢溴酸盐,及N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-苄基-甘氨酸盐酸盐,m.p.=205℃(分解)。实施例32:
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-乙酰胺
在50℃将103mg(0.34mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-乙酰胺在3mL 25%溴化氢的乙酸溶液中搅拌24小时。用乙醚稀释反应混合物,滤出固体,用乙醚洗涤并干燥。m.p.=269-272℃(分解)。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-乙酰胺
将用类似实施例9所述方法但起始原料为5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉得到的111mg(0.437mmol)5-氨基在室温下与0.04mL(1.1当量)乙酐和0.073mL(1.2当量)三乙胺的5mL N,N-二甲基甲酰胺一起搅拌24小时。用乙醚稀释反应混合物,滤出固体,用乙醚洗涤并干燥。1H-NMR(DMSO-D6,250MHz):8.52(t,NH),8.42,8.16(2d,2H),4.79(d,2H),4.15,4.12(2s,2Me),1.98(s,Me).实施例33:
用类似实施例21-32所述方法制备下列化合物:N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-苯基乙酰胺,m.p.>250℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-苯基-丙酰胺,m.p.=237℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-噻吩-2-羧酸酰胺,m.p.>250℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-噻吩基-乙酰胺,m.p.>260℃;及N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-甲氧基苯基乙酰胺,m.p.>250℃。实施例34:
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-N-甲基-苄胺氢溴酸盐
将213mg(0.53mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-甲基-苄胺溶解于4mL约25%溴化氢的乙酸溶液,并将溶液在室温搅拌20小时。用乙醚稀释混合物,然后搅拌10分钟。滤出固体,用乙醚和少量水洗涤。高真空干燥后得到标题化合物为米色固体。1H-NMR(DMSO-D6,250MHz):12.17,11.8(2s,2NH),9.7(br s,NH),7.52(m,Ph+H),7.38(d,H),4.8-4.15(m,4H),2.5(s,Me);MS(El):373(M+).M.p.=208-212℃(分解)
或者,用下列方法制备标题化合物:
将213mg(0.53mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-甲基-苄胺在10mL 2N盐酸水溶液中加热回流18小时。蒸发浓缩反应混合物,将所得固体悬浮于乙醚和少量水中,得到标题化合物为米色固体。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-甲基 -苄胺
将200mg 5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉和0.016mL(2.2当量)溶解于10mL乙腈,并将溶液回流搅拌20小时。蒸发浓缩混合物,剩余物溶解于乙酸乙酯,并用5%碳酸钠水溶液和盐水洗涤。用硫酸镁干燥有机相,蒸发浓缩溶剂。1H-NMR(CDCl3,250MHz):7.84,7.78(2d,2H),7.4-7.2(m,Ph),4.13,4.08(2s,2Me),4.03,3.65(2s,2CH2),2.26(s,Me).实施例35:
用类似实施例34所述方法制备下列化合物:N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-糠胺氢溴酸盐,m.p.=282℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-吗啉代-乙胺氢溴酸盐,m.p.=228℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-二乙胺氢溴酸盐,m.p.=290℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-二甲胺氢溴酸盐,m.p.=325℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-(2-吡啶基)-乙基-甲胺二氢溴酸盐,m.p.=205℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-环丙胺氢溴酸盐,m.p.=268℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-二乙醇胺盐酸盐,m.p.=251℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-2-噻唑氢溴酸盐,m.p.=271℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基吡嗪二氢溴酸盐,m.p.=183℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基噻唑氢溴酸盐,m.p.=153℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-苯胺氢溴酸盐,m.p.>250℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-氟苯胺氢溴酸盐,m.p.=218℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-3-氟苯胺氢溴酸盐,m.p.>250℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氟苯胺氢溴酸盐,m.p.=222-235℃;[N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-4-噻唑基]-乙酸乙酯氢溴酸盐,m.p.=258℃(分解);[N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-4-噻唑基]-乙酸乙酯氢溴酸盐,MS(EI):438(M+)。实施例36:
[N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5- 基甲基)-2-氨基-4-噻唑基]-乙酸盐酸盐
在室温下将80mg(0.2mmol)[N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-4-噻唑基]-乙酸乙酯氢溴酸盐在2mL 2N氢氧化钠溶液中搅拌16小时。用3N HCl酸化混合物,滤出所得固体,用少量水和2×20mL乙醚洗涤。干燥后得到标题化合物为黄色固体。1H-NMR(DMSO-D6,250MHz):12.4,12.3(2s,2NH),9.0(s,NH),8.09,8.02(2d,2H),6.75(s,H),4.8(br s,2H),3.7(s,2H);m.p.=284℃(分解)实施例37:
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-N-(2-吡啶基-甲基)-甘氨酸二氢溴酸盐
在70℃将49mg(0.1mmol)N-(2,3-二甲氧基-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(2-吡啶基甲基)-甘氨酸二盐酸盐在2mL 48%溴化氢的乙酸溶液中搅拌18小时。用乙醚稀释混合物,滤出所得固体,用乙醚洗涤并干燥,得到标题化合物为黄色固体。1H-NMR(DMSO-D6,250MHz):12.3(s,2NH),8.8,8.25,7.72,7.68(4m,Py),7.92,7.89(2d,2H),4.1(m,2H),3.6(s,2H);MS(FAB+)386(M+H);m.p.>280℃.
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-(2 -吡啶基甲基)-甘氨酸乙酯
将150mL(0.46mmol)5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉,98mg(1.1当量)N-(2-吡啶基甲基)-甘氨酸乙酯和0.076mL(1.2当量)三乙胺在5mL乙腈中回流搅拌20小时。蒸发浓缩混合物,并将剩余物悬浮于乙醚,然后过滤。干燥后得到标题化合物为白色粉末。1H-NMR(DMSO-D6,250MHz):8.45,8.37(2d,2H),8.45,7.72,7.43,7.22(4m,Py),4.39(s,2H),4.05(m,2Me+2H),4.0(s,2H),3.53(s,2H),1.18(t,Me).b)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-(2 -吡啶基甲基)-甘氨酸二盐酸盐
室温下将80mg(0.186mmol)N-(2,3-二甲氧基-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(2-吡啶基甲基)-甘氨酸乙酯和51mg(2当量)碳酸钾在5mL甲醇和2mL水中搅拌20小时。浓缩混合物,用2N HCl酸化并蒸发浓缩。剩余物从热乙酸乙酯重结晶,滤出晶体,用水和乙醚洗涤并干燥。实施例38:
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-3-氨基-苯甲酸氢溴酸盐
在20℃将60mg(0.156mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-3-氨基苯甲酸在4mL约24%HBr的乙酸中搅拌20小时。用乙醚稀释反应混合物,滤出固体并用乙醚洗涤。m.p.=275℃(分解)。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-3-氨基 -苯甲酸
将350mg(1.06mmol)5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉,153mg(1.05当量)3-氨基苯甲酸和0.165mL(1.1当量)三乙胺在10mL乙腈中合并,并加热沸腾回流24小时。蒸发浓缩反应混合物,用乙酸乙酯和1N HCl萃取,盐水洗涤一次。合并有机相,硫酸镁干燥并蒸发浓缩。1H-NMR(CDCl3,250MHz)8.50,8.27(2d,2H),7.32,7.15,7.10,6.75(4m,4H),4.85(s,2H),4.13,4.12(2s,2Me).实施例39:
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-2-甲基氮丙啶氢溴酸盐
在70℃将180mg(0.59mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶在33%溴化氢的乙酸溶液中搅拌2小时。用乙醚稀释混合物,滤出固体并用乙醚洗涤。干燥后的标题化合物为黄色固体。m.p.=241℃(分解)。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基 氮丙啶
室温下将200mg(0.61mmol)5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉,0.086mL(2当量)丙二亚胺(propyleneimine)和0.295mL(0.3当量)40%叔丁基氢氧化铵水溶液在8mL二氯甲烷中搅拌20小时。蒸发浓缩混合物,剩余物用乙酸乙酯和5%碳酸钠溶液萃取。合并的有机相用盐水洗涤一次,硫酸镁干燥并蒸发浓缩。1H-NMR(CDCl3,250MHz):8.6(m,2H),4.18(m,2Me+H),3.95(s,2H),3.38(m,2H),1.0(t,Me).实施例40:
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-氮杂环丁烷氢溴酸盐
可用类似实施例39所述方法制备标题化合物。m.p.=265℃(分解)。实施例41:
N-(2,3-二氢-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲基)-4-甲基哌啶氢溴酸盐
可用类似实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-4-甲基哌啶代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶。m.p.=296℃(分解)。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-4-甲基 哌啶
将100mg(0.304mmol)5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉,0.04mL(1.1当量)4-甲基哌啶和0.05mL(1.2当量)三乙胺回流搅拌20小时。蒸发浓缩混合物,剩余物用乙酸乙酯和5%碳酸钠溶液萃取。合并的有机相用硫酸镁干燥并蒸发浓缩。1H-NMR(CDCl3,250MHz):8.58,8.43(m,2H),4.19,4.17(2s,2Me),4.06(s,2H),2.97,2.15,1.62,1.40-1.25(4m,9H),0.93(d,Me).实施例42:
用类似实施例1-41所述方法制备下列化合物:N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N’-(4-甲氧基苯基)哌嗪氢溴酸盐,m.p.=241℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶氢溴酸盐,m.p.>300℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2,6-二甲基哌啶氢溴酸盐,m.p.=277℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯烷氢溴酸盐,m.p.>300℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-哌啶酮氢溴酸盐,m.p.=259℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-六亚甲基亚胺氢溴酸盐,m.p.=298℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-3-吡咯啉氢溴酸盐,m.p.>300℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-硫杂吗啉氢溴酸盐,m.p.=291℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-吗啉氢溴酸盐,m.p.>300℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-噻唑烷氢溴酸盐,m.p.=250℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-3-吡咯烷醇(pyrrolidinole)氢溴酸盐,m.p.=286℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基哌嗪二氢溴酸盐,m.p.=295℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-(2-羟乙基)哌啶盐酸盐,m.p.=298℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-哌嗪二氢溴酸盐,m.p.>300℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-3-氮杂双环[3.2.2]壬烷氢溴酸盐,m.p.=271℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-四氢吡啶氢溴酸盐,m.p.=279℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-吡唑氢溴酸盐,m.p.=298℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-3-乙氧羰基-吡唑氢溴酸盐,m.p.=195℃;[1-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-1H-吲哚-3-基]-乙酸甲酯氢溴酸盐,m.p.=230℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3,4-四氢喹啉氢溴酸盐,m.p.=212-215℃。实施例43:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-甲磺酰胺
将83mg(0.31mmol)5-氨基甲基-7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉悬浮于4mL DMF。加入0.063mL(1.6当量)三乙胺和82mg(1.4当量)甲磺酸酐,并将溶液搅拌18小时。蒸发浓缩溶剂,将剩余物悬浮于乙醚。滤出固体,用水和乙醚洗涤。干燥后的标题化合物为白色粉末。m.p.>300℃。实施例44:
N-甲基-2-苯基乙酸(7-溴-2,3-二氧-1,2,3,4-四 氢喹喔啉-5-基甲基)-酰胺
将2mL盐酸(2N水溶液)加到129mg(0.3mmol)N-甲基-2-苯基乙酸(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-酰胺的3mLTHF中,并将混合物在沸点加热回流16小时。在冰浴冷却后滤出沉淀,用冷水洗涤。将之放入热DMF,在冰箱中过夜后形成无色晶体。滤出并高真空干燥。1H-NMR(300MHz,DMSO-D6)12.05-11.95(br.s,1H),11.51-11.33(br.s,1H),7.38-7.10(m,7H),4.78(s,0.2H).4.59(s,1.8H),3.82(s,1.8H),3.62(s,0.2H),2.99(s,2.7H),2.82(s,0.3H).MS(FAB):402(M+),m.p.>260℃.
起始原料可,例如,制备如下:a)
2-苯基乙酸(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-酰 胺
可用实施例27所述方法制备。b)
N-甲基-2-苯基乙酸(7-溴-2,3-二甲氧基-喹喔啉-5-基 甲基)-酰胺
将208mg(0.5mmol)2-苯基乙酸(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-酰胺的4mLTHF(绝对)溶液用15分钟时间滴加到30.5mg(0.7mmol)氢化钠的3mL绝对THF悬浮液中。在沸点加热回流90分钟后将混合物在冰浴冷却。加入85mg(0.6mmol)甲基碘后将悬浮液在0℃搅拌1小时,然后在室温搅拌15小时。加入0.9g硅胶并浓缩悬浮液,干燥,用二氯甲烷/己烷/乙醚(8∶4∶1)作洗脱剂在硅胶柱上纯化。浓缩后高真空干燥,得到实际上无色的蜜状标题化合物,它是比例约为2∶3的顺/反异构体混合物。1H-NMR(300MHz,CDCl3)7.87(d,1Hz,0.4H),7.83(d,1Hz,0.6H),7.4-7.15(m,6H),5.10(s,1.2H),5.00(s,0.8H),4.15(s,1.2H),4.12(s,1.8H),4.09(s,3H),3.82(s,1.2H),3.75(s,0.8H),3.03(s.1.2H),2.98(s,1.8H).实施例45:
N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲 基)-α-氨基磷酸
氮气下将255mg(0.607mmol)N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-α-氨基磷酸二甲酯溶解于5mL绝对二氯甲烷,并在室温加入0.33mL(2.55mmol)三甲基甲硅烷基溴化物。在室温3小时后加入5mL乙醇,并在室温继续搅拌22小时。将混合物浓缩至干,然后在米色泡沫中加入5mL HBr(33%的冰醋酸溶液)。将混合物在室温搅拌3小时,然后再次浓缩至干。将米色剩余物放入K2CO3溶液(约1N的水溶液)。用盐酸将pH值调节至6,趁热过滤所得悬浮液。在滤液中加入热DMF,然后加入少量乙醇直到混合物变得稍微浑浊。经过3天时间形成米色晶体,分离后得到标题化合物。1H-NMR(300MHz,D2O)7.53(br.s,1H),7.47(brs,1H),4.57(br.s,2H),3.15(d,11.8Hz,2H);31P-NMR 8ppm;MS(FAB+)364,366[M+H+]+,(FAB-)362,364[M-H+]-;m.p.>270℃.
起始原料可,例如,制备如下:a)
三-N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-三嗪
将2.98g(10mmol)(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-胺溶解于40mL加热着的乙醇。冷却到室温后将1mL甲醛水溶液(37%的水溶液)滴加到浅黄色溶液中。添加结束时形成含有产物的无色沉淀。搅拌3小时后滤出沉淀。高真空干燥后得到标题化合物为无色非晶形结晶物质。1H-NMR(300MHz,CDCl3)7.83(d,2.3Hz,3H),7.72(d,2.3Hz,3H),4.24(s,6H),4.13(s,9H),4.04(s,9H),3.69(br.s,6H).MS(FAB):930,932.b)
N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-α-氨基磷 酸二甲酯
在0℃及氮气下将0.23mL(2.5mmol)亚磷酸二甲酯,0.383mL(2.75mmol)三乙胺和0.476mL(3.75mmol)三甲基甲硅烷基氯化物溶解于25mL二氯甲烷。在0℃搅拌15分钟后滴加0.78g(0.83mmol)三-N-(7-溴-2,3-二甲氧基-喹喔啉-5-基甲基)-三嗪的25mL二氯甲烷。在室温搅拌30小时后将所得悬浮液倒入冰冷的盐酸(0.1N水溶液),并加入三份乙醚。用0.1N盐酸水溶液通过强烈摇动萃取有机相。用K2CO3将合并的水相的pH值调节至12-13,并用氯仿萃取6次。硫酸钠干燥和浓缩有机相后得到黄色油,将其硅胶柱上纯化,用乙酸乙酯/二氯甲烷/甲醇(10∶10∶1)混合物作洗脱剂。浓缩和高真空干燥后得到标题化合物为浅黄色油,固化后呈玻璃状。1H-NMR(300MHz,CDCl3)7.88(d,2.3Hz,1H),7.54(d,2.3Hz,1H),4.25(s,2H),4.15(s,3H),4.14(s,3H),3.78(d,10Hz,6H),2.95(d,13.1Hz,2H),MS(ES+)422,420(MH+).实施例46:
1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-3-(4-甲氧基苯基)-脲
可用实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-3-(4-甲氧基苯基)-脲代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;FAB-MS:M+=385;TLC:乙酸乙酯/甲醇(3∶1)Rf=0.5。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-3-(4 -甲氧基苯基)-脲
将62mg(0.416mmol)4-甲氧基苯基异氰酸酯在室温下加到100mg(0.379mmol)5-氨基甲基-2,3-二甲氧基-7-硝基-喹喔啉的2mL叔丁基甲酯悬浮液中,并将混合物搅拌3小时。滤除悬浮物,剩余的滤液用叔丁基甲酯洗涤,然后高真空干燥,得到标题化合物为米色固体。1H-NMR(CDCl3,200MHz):8.47,8.26(2d,2H),7.70(s,NH),7.22(d,2H),6.74(d,2H),6.15(m,NH),4.89(d,CH2),4.11,4.09(2s,2Me),3.70(s,Me).实施例47:
用类似实施例46所述方法制备下列化合物:1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-(2-甲氧基苯基)-脲,FAB-MS:M+=385;TLC:乙酸乙酯/甲醇(3∶1)Rf=0.5;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-(2-乙氧羰基乙基)-脲;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-(2-羧乙基)-脲,FAB-MS:M+=351;TLC:乙酸乙酯/甲醇(1∶3)Rf=0.67;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-苯基-脲,FAB-MS:M+=355;TLC:乙酸乙酯/甲醇(3∶1)Rf=0.70;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-(4-三氟甲氧基苯基)-脲,FAB-MS:M+=439;TLC:乙酸乙酯/甲醇(3∶1)Rf=0.50。实施例48:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-戊酸酰胺
可用实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-戊酸酰胺代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;FAB-MS:M+=320;1H-NMR(DMSO-D6,200MHz):12.23,11.82(2s,2NH)8.73(t,NH),7.94,7.89(2d,2H),4.46(d,CH2),2.20(t,CH2),1.53(quint.,CH2),1.28(hex.,CH2),0.87(t,CH3).TLC:ethylacetate/methanol(1∶1+2%acetic acid)Rf=0.80.
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-戊酸酰胺
将79μL(0.567mmol)三乙胺和55μL(0.454mmol)正戊酰氯加到100mg(0.378mmol)5-氨基甲基-2,3-二甲氧基-7-硝基-喹喔啉的2mL叔丁基甲酯悬浮液中,并将混合物在室温搅拌16小时。将混合物放入二氯甲烷,先后用1N盐酸和1N氢氧化钠溶液洗涤,硫酸钠干燥并蒸发浓缩,得到标题化合物为黄色粉末。实施例49:
用类似实施例48所述方法制备下列化合物:N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-萘甲酰胺,FAB-MS:M+=390;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.80;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3,3-二甲基-丁酰胺,FAB-MS:M+=334;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.67;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-乙酰氧基)-苯甲酰胺;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(2-羟基)-苯甲酰胺,ESCI+-MS:(M+H)+=357;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.33。实施例50:N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-甲氧基乙酰胺
可用实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲氧基-乙酰胺代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;FAB-MS:M+=308;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.80。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲氧 基-乙酰胺
可用实施例29a)所述方法制备标题化合物,但起始原料要用5-氨基甲基-2,3-二甲氧基-7-硝基-喹喔啉和2-甲氧基-乙酸代替5-氨基甲基-7-溴-2,3-二甲氧基-喹喔啉盐酸盐和呋喃-2-羧酸。实施例51:
用类似实施例50所述方法制备下列化合物:N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N’,N’-二甲基-甘氨酰胺,APCI+-MS:(M+H)+=321;TLC:甲醇/乙酸(9∶1)Rf=0.29;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3,4,5-三甲氧基-苯甲酰胺,ESCI--MS:(M+H)+=429;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.30;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3,5-二甲氧基-4-羟基苯甲酰胺,FAB-MS:M+=416;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.90;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N,-乙酰基-甘氨酰胺,FAB-MS:M+=335;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.80;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N’-氨基甲酰基-甘氨酰胺,FAB-MS:M+=336;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.60;4-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨磺酰基]-苯甲酰胺,ESCI+-MS:(M+H)+=420;TLC:甲醇/乙酸(9∶1)Rf=0.88;2-氨基-3-甲基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-丁酰胺,ESCI+-MS:(M+H)+=336;TLC:甲醇/乙酸(9∶1)Rf=0.68;2-氨基-3-羟基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-丁酰胺,ESCI+-MS:(M+H)+=338;TLC:甲醇/乙酸(9∶1)Rf=0.48;2-氨基-4-羧基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-丁酰胺,FAB-MS:M+=365;TLC:甲醇/乙酸(9∶1)Rf=0.39;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-乙酰基-色氨酸酰胺氢溴酸盐,FAB-MS:M+=464;TLC:甲醇/乙酸(9∶1)Rf=0.25;2-氨基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-L-丝氨酸-酰胺,ESCI+-MS:(M+H)+=324;TLC:甲醇/乙酸(9∶1)Rf=0.50;2-氨基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-D-丝氨酸-酰胺;2-L-氨基-3-氨基甲酰基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-丙酸酰胺,FAB-MS:M+=351;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.90;2-D-氨基-3-氨基甲酰基-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-丙酸酰胺;L-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-组氨酸-酰胺;D-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-组氨酸-酰胺。实施例52:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-琥珀酸酰胺
可用实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-琥珀酸酰胺代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;FAB-MS:M+=336;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.48。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-琥珀酸酰 胺
将55μL(0.397mmol)三乙胺和40mg(0.397mmol)琥珀酸酐加到100mg(0.378mmol)5-氨基甲基-2,3-二甲氧基-7-硝基-喹喔啉的2mL叔丁基甲酯悬浮液中,并将混合物在室温搅拌3小时。过滤混合物,剩余物用叔丁基甲酯洗涤两次。过滤产生的剩余物经硅胶色谱纯化,用二氯甲烷/甲醇/乙酸(95∶4.5∶0.5)作洗脱剂,得到标题化合物为米色粉末。实施例53:
用类似实施例52所述方法制备下列化合物:N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-邻苯二甲酸酰胺;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-戊二酸酰胺,FAB-MS:M+=350;TLC:乙酸乙酯/甲醇(1∶1+2%乙酸)Rf=0.70;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-琥珀酸酰胺,FAB-MS:M+=350;TLC:二氯甲烷/甲醇/乙酸(80∶18∶2)Rf=0.46。实施例54:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-N-(2-二乙氨基乙基)-胺二氢溴酸盐
可用实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-(2-二乙氨基乙基)-胺代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;FAB-MS:M+=335;TLC:甲醇/水(5∶1)Rf=0.16。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-(2 -二乙氨基乙基)-胺
可用实施例39 a)所述方法制备标题化合物,也就是说,从5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉和2-二乙氨基乙胺开始制备,得到标题化合物为无色油。实施例55:
用类似实施例54所述方法制备下列化合物:N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-胺氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(1,1-二氧-2,3,4,5-四氢-噻吩-3-基)-胺氢溴酸盐,FAB-MS:M+=354;TLC:甲醇/乙酸(9∶1)Rf=0.69;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-N-(2-羟乙基)-胺氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(3,4-亚甲基二氧基苄基)-胺氢溴酸盐,APCI+-MS:(M+H)+=371;TLC:甲醇/乙酸(9∶1)Rf=0.70;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-N-甲氧基-胺氢溴酸盐,ESCI+-MS:(M+H)+=281;TLC:甲醇/乙酸(9∶1)Rf=0.86;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-异丙基-胺氢溴酸盐,APCI+-MS:(M+H)+=279;TLC:甲醇/乙酸(9∶1)Rf=0.53;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N’-乙酰基-乙二胺氢溴酸盐,FAB-MS:M+=321;TLC:甲醇/乙酸(9∶1)Rf=0.40;顺-2-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]-环己烷-1-甲酰胺氢溴酸盐,FAB-MS:M+=359;TLC:甲醇/乙酸(9∶1)Rf=0.50;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-牛磺酸氢溴酸盐,FAB-MS:M+=357;TLC:甲醇/乙酸(9∶1)Rf=0.69;顺-3-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]-环己烷-1-羧酸氢溴酸盐,FAB-MS:M+=362;TLC:甲醇/乙酸(9∶1)Rf=0.70;3-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]3-苯基-丙酸氢溴酸盐,ESCI+-MS:(M+H)+=385;TLC:甲醇/乙酸(9∶1)Rf=0.34;顺-2-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]-环戊烷-羧酸氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯烷-2-酮,FAB-MS:M+=304;TLC:乙酸乙酯/甲醇(2∶1+%乙酸)Rf=0.60;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯烷-4-(4-氯苯基)-2-酮,FAB-MS:M+=414;TLC:甲醇/水(10∶1)Rf=0.78;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(1-乙酰氧基-2-甲基-丙-2-基)-胺氢溴酸盐,FAB-MS:M+=350;TLC:甲醇/乙酸(9∶1)Rf=0.86;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-环己基-N-甲基-胺氢溴酸盐,FAB-MS:M+=332;TLC:甲醇/乙酸(9∶1)Rf=0.70;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(1,1-二甲基-2-羟乙基)-胺盐酸盐,ESCI+-MS:(M+H)+=309;TLC:甲醇/乙酸(9∶1)Rf=0.62。实施例56:
顺-2-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔 啉-5-基甲基)氨基]-环己烷-1-羧酸氢溴酸盐
可用实施例39所述方法制备标题化合物,但起始原料要用顺-2-[N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)氨基]-环己烷-1-羧酸代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;m.p.249-251℃;ESCI--MS:(M-H)+=361;TLC:甲醇/乙酸(9∶1)Rf=0.1-0.45。
起始原料可,例如,制备如下:a)
2,3-二甲氧基-喹喔啉-5-甲醛(carbaldehyde)
将17mL(188mmol)2-硝基丙烷加到3.7g(163mmol)钠的700mL甲醇溶液中。搅拌5分钟后加入35.5g(125.4mmol)2,3-二甲氧基-5-溴甲基-喹喔啉。将混合物加热回流1小时形成均匀溶液。冷却后减压浓缩溶液。将剩余物放入乙酸乙酯和1N HCl,分离各相,有机相用水和盐水洗涤,硫酸钠干燥并浓缩。从乙酸乙酯结晶,分离得到标题化合物为白色晶体。m.p.=137-140℃;TLC:EtOAc/己烷(1∶3)Rf=0.45。b)
2,3-二甲氧基-7-硝基-喹喔啉-5-甲醛
将44mL 100%硝酸,44mL 97%硫酸和44mL三氟乙酸酐依次加到冷却到0℃的22g(100.8mmol)2,3-二甲氧基-5-溴甲基-喹喔啉的88mL三氟乙酸中。将混合物在0℃保持2小时,然后小心倒入4N NaOH和冰的混合物中,保持温度不超过20℃。用乙酸乙酯萃取混合物。有机相用1N NaOH溶液,水和盐水洗涤,硫酸钠干燥。将粗产物结晶后得到标题化合物为浅黄色晶体。m.p.=147-149℃;TLC:EtOAc/己烷(1∶3)Rf=0.25。c)
顺-2-[N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基) 氨基]-环己烷-1-羧酸
将105mg(0.588mmol)顺-2-氨基-环己烷羧酸和82μL(0.588mmol)三乙胺依次加到129mg(0.490mmol)2,3-二甲氧基-7-硝基-喹喔啉-5-甲醛的1mL二氯甲烷和2mL乙醇溶液中。在室温搅拌3小时后将1g无水硫酸钠加到悬浮液中,并将混合物在室温搅拌20小时。用0.5mL乙醇稀释稠悬浮液,并加入46mg(1.23mmol)硼氢化钠。搅拌3小时后加入0.5mL丙酮,10分钟后加入0.3mL乙酸,并进行过滤。过滤留下的物质用乙醇和二氯甲烷洗涤。滤液经硅胶色谱纯化,首先用二氯甲烷/乙酸乙酯(97∶3),然后用二氯甲烷/甲醇/冰醋酸(90∶9∶1)洗脱。得到标题化合物为白色粉末。实施例57:
用类似实施例56所述方法制备下列化合物:N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基-甲膦酸氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基-(3-甲氧基苯基)-甲膦酸盐酸盐,FAB-MS:M+=436;HPLC:CH3CN/H2O+0.1%三氟乙酸20∶80 Rt=4.2min.(NucleosiLl00.C18,5μM,250×4.6mm);[(7-硝基-2,3-二氧-l,2,3,4-四氢喹喔啉-5-基-甲氨基)-(3-羟基-苯基)-甲基]-磷酸氢溴酸盐,FAB-MS:M+=422;HPLC:CH3CN/H2O+0.1%三氟乙酸20∶80 Rt=2.9min.(NucleosiLl00.C18,5μM,250×4.6mm);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-[(4-二乙氧基-磷酰基)-苄基]-胺盐酸盐,ESCI--MS:(M-H)+=421;TLC:二氯甲烷/甲醇/乙酸(9∶0.5∶0.5)Rf=0.28;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-氨基-丙烷-1-磷酸氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-乙磺酸氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-2-苯基-乙烷羧酸氢溴酸盐;顺-2-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]-环戊烷-1-羧酸氢溴酸盐;反-2-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]-环丙烷-1-磷酸氢溴酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基-(3-吡啶基)-甲膦酸盐酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-氨基-1-羧基-丙烷-1-磷酸氢溴酸盐;4-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]-丁酸,FAB-MS:M+=322;TLC:甲醇/乙酸(9∶1)Rf=0.30。实施例58:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲氨基甲基)四唑盐酸盐
将160mg(0.461mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲氨基甲基)四唑在6mL 2N HCl水溶液中回流搅拌20小时。冷却反应混合物,滤出所得固体用乙醚洗涤。m.p.=230℃(分解)。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-氨基乙腈
将300mg(0.914mmol)5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉,338mg(4当量)氨基乙腈盐酸盐和0.66mL(4当量)Hunig碱在10mL乙腈中回流搅拌20小时。蒸发浓缩混合物,剩余物用乙酸乙酯和约5%碳酸钠溶液萃取。合并的有机相用盐水洗涤,硫酸镁干燥并蒸发浓缩。所得棕色油经硅胶色谱纯化(乙酸乙酯/石油醚1∶2,然后是1∶1),得到标题化合物为黄色固体。b)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲氨基甲基)-四 唑
将140mg(0.461mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-氨基乙腈,50mg(0.43当量)二丁基氧化锡和0.244mL(4当量)三甲基甲硅烷基叠氮化物在6mL甲苯中回流搅拌16小时。冷却混合物,得到标题化合物为棕色固体。实施例59:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-2-氨基-乙膦酸氢溴酸盐
将380mg(0.949mmol)N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-氨基乙膦酸二甲酯和1.23mL(10当量)三甲基甲硅烷基溴化物溶解于20mL二氯甲烷,并将溶液在室温搅拌90分钟。蒸发浓缩反应混合物,在40℃将剩余物在6mL约33%溴化氢的乙酸溶液中搅拌17小时。用乙醚稀释反应混合物,滤出固体,整个用乙醚洗涤并干燥,得到标题化合物为黄色固体。m.p.=235℃(分解)。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-氨基 乙膦酸二甲酯
将0.19mL(1.2当量)三乙胺,0.215(1.5当量)三甲基氯甲硅烷和0.104mL(4当量)次膦酸二甲酯溶解于0℃的二氯甲烷,并将溶液搅拌20分钟。在反应混合物中加入329mg(1.135mmol)2,3-二甲氧基-5-亚乙基-氨基甲基-7-硝基-喹喔啉的二氯甲烷溶液,并在0℃搅拌5小时,然后在室温搅拌12小时。用水稀释溶液,并用二氯甲烷萃取三次。合并有机相,硫酸镁干燥并蒸发浓缩,得到标题化合物为黄色固体。b)
2,3-二甲氧基-5-亚乙基氨基甲基-7-硝基-喹喔啉
室温下将300mg(1.135mmol)2,3-二甲氧基-5-氨基甲基-7-硝基-喹喔啉,500mg(3.7当量)硫酸镁和200mg(1.28当量)碳酸钾悬浮于20mL二氯甲烷。15分钟后加入0.13mL乙醛,并将反应混合物在室温搅拌7小时,然后过滤并蒸发浓缩。实施例60:
2-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基 甲氧基)-乙酸
将270mg(0.711mmol)2-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲氧基)-乙酸叔丁酯溶解于6mL约16%溴化氢的乙酸溶液,并将溶液在室温搅拌20小时。用乙醚稀释反应混合物,滤出固体,整个用乙醚洗涤并干燥,得到标题化合物为固体(m.p.>300℃)。
起始原料可,例如,制备如下:a)
2-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲氧基)-乙酸叔 丁酯
将300mg(1.13mmol)2,3-二甲氧基-5-羟甲基-7-硝基-喹喔啉放入8mL四氢呋喃,并冷却到0℃。加入52mg(1.05当量)约55%NaH的油,然后在0℃搅拌混合物30分钟。加入0.2mL(1.5当量)溴乙酸-丁酯,20分钟后除去冰浴,将反应混合物在室温搅拌20小时,用水稀释,用乙酸乙酯萃取。合并的有机相用盐水洗涤一次,硫酸镁干燥并蒸发浓缩。剩余物经色谱纯化(SiO2,乙酸乙酯/石油醚,得到标题化合物为固体(340mg)。b)
2,3-二甲氧基-5-羟甲基-7-硝基-喹喔啉
用实施例14a)所述方法,但从5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉开始,制备标题化合物。实施例61:
2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲氧基)-乙酸
用类似实施例60所述方法,但从2-溴丙酸叔丁酯开始,制备标题化合物;m.p.=268℃(分解)。实施例62:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-4-氨基-溴化吡啶鎓
室温下将212mg(0.5mmol)4-氨基-1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-溴化吡啶鎓在3mL 48%溴化氢的冰醋酸溶液中搅拌18小时。用7mL乙醚稀释棕色反应混合物,然后搅拌10分钟。滤出所得固体,用少量乙醚洗涤并干燥,得到标题化合物为黄色固体。m.p.>245℃(分解)。
起始原料可,例如,制备如下:a)
4-氨基-1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基) -溴化吡啶鎓
室温下将197mg(0.6mmol)-5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉的2mL二氯甲烷加到282mg(3mmol)4-氨基吡啶的1mL二氯甲烷和3mL乙腈悬浮液中,然后将混合物在室温搅拌3.5小时。滤出所得沉淀,然后在滤液上用少量乙腈洗涤,得到标题化合物为无色粉末。实施例63:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-3-氨基-溴化吡啶鎓
用类似实施例62所述方法,但从3-氨基吡啶开始,制备标题化合物;m.p.>248℃(分解)。实施例64:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-2-氨基-溴化吡啶鎓
用类似实施例62所述方法,但从2-氨基吡啶开始,制备标题化合物;m.p.>350℃(分解)。实施例65:
3-(7-氯-2,3-二氧-喹喔啉-5-基)-丙烷-1- 醇
用类似实施例15所述方法,通过加热3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙-1-醇和乙酸/2N盐酸,制备标题化合物。
起始原料可,例如,制备如下:a)
5-碘-2,3,7-三氯-喹喔啉
将406.9g(1.953mol)五氯化磷加到195.9g(0.93mol)7-氯-5-碘-喹喔啉-二酮的1200mL氯氧化磷混合物中,并将混合物回流搅拌18小时。在150℃浴温下从反应混合物中蒸馏掉过量氯氧化磷。将剩余物倒在6000mL冰水上,并将所得悬浮液搅拌2小时,吸滤,然后用大量水洗涤。将过滤的剩余物在60℃真空干燥,得到205.89g(89.4%)5-碘-2,3,7-三氯-喹喔啉为淡棕色,无需进-步纯化将此粗晶体用于反应。b)
7-氯-2,3-二甲氧基-5-碘-喹喔啉
室温下将205g(0.828mol)5-碘-2,3,7-三氯喹喔啉加到2255mL甲醇中,然后加入463.9mL(约5.4mol)甲醇钠的甲醇溶液。将混合物加热回流并搅拌18小时。将混合物冷却到0℃,然后吸滤悬浮液。过滤的剩余物用甲醇洗涤,然后在60℃真空干燥。通过用乙醚连续萃取粗产物进行纯化,得到96.4g(48.8%)7-氯-2,3-二甲氧基-5-碘-喹喔啉。m.p.=94-96℃。c)
3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙-2-炔-1 -醇
将12.9g(36.8mmol)7-氯-2,3-二甲氧基-5-碘-喹喔啉,7.6mL(128.4mmol)炔丙醇,2.1g(3mmol)双(三苯膦)-二氯化钯,6.6mL(47.4mmol)三乙胺和0.34g(1.8mmol)碘化亚铜加到125mL二甲基甲酰胺中,并将浴温加热到70℃。将混合物在此温度搅拌3.5小时,然后冷却到室温。在反应混合物中加入乙酸乙酯,先后用水,1N盐酸和盐水萃取。用乙酸乙酯洗涤水相。合并有机相,用硫酸钠干燥,吸滤并浓缩。粗产物在硅胶上进行色谱分离,用己烷/乙酸乙酯(3∶1)洗脱,得到1.1g 3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙-2-炔-1-醇为棕色晶体。m.p.=137-140℃。d)
3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙烷-1-醇
常压下将2.05g(7.36mmol)3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙-2-炔-1-醇在20mL四氢呋喃中用约0.4g阮内镍氢化直到吸收了两倍摩尔量的氢。用玻璃纤维过滤器吸滤氢化的混合物,并浓缩滤液,得到2.04g(98%)3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙-1-醇为米色晶体。m.p.104-105℃。实施例66:
4-(7-氯-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基) -丁醇
用类似实施例65所述方法,但在步骤c)用4-(7-氯-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基)-丁醇代替炔丙醇,得到相应量的丁-3-炔醇,制备标题化合物。实施例67:
N-[3-(7-氯-2,3-二氧-1,2,3,4-四氢喹喔啉-5 -基)丙基]-甘氨酸氢溴酸盐
用类似实施例1所述方法,通过5-(3-溴丙基)-7-氯-2,3-二甲氧基-喹喔啉与三乙胺和甘氨酸叔丁酯盐酸盐和三乙胺的乙腈反应,然后经过水解,制备标题化合物。
起始原料可,例如,制备如下:a)
5-(3-溴丙基)-7-氯-2,3-二甲氧基-喹喔啉
氮气下将0.5g(1.77mmol)3-(7-氯-2,3-二甲氧基-喹喔啉-5-基)-丙-1-醇和0.287g(1.77mmol)1,1’-羰基二咪唑加到5mL乙腈中。加入0.75mL烯丙基溴,将混合物在室温搅拌30分钟,然后回流2小时。将反应混合物冷却到室温,加入乙醚,并先后用水,0.1N盐酸,饱和碳酸氢钠溶液和盐水进行萃取。水相用乙醚洗涤。合并有机相,硫酸钠干燥,硅胶过滤,然后浓缩,得到0.438g(79.9%)5-(3-溴丙基)-7-氯-2,3-二甲氧基-喹喔啉为黄色油,无需进一步纯化即可使用。实施例68:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-N-甲基-胺
用类似实施例34所述方法,通过用25%溴化氢的乙酸溶液处理N-(7-硝基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基亚甲基)-N-甲基-胺得到标题化合物。
起始原料可,例如,制备如下:a)
N-(7-硝基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基甲 基)-N-甲基-胺
用硼氢化钠的乙醇还原N-(7-硝基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基亚甲基)-N-甲基-亚胺,形成标题化合物。b)
7-溴-5-甲酰基-2,3-二甲氧基-喹喔啉
在0℃的氮气下将1.38g(60mmol)钠分批溶解于200mL甲醇。在0℃滴加5.85mL(65mmol)2-硝基丙烷,然后加入18.1g(50mmol)5-(溴甲基)-7-溴-2,3-二甲氧基-喹喔啉。将米色悬浮液加热回流并搅拌1小时。将反应混合物倒入600mL水中,并蒸馏掉甲醇。剩余物用乙酸乙酯萃取两次,有机相用硫酸钠干燥,然后吸滤。浓缩滤液,剩余物经高真空干燥,得到7-氯-5-甲酰基-2,3-二甲氧基-喹喔啉为米色晶体。m.p.=179-182℃。c)
N-(7-硝基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基亚 甲基)-N-甲基-亚胺
将7-氯-5-甲酰基-2,3-二甲氧基-喹喔啉与甲胺缩合得到标题化合物。d)
N-(7-硝基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基亚 甲基)-N-甲基-胺
用常规方法,例如,用硼氢化钠的四氢呋喃还原N-(7-硝基-2,3-二甲氧基-1,2,3,4-四氢喹喔啉-5-基亚甲基)-N-甲基-亚胺,得到标题化合物。实施例69:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基 甲基)-N-三乙基-溴化铵
用类似实施例39所述方法制备标题化合物,但起始原料要用N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-三乙基-溴化铵代替N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-2-甲基氮丙啶;ESCI--MS:(M-H)+=361;TLC:甲醇/乙酸(9∶1)Rf=0.1-0.45。
起始原料可,例如,制备如下:a)
N-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲基)-N-三乙 基-溴化铵
将0.795g(3.65mmol)双-叔丁氧羰基-胺和64μL(4.58mmol)三乙胺依次加到1.0g(3.05mmol)5-溴甲基-2,3-二甲氧基-7-硝基-喹喔啉的5mL二甲基甲酰胺溶液中。在50℃搅拌4小时后在悬浮液中加入10mL叔丁基甲醚,然后过滤。过滤的剩余物用叔丁基甲醚洗涤,得到的标题化合物是不需要的副产物,为白色晶体。实施例70:
3-[1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)- 乙氨基]-丙酸乙酯
将0.139g(0.5mmol)1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-乙酮,0.071g(0.5mmol)β-氨基丙酸乙酯盐酸盐和0.082g(0.5mmol)乙酸钠的50mL甲苯溶液与2mL水和20mL乙醇一起在250mbar和70℃浓缩。将产物放入甲苯/乙醇(3∶1)混合物,然后减压蒸发浓缩至干。
将剩余物溶于3mL四氢呋喃,并加入0.023g(0.6mmol)硼酸钠和1mL甲醇。在25℃甲苯18小时后用1N HCl酸化混合物。15分钟后再用10%碳酸氢钠水溶液进行碱化。用乙酸乙酯萃取混合物。有机相用盐水洗涤,硫酸钠干燥,并通过旋转蒸发浓缩至干。用乙酸乙酯/己烷(1∶1)作洗脱剂进行硅胶色谱分离,得到标题化合物为很快固化丁的油。TLC:EtOAc/己烷(1∶1)Rf=0.20。1H-NMR(CDCl3):δ8.57(d,J=3Hz,1H);8.39(d,J=3Hz,1H);4.73(q,J=7Hz,1H);4.21(s,3H);4.18(s,3H);4.12(q,J=7Hz,2H);2.86-2.62(m,2H);2.55-2.47(m,2H);2.0-1.7(br,NH);1.51(d,J=7Hz,3H);1.23(t,J=7Hz,3H).
起始原料可,例如,制备如下:a)
5-溴-7-硝基-喹喔啉-2,3-二酮
将在氮气中通过简单加热回流8.91g(40mmol)结晶硫化钠多水合物(硫化钠含量为33-38wt%)和在40mL水和10mL乙醇混合物中的1.28g(40mmol)硫制成的Na2S2溶液加到搅拌的10.48g(40mmol)2-溴-4,6-二硝基苯胺和2.08g(40mmol)氯化铵的70mL乙醇和40mL水的悬浮液中。将混合物在65℃搅拌30分钟后用30分钟滴加40mL 2N NaOH,并将混合物在65℃进行搅拌15分钟。冷却后将反应混合物倒入40mL 2N HCl,100g冰和700mL水的混合物中,搅拌15分钟使反应完成,然后用乙酸乙酯萃取两次。合并的有机相用硫酸钠干燥,伴随着简单加热用3g动物活性炭处理混合物,然后经High-Flow过滤。用旋转蒸发器浓缩,得到红棕色3-溴-5-硝基-1,2-二胺;TLC:乙酸乙酯/己烷(1∶1)Rf=0.40。
无需进一步纯化,将产物与17g(135mmol)草酸二水合物和50mL草酸二乙酯的100mL甲苯一起加热到150℃(浴温)。将反应过程中形成的乙醇和水与在短Vigreux柱方法反应中形成的甲苯一起蒸馏掉。然后将混合物继续加热到190℃直到再没有液体被蒸馏掉。真空过滤除去草酸二乙酯。将橄榄绿色的剩余物悬浮于100mL乙酸,并用大量乙酸,水,乙醇和叔丁基甲醚洗涤,得到标题化合物。TLC(EtOAc/HOAc 98∶2):R1=0.451H-NMR(DMSO-D6):δ12.3(br,1H,NH),11.6(br,1H,NH),8.19(1H,d,J=2.5Hz),7.96(1H,d,J=2.5Hz).b)
2,3-二甲氧基-5-溴-7-硝基-喹喔啉
用类似实施例4b2)和4c2)所述方法,从5-溴-7-硝基-喹喔啉-2,3-二酮开始制备标题化合物,为黄色晶体。M.p.=171-175℃;1H-NMR(CDCl3):δ8.61(d,J=3Hz,1H),8.58(d,J=3Hz,1H),4.28(s,3H),4.20(s,3H).c)
1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-乙酮
将3.84g(12.23mmol)2,3-二甲氧基-5-溴-7-硝基-喹喔啉,4.41g(12.23mmol)三丁基-(1-乙氧基-乙烯基)-锡烷和0.055g(0.244mmol)Pd(OAc)2的50mL DMF混合物在80℃搅拌4小时。减压除去大部分溶剂。将剩余物放入乙酸乙酯,用水和盐水洗涤,干燥并旋转蒸发浓缩。用二氯甲烷/己烷(1∶1)作洗脱剂进行硅胶色谱分离,得到浅黄色固体状乙烯醚中间体。将该物质在25℃的四氢呋喃/1N HCl中搅拌1小时。所得混合物用乙酸乙酯稀释,盐水洗涤三次,硫酸钠干燥,及旋转蒸发浓缩,用乙酸乙酯/己烷分离得到标题化合物为亮黄色针状物。m.p.:155-157℃。TLC(EtOAc/hexane 1∶3):Rf=0.25实施例71:
3-[1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5 -基)-1-乙氨基]-丙酸盐酸盐
将0.13g(0.34mmol)3-[1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-乙氨基]丙酸乙酯的3mL甲醇和2mL 2N NaOH的悬浮液在25℃搅拌。1小时后将混合物调节至pH4并用氯仿/乙醇萃取。萃取合并的有机相,Na2SO4干燥并旋转蒸发浓缩。剩余物与4N HCl一起加热沸腾18小时。经过旋转蒸发将混合物浓缩至干。从水中结晶得到标题化合物为亮米色晶体。m.p.>300℃1H-NMR(DMSO-D6):δ12.4(s,2H);8.32(d,J=3Hz,1H);8.02(d,J=3Hz,1H);5.1-4.95(br,1H);3.2-2.9(br,2H);2.67(t,J=7Hz);1.57(d,J=7Hz,3H).MS(ES-):321(M-H)-.实施例72:
1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5 -基)-乙基]-哌啶-4-羧酸叔丁酯
用类似实施例1所述方法,通过(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-甲磺酸乙酯与哌啶-4-羧酸叔丁酯反应,制备标题化合物。
起始原料可,例如,制备如下:a)
2,3-二甲氧基-7-硝基-5-乙烯基-喹喔啉
将3.14g(1mmol)5-溴-2,3-二甲氧基-7-硝基-喹喔啉,6.34g(2mmol)三丁基乙烯基锡烷,1.26g(3mmol)氯化锂和1.4g(0.2mmol)双(三苯膦)-氯化钯(II)的20mL二甲基甲酰胺混合物在100℃加热2小时。将混合物冷却到室温,并减压蒸发浓缩至干。用甲苯作洗脱剂进行快速色谱纯化,得到标题化合物为微黄色固体。b)
2-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-乙醇
用常规氢硼化方法,例如用二甲基硫化物/甲硼烷复合物,制备标题化合物。c)
2-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-甲磺酸乙酯
通过与甲磺酰氯的常规反应制备标题化合物。实施例73:
1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5 -基)-乙基]-哌啶-4-羧酸
用类似实施例6所述方法,从1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-哌啶-4-羧酸叔丁酯开始,制备标题化合物。实施例74:
2-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5 -基)-乙氨基]-丙酸甲酯
用类似实施例72所述方法,从丙氨酸甲酯开始,制备标题化合物。实施例75:
2-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5 -基)-乙氨基]-丙酸
用类似实施例22所述方法,从2-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙氨基]-丙酸甲酯盐酸盐开始,制备标题化合物。实施例76:
2-氨基-3-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔 啉-5-基)-丙酸
将0.29g(0.62mmol)2-乙酰胺基-2-(7-硝基-2,3-二甲氧基-喹喔啉-5-基甲基)-丙二酸二乙酯的6mL 6N盐酸悬浮液加热回流24小时,然后减压浓缩至干。剩余物与水一起沸腾后离心并干燥,得到标题化合物为黄色粉末。1H-NMR(DMSO-D6):δ12.3-11.9(br,2H),10.3-9.2(br),7.98(d,J=3Hz,1H),7.90(d,J=3Hz,1H),3.50-3.45(m,1H),3.40-3.32(m,1H),3.06-2.98(m,1H).(ES+)-MS:[M+Na+NH4]+
起始原料可,例如,制备如下:a)
2-乙酰胺基-2-(2,3-二甲氧基-7-硝基-喹喔啉-5-基甲 基)-丙二酸二乙酯
将0.217g(1mmol)二乙基乙酰胺基丙二酸酯加到氩气下搅拌的0.026g(1.2mmol)钠的3mL乙醇溶液中。5分钟后加入0.328g(1mmol)2,3-二甲氧基-5-溴甲基-7-硝基-喹喔啉,并将混合物在25℃搅拌18小时。用乙酸乙酯稀释混合物,先后用1N盐酸和盐水洗涤,硫酸钠干燥,然后旋转蒸发浓缩。用乙酸乙酯/己烷(1∶2)作洗脱剂进行硅胶色谱分离,得到标题化合物为很快固化的油。TLC(EtOAc/hexane 1∶2):R1=0.351H-NMR(CDCl3):δ8.57(d,J=3Hz,1H),8.01(d,J=3Hz,1H),6.34(s,1H),4.36-4.24(m,4H),4.25(s,3H),4.18(s,3H),1.85(s,3H),1.31(t,J=7Hz,6H).实施例77:
3-氨基-3-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔 啉-5-基)-丙酸氢溴酸盐
将0.15g(0.39mmol)3-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-3-甲氧羰基氨基-丙酸的5mL 33%HBr/HOAc溶液在70℃加热16小时。冷却后灰色悬浮液用叔丁基甲醚稀释,然后吸滤,得到标题化合物为灰色粉末。1H-NMR(DMSO-D6):δ12.41(s,1H),12.4-11.8(br,1H),8.7-8.3(br,NH3+),5.4-5.28(m,2H),3.16-2.96(m,2H);FAB-MS:[M+1]+295.
起始原料可,例如,制备如下:a)
[1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-丁-3-烯基] 氨基甲酸甲酯SV-2560
将1.26mL BF3·OEt2一次全部加到在0℃搅拌的2.63g(10mmol)2,3-二甲氧基-7-硝基-喹喔啉-5-甲醛(carbaldehyde),0.75g(10mmol)氨基甲酸甲酯和1.2g(10.5mmol)烯丙基三甲基甲硅烷的30mL乙腈悬浮液中。将混合物在25℃搅拌30分钟,然后倒入10%碳酸氢钠水溶液中,并用盐水和乙酸乙酯稀释。分离有机相,干燥并旋转蒸发浓缩。粗产物结晶后得到标题化合物为几乎无色的晶体。m.p.=135-136℃;TLC(EtOAc/己烷1∶3):Kf=0.17。b)
3-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-3-甲氧羰基 氨基-丙酸
将0.31g(0.85mmol)[1-(2,3-二甲氧基-7-硝基-喹喔啉-5-基)-丁-3-烯基]氨基甲酸甲酯,0.733g(3.42mmol)碘酸钠(NaIO4)和0.01g氧化钌(RuO2)的5mL乙腈混合物及5mL四氯化碳和5mL水在25℃剧烈搅拌4小时。混合物经High-Flow过滤,然后用乙酸乙酯和水洗涤。有机相依次用1N盐酸和盐水洗涤,硫酸钠干燥并旋转蒸发浓缩。剩余物再与0.50g碘酸钠和0.005g氧化钌的5mL水,5mL乙腈和5mL四氯化碳的混合物混合,并剧烈搅拌1小时。混合物经High-Flow过滤,然后用乙酸乙酯和水洗涤。分离有机相,用盐水洗涤,硫酸钠干燥及旋转蒸发浓缩。粗产物从叔丁基甲醚结晶后得到标题化合物为灰色晶体。
TLC(FtOAc/HOAc 98∶2):Rt=0.52.1H-NMR(CDCl3):δ8.61(d,J=3Hz,1H),8.32(d,J=3Hz,1H),6.36-6.28(m,1H),6.02-5.88(m,1H),4.23(s,3H),4.19(s,3H),3.68(s,3H),3.18-3.09(m,2H).实施例78:
用类似实施例1-77所述方法制备下列化合物:N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-三氟甲基哌啶氢溴酸盐,m.p.=273℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基苯并咪唑氢溴酸盐,m.p.>300℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-二异丙胺氢溴酸盐,m.p.=284℃(分解);N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-正丙基哌啶氢溴酸盐,m.p.=286℃;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-氨基-正丁基磷酸氢溴酸盐,MS(ES+):(M+H)+=373;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-4-氨基-正丁基磷酸氢溴酸盐,MS(ES+):(M+H)+=387;N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-12-氨基-正十二烷酸,m.p.=232-238℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-羟基-3-甲氧基-苄胺,m.p.>270℃;N-[1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-基甲基]-甲磺酰胺氢溴酸盐,(ES)-MS:410[M-H]-;N-[1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-基甲基]-乙酰胺氢溴酸盐,(ES-)-MS:374[M-H]-;N-[1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-4-基甲基]-烟酰胺氢溴酸盐,(ES-)-MS:437[M-H]-;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-(4-氟苯甲酰基)-哌啶,(AP-)-MS:425[M-H]-;{3-[(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基]-2-氧-2,3,4,5-四氢-苯并[.b.]吖庚因-1-基}-乙酸氢溴酸盐,(ES+)-MS:454[M+H]+;4-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-2-羧酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-氯-苯基)-磺酰胺,m.p.>270℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-羧基-苯基)-磺酰胺,m.p.>270℃;4-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-甲基-3,5-二氧-哌嗪,(AP-)-MS:346[M-H]-;4-{[(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基]-甲基}-苯磺酰胺盐酸盐,m.p.>270℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氧-吖庚因-3-基-胺氢溴酸盐,m.p.>270℃;4-{[(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基]-甲基}-苯甲酸盐酸盐,m.p.>270℃;4-[(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基]-苯甲酸盐酸盐,m.p.>270℃;5-[(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基]-3H-咪唑-4-羧酸酰胺,m.p.>270℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3,5-二甲基-吗啉氢溴酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4,4-亚乙基二氧基-哌啶盐酸盐,m.p.=290℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-甲基-哌啶氢溴酸盐,m.p.>300℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-羟基-哌啶盐酸盐,m.p.=290℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-羟甲基-吡咯烷盐酸盐,m.p.=247℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-乙酰氧基甲基-吡咯烷氢溴酸盐,m.p.=175℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-羟-吡咯烷-2-羧酸盐酸盐,m.p.=241℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-羟基-哌啶氢盐酸盐,m.p.>300℃;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-(L)-丁酸盐酸盐,m.p.=238℃(分解);2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-(L)-丁酸甲酯氢溴酸盐,m.p.=218℃(分解);2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-异丁酸盐酸盐,m.p.>300℃;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-异丁酸甲酯氢溴酸盐,m.p.=243℃(分解);1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-环丙烷-1-羧酸盐酸盐,m.p.=254℃(分解);N-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-(L)-丙氨酸盐酸盐,m.p.=277℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-亮氨酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-苏氨酸氢溴酸盐,m.p.=215℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-甲基-β-氨基丙酸盐酸盐,m.p.=238℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-吡啶甲胺二氢溴酸盐,m.p.=218℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-吡啶甲胺二氢溴酸盐,m.p.=229℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基乙腈氢溴酸盐,m.p.=275℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-亚苄基哌啶氢溴酸盐,m.p.=242℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-苯基哌啶-4-羧酸酯盐酸盐,m.p.>280℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-氨基甲酰基哌啶氢溴酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-甲基-β-氨基丙酸盐酸盐,m.p.=298℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-苯基-4-甲氧羰基-哌啶氢溴酸盐,m.p.=258℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-亚氨基二乙酸盐酸盐,m.p.=257℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3,4-四氢异喹啉氢溴酸盐,m.p.=300℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基苯并噻唑氢溴酸盐,m.p.=272℃(分解);1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-乙膦酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-乙酰基-(L)-丙氨酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-苯基-哌啶氢溴酸盐,m.p.>230℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-羟甲基-哌啶盐酸盐,m.p.=248℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-羟甲基哌啶盐酸盐,m.p.=286℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-(1-羟乙基)-哌啶盐酸盐,m.p.=238℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-甲氧基-哌啶盐酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-甲基-哌啶;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-甲氧基-4-甲基-哌啶;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4,4-二甲氧基-哌啶;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(L)-丝氨酸盐酸盐,m.p.=228℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-O-乙酰基-(L)-丝氨酸氢溴酸盐,m.p.=250℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吖庚因-2-酮;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶-2-酮;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-乙基-4-甲基咪唑;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-氧-吡咯烷-2-羧酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-5-溴-嘧啶氢溴酸盐,m.p.>274℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-5-氨基-2-甲氧基-吡啶氢溴酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基嘧啶氢溴酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基吡啶氢溴酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-氨基-吡啶氢溴酸盐,m.p.=213℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-4-甲基-嘧啶氢溴酸盐,m.p.=200℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-氨基-5-叔丁基异噁唑,m.p.=148-150℃(分解);N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基-4,5-二氰基-咪唑氢溴酸盐,m.p.>300℃;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N,N,N-三乙基溴化铵;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,4-三唑-3-羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,4-三唑-5-羧酸;4-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,4-三唑-3-羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4,5-二羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,4-三唑;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,4-三唑-5-羧酸乙酯;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4,5-二羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4,5-二羧酸二甲酯;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4-羧酸酰胺;1-(氯-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4-羧酸酰胺;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4,5-二羧酸二甲酯,m.p.=173-175℃;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3-三唑-4,5-二羧酸,m.p.=290℃(分解);1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-咪唑-2,4,5-三羧酸;P-苄基-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-甲烷亚膦酸;P-甲基-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-甲烷亚膦酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-氨基甲酰基甲膦酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氧-1,2-二氢吡啶;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,3,4-四氢异喹啉-1-酮;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2,3,4,5-四氢-1H-1-苯并吖庚因-2-酮;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氧-3-苯基-哌啶;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氧-5-苯基-哌啶;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-5-甲基-吡咯烷-2-酮;4-(2-氧杂咪唑烷-1-基)-N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌啶;N-{2-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)氨基]乙基}-吡咯烷-2-酮;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-苯基-吡咯烷-2-酮;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-(4-氟苯甲酰基)-哌啶;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氧-2-苯基-乙酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-丙基-戊酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(4-甲基呋喃)-2-羧酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-噻吩-3-羧酸酰胺,m.p.>250℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-咪唑-4-羧酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-(噻吩-3-基)-丙烯酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-苯基异丁酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1-苯基环丙烷-羧酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-苯基丙酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-苯基乙醇酸酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3,4-二甲氧基苯基)-乙酰胺,m.p.>280℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(4-氯苯基)-乙酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-氯苯基)-乙酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(2-氯苯基)-乙酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-甲基噻吩)-2-羧酸酰胺,m.p.>280℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(5-甲基噻吩)-2-羧酸酰胺,m.p.>280℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(1-甲基吡咯)-2-羧酸酰胺,m.p.>280℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-烟酸酰胺盐酸盐,m.p.=272℃(分解);N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(4-硝基苯基)-乙酰胺,m.p.>270℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-硝基苯基)-乙酰胺,m.p.>270℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(2-硝基苯基)-乙酰胺,m.p.>270℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3,4-亚甲基二氧基苯基)-乙酰胺,m.p.>270℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-(3-苯氧基苯基)-乙酰胺;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡啶甲酸酰胺;7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基甲膦酸,m.p.>270℃;1-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-乙膦酸;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-苄氧羰基-氨基-甲膦酸;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-苄基尿烷;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-苯基尿烷;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-苯基乙酰基-氨基-甲膦酸;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-苯基乙酰基-甘氨酸;3-乙酰基-1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯氢溴酸盐,m.p.=225℃(分解);1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯-3-羧酸乙酯氢溴酸盐,m.p.=195℃(分解);N-甲基-N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-苯基乙酰胺,m.p.>260℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-乙酰氧基吡咯烷氢溴酸盐,m.p.=246℃;N-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3-羟基吡咯烷盐酸盐,m.p.=263℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯-3-羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯-2-羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯-2-羧酸叔丁酯;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吲哚-3-基乙酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吲哚-3-基乙酸乙酯;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吲哚-3-基羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吲哚-2-羧酸叔丁酯;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吲哚-2-羧酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-咪唑氢溴酸盐,m.p.>300℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-羟甲基-咪唑;1-[1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-咪唑-4-基]-乙酸;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-甲基-咪唑氢溴酸盐,m.p.>300℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-甲基-咪唑氢溴酸盐,m.p.>300℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-乙基-咪唑氢溴酸盐,m.p.>300℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡唑氢溴酸盐,m.p.>300℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-3,5-二甲基-吡唑氢溴酸盐,m.p.>300℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-1,2,4-三唑氢溴酸盐,m.p.>250℃;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-吡咯;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-哌嗪-3-酮;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-噁唑烷-2-酮;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-4-甲基-哌嗪-3,5-二酮;3-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2,3,5,6-四氢-4H-1,2-噁嗪;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨茴酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨茴酸甲酯;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨茴酸乙酯;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-苄基-4-乙酰胺基-哌啶;1-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-苯基-4-乙酰胺基-哌啶;{3-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氧-1,2,3,4-四氢-苯并[b]吖庚因-1-基}-乙酸;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-异丙基-N-(喹啉-4-基甲基)-胺;4-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-5-苯基-戊-1-烯;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-N-(4-硝基苯基)-乙酰胺;N-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酰基]-甘氨酸;N-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酰基]-N-甲基-甘氨酸;1-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酰基]-吡咯烷-2-羧酸;N-[N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-甘氨酰基]-苯基丙氨酸;2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-丙氨酸;3-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-丙醇盐酸盐;3-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-乙醇盐酸盐;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氨基)-5-二甲氨基-萘磺酰胺;N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙-苄基-氮丙啶;2-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙氨基]-乙酸;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-哌啶;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-哌啶-4-酮;1-[2-(7-硝基-2,3-二氧1,2,3,4-四氢喹喔啉-5-基)-乙基]-吡咯烷-3-醇;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-哌啶-4-羧酸;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙其]-4-乙酰胺基-哌啶;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-吡咯烷-2,5-二酮;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-哌啶-2,6-二酮;1-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-吡咯烷;N-{2-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]}-N-(吡嗪-2-基)-胺;N-{2-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]}-N-(噻唑-2-基)-胺;N-{2-2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]}-喹啉-4-羧酸酰胺;N-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-甲磺酸酰胺;N-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-苯磺酸酰胺;N-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-乙酰胺;N-[2-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基)-乙基]-(4-甲氧基)-苯甲酰胺。实施例79:
每粒含有50mg活性成分如7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙酸或其盐的片剂可制备如下:
组合物(10,000片)
活性成分 500.0g
乳糖 500.0g
马铃薯淀粉 352.0g
明胶 8.0g
滑石 60.0g
硬脂酸镁 10.0g
二氧化硅 (极为分散的) 20.0g
乙醇 适量
将活性成分与乳糖和292g马铃薯淀粉混合,混合物用明胶的乙醇溶液润湿,并用筛子粒化。干燥后将剩下的马铃薯淀粉,硬脂酸镁,滑石和二氧化硅与其混合,并将混合物压制成片,每片重145.0mg,含有50.0mg活性成分;如果需要,可在片剂上留下破碎用的缺口以便更好地使用该片剂。实施例80:
将含有20%作为溶解剂的环糊精和3mg作为活性成分的7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙酸或其盐如钠盐的明胶过滤灭菌水溶液在无菌和加热条件下与含有作为防腐剂的苯酚的灭菌明胶溶液混合,在这种情况下每1.0mL溶液含有下列组分:
活性成分 3mg
明胶 150.0mg
苯酚 4.7mg
用含有20%作为溶解剂
的环糊精蒸馏水补充到 1.0mL实施例81:
为了制备注射用无菌干燥物质,可将5mg 7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙酸或其盐如钠盐,或5mg上述实施例中所述任何一种式I化合物作为活性成分溶解于1mL含有20mg甘露糖醇和20%作为溶解剂的环糊精的水溶液。对该溶液进行过滤灭菌,并在无菌条件下装入2mL安瓿,然后极低温冷冻并冻干。使用前将冻干的物质溶解于1mL蒸馏水或1mL生理盐水。所得溶液用于肌肉内或静脉内给药。也可将该制剂装入双腔(double-chamber)注射安瓿。实施例82:
每粒含有100mg 7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲氧基乙酸或其盐如钠盐的10,000粒膜衣片剂可制备如下:
活性成分 1000g
玉米淀粉 680g
胶状硅酸 200g
硬脂酸镁 20g
硬脂酸 50g
羧甲基钠淀粉 250g
水 适量
将作为活性成分的上述实施例所述任何一种式I化合物,50g玉米淀粉和胶状硅酸的混合物与含有250g玉米淀粉和2.2kg软化水的淀粉糊混合,制成潮湿的物质。用外力使这种潮湿物通过筛径为3mm的筛子,然后在45℃的流化床干燥器中干燥30分钟。将通过筛径为1mm筛子的干燥颗粒与已通过1mm筛子的330g玉米淀粉,硬脂酸镁,硬脂酸和羧甲基钠淀粉混合,然后挤压制成两面稍微凸起的片剂。实施例83:
用类似实施例79-82所述方法可以制成含有上述实施例1-78中任何一种化合物的不同种类的药剂。
Claims (3)
1.式I的2,3-二氧-1,2,3,4-四氢喹喔啉基衍生物或其盐,其中,
基团R1和R2之一是R5基团,另一个是式-alk-N(R8)-X-R7的基团,
R3,R4和R5各自独立地是氢、C1-C4烷基、卤素、氰基或硝基,
R7是膦酰基,单-、二-或三-(C1-C4烷基)膦酰基,
R8是氢,C1-C4烷基,苯氧羰基或苯羰氧基,
alk是C1-C4亚烷基,和
X是直键,C1-C4亚烷基,C3-C7亚环烷基,羧基-(C1-C4)亚烷基,羰基或羟基取代的苯基-(C1-C4)亚烷基。
2.权利要求1的化合物,选自:
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-2-氨基乙膦酸;
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基甲膦酸;
N-(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基)-氨基-(3-甲氧基苯基)甲膦酸;
7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基氨基甲膦酸;
1-(7-溴-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基氨基)乙膦酸;
〔(7-硝基-2,3-二氧-1,2,3,4-四氢喹喔啉-5-基甲基氨基)-(3-羟基苯基)-甲基〕-膦酸氢溴酸盐;
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-4-氨基-正丁基膦酸;
N-(2,3-二氧-7-硝基-1,2,3,4-四氢喹喔啉-5-基甲基)-N-甲基-4-氨基-正丁基膦酸;
及它们的盐。
3.一种药物组合物,包含权利要求1或2的化合物或其药学可接受的盐,及常规的药物赋形剂和载体,该药物组合物用于治疗阻断AMPA受体,红藻氨酸盐受体和/或NMDA受体的甘氨酸结合部位所产生的状况。
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CH273495 | 1995-09-27 | ||
CH2734/1995 | 1995-09-27 | ||
CH2747/95 | 1995-09-28 | ||
CH274795 | 1995-09-28 | ||
CH2747/1995 | 1995-09-28 | ||
CH121396 | 1996-05-10 | ||
CH1213/96 | 1996-05-10 | ||
CH1213/1996 | 1996-05-10 | ||
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US7361666B2 (en) | 1999-05-25 | 2008-04-22 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6677332B1 (en) | 1999-05-25 | 2004-01-13 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6635661B2 (en) | 2000-05-25 | 2003-10-21 | Sepracor Inc. | Heterocyclic analgesic compounds and methods of use thereof |
AU2001216218A1 (en) | 2000-05-25 | 2001-12-11 | Sepracor, Inc. | Heterocyclic analgesic compounds and method of use thereof |
CA2440284A1 (en) * | 2001-03-08 | 2002-09-19 | Emory University | Ph-dependent nmda receptor antagonists |
TW200403066A (en) * | 2002-04-30 | 2004-03-01 | Novartis Ag | New uses of substituted aminoalkanephosphonic acids |
GB0310868D0 (en) * | 2003-05-12 | 2003-06-18 | Novartis Ag | Organic compounds |
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CA2540638A1 (en) * | 2003-09-30 | 2005-04-14 | Janssen Pharmaceutica N.V. | Quinoxaline compounds |
US20060020029A1 (en) * | 2004-07-02 | 2006-01-26 | Shimasaki Craig D | Pharmaceutical compositions from ethnobotanicals |
UA95788C2 (en) * | 2005-12-15 | 2011-09-12 | Ф. Хоффманн-Ля Рош Аг | Fused pyrrole derivatives |
CA2693032A1 (en) * | 2007-06-29 | 2009-01-08 | Emory University | Nmda receptor antagonists for neuroprotection |
CN102906085A (zh) * | 2010-05-20 | 2013-01-30 | 诺瓦提斯公司 | 2,4-二氧代-1,4-二氢-2h-喹唑啉-3-基-磺酰胺衍生物 |
US9737531B2 (en) | 2012-07-12 | 2017-08-22 | Glytech, Llc | Composition and method for treatment of depression and psychosis in humans |
JO3225B1 (ar) * | 2012-11-27 | 2018-03-08 | Lilly Co Eli | 6-((s)-1-{1-[5-(2-هيدروكسي-إيثوكسي)-بيريدين-2-يل]-1h-بيرازول-3-يل}إيثيل)-3h-1 ، 3-بنزو ثيازول-2- أون باعتباره مضاد مستقبل ampa يعتمد على tarp- جاما 8 |
CN103435561B (zh) * | 2013-08-19 | 2016-08-10 | 上海交通大学 | 一种新型d-氨基酸氧化酶抑制剂及其制备和应用 |
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