CN1038840C - 对二氮荼衍生物、其制法及其医药用途 - Google Patents
对二氮荼衍生物、其制法及其医药用途 Download PDFInfo
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- CN1038840C CN1038840C CN92113338A CN92113338A CN1038840C CN 1038840 C CN1038840 C CN 1038840C CN 92113338 A CN92113338 A CN 92113338A CN 92113338 A CN92113338 A CN 92113338A CN 1038840 C CN1038840 C CN 1038840C
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- Prior art keywords
- amino
- alkyl
- phenopiazine
- dioxo
- tetrahydrochysene
- 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.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 229910001873 dinitrogen Inorganic materials 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical group FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 150000002912 oxalic acid derivatives Chemical class 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910004013 NO 2 Inorganic materials 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 230000008569 process Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- -1 1-carboxyl-1-phenmethyl Chemical group 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000003513 alkali Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 238000013375 chromatographic separation Methods 0.000 description 8
- 229940095102 methyl benzoate Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 150000002460 imidazoles Chemical class 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
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- 239000003814 drug Substances 0.000 description 5
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- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- JRMAQQQTXDJDNC-UHFFFAOYSA-M 2-ethoxy-2-oxoacetate Chemical compound CCOC(=O)C([O-])=O JRMAQQQTXDJDNC-UHFFFAOYSA-M 0.000 description 4
- 102000003678 AMPA Receptors Human genes 0.000 description 4
- 108090000078 AMPA Receptors Proteins 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000000052 vinegar Substances 0.000 description 4
- 235000021419 vinegar Nutrition 0.000 description 4
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 3
- XPRXSVUVVFZBIB-UHFFFAOYSA-N 1-[2-nitro-4-(trifluoromethyl)anilino]ethylphosphonic acid Chemical class OP(=O)(O)C(C)NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O XPRXSVUVVFZBIB-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- SCHRRICRQNJJKN-UHFFFAOYSA-N P.[O] Chemical compound P.[O] SCHRRICRQNJJKN-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
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- 239000007789 gas Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 230000002186 photoactivation Effects 0.000 description 3
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- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- 238000005406 washing Methods 0.000 description 3
- RQEIUNRFWLZDPY-UHFFFAOYSA-N 2-(2,4-dinitroanilino)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O RQEIUNRFWLZDPY-UHFFFAOYSA-N 0.000 description 2
- PWWSBXCEIIQXQB-UHFFFAOYSA-N 2-(2-amino-4-nitroanilino)benzoic acid Chemical compound NC1=CC([N+]([O-])=O)=CC=C1NC1=CC=CC=C1C(O)=O PWWSBXCEIIQXQB-UHFFFAOYSA-N 0.000 description 2
- PMCPRCXYFGNSSL-UHFFFAOYSA-N 3-(2-amino-4-nitroanilino)propanoic acid Chemical compound NC1=CC([N+]([O-])=O)=CC=C1NCCC(O)=O PMCPRCXYFGNSSL-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
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- 150000008065 acid anhydrides Chemical class 0.000 description 2
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- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
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- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical class CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
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- 210000000936 intestine Anatomy 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 2
- LCUSJKHFDGIFGP-UHFFFAOYSA-N n'-ethenylmethanimidamide Chemical compound NC=NC=C LCUSJKHFDGIFGP-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- QQVDJLLNRSOCEL-UHFFFAOYSA-N (2-aminoethyl)phosphonic acid Chemical compound [NH3+]CCP(O)([O-])=O QQVDJLLNRSOCEL-UHFFFAOYSA-N 0.000 description 1
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
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- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- NQWYMLDUPPXVTD-UHFFFAOYSA-N 1-(2,4-dinitroanilino)ethylphosphonic acid Chemical class OP(=O)(O)C(C)NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O NQWYMLDUPPXVTD-UHFFFAOYSA-N 0.000 description 1
- JPKQUYAOYIEWIJ-UHFFFAOYSA-N 1-(2-amino-4-chloroanilino)ethylphosphonic acid Chemical class OP(=O)(O)C(C)NC1=CC=C(Cl)C=C1N JPKQUYAOYIEWIJ-UHFFFAOYSA-N 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 239000002184 metal Substances 0.000 description 1
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- YUHSMQQNPRLEEJ-UHFFFAOYSA-N methyl 3-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CBr)=C1 YUHSMQQNPRLEEJ-UHFFFAOYSA-N 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
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- 229920001592 potato starch Polymers 0.000 description 1
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- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- 235000010288 sodium nitrite Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 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
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- 230000008673 vomiting Effects 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
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- 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
描述了式Ⅰ的对二氮萘衍生物及其制法和医药应用：
Description
本发明涉及对二氮萘二酮-羧酸和-膦酸衍生物、其制法及其医药用途。
已知对二氮萘衍生物对quisqualat受体有亲和性，并由于该亲合性而适于作为治疗中枢神经系统疾病的药物。
现已发现，本发明的化合物由于对quisqualat受体的结合能力好，因而优于EP-A-315959和WO91-13878所公开的对二氮萘。
本发明化合物的结构式为下式I：
式中：
R1为由R2取代的C1-12-烷基、由R2取代的C2-12-链烯基、由R2取代的C2-12-炔基、由R2取代的C3-7环烷基、-(CH2)n-C5-10-芳基，在芳基或烷基上由R2所取代，或为在杂芳基或烷基上被R2所取代的-(CH2)n-杂芳基，
R4为氢、由R2取代的C1-12-烷基，由R2取代的C2-12-链烯基、由R2取代的C2-12-炔基、在芳基成烷基上由R2所取代的(CH2)n-C6-12-芳基或者为在杂芳基或烷基上由R2所取代的-(CH2)n-杂芳基，
R5、R6、R7和R8可相同或不同，代表氢、卤素、硝基、NR9R10、NHCOR11、SO2R12、C3-7-环烷基氧、COR13、氰基、CF3、C1-6-烷基、C1-4烷氧基或必要时由氰基、C1-4-烷基或-COO-C15-烷基取代的咪唑，或者
R5和R6或R7和R6表示一个稠合的苯环，其中：
R2为-CO-R3或-PO-XY且R2可一或两次相同或不同，
n为0、1、2、3、4或5，
R3为羟基、C1-5-烷氧基或NR9R10，
X和Y相同或不同，表示羟基、C1-5烷氧基、C1-4-烷基或NR9R10，
R9和R10相同或不同，表示氢、C1-4-烷基或与氮原子共同形成一个饱和的5或6元杂环，该环还可含有一个氧、硫或氮原子，
R11为C1-5烷基或苯基，
R12为氢、C1-4烷基、NH2、N(C1-4-烷基)2和
R13为羟基、C1-5-烷氧基、C1-6-烷基或NR9R10及其异构体或盐类，其中，
如果R4、R5、R6、R7和R5为氢，R1不能为氨基甲酰基甲基、1-羧基-1-苯甲基或在1位上由-COOH或-COO-C1-5-烷基取代的直链C1-6-烷基，和
如果R1为在1位上由-COOH或-COO-C1-5-烷基取代的直链C1-5-烷基，R6和/或R7以及R6和R8不能为氟、氯或溴且R4-R8总是为氢，和
如果R1为-CH2-COOH，
a)R6和R7不能同时为甲基或
b)R6或R7不能为NO2且R4-R8总是为氢。
通式I化合物还包括可能的互变异构体式且包括E-或Z-异构体，或者出现一个手性中心，则包括消旋体或对映体。
取代基优选在6和/或7位上。
取代基R2可一至二次相同或不同地位于烷基、链烯基、炔基、环烷基、杂芳基或芳基的任何位置上。
烷基指一个直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、庚基、辛基、壬基、癸基，其中优选C1-5-烷基。
链烯基特别包括可为直链或支链的C2-6-烯基，例如2-丙烯基、2-丁烯基、3-甲基-2-丙烯基、1-丙烯基、1-丁烯基、乙烯基。
作为炔基，特别合适的是有2-4个碳原子的乙炔基、1-丙炔基、2-丙炔基、1-丁炔基。
C3-7-环烷基指环丙基、环丁基、环戊基、环己基和环庚基，尤其是C3-5-环烷基。
芳基例如可为苯基、萘基、联苯基和茚基，尤其是(CH2)n-苯基，n为0、1或2。
作为杂芳基合适的是1-3个氮原子的5或6元杂芳香物质，例如吡唑、咪唑、吡嗉、吡啶、嘧啶、哒嗪、三嗪。
卤素指氟、氯、溴和碘。
当R9和R10与氮原子共同形成一个饱和杂环时，例如是指哌啶、吡咯烷、吗啉、硫代吗啉或哌嗪。
若R1为C1-12-烷基和R2为COR3，则R5-R8为特别的取代基如NO2、NR9R10、NHCOR11、SO2R12、C3-7-环烷基氧、COR12、氰基、CF3、C1-4-烷氧基，必要时取代的咪唑或一个稠合的苯环。式I中R2＝-PO-XY的优秀化合物有很好的水溶性。
生理可容盐类指有机和无机碱的盐类，例如易溶的碱金属和碱土金属盐及N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、1，6-己二胺、乙醇胺、葡糖胺、肌氨酸、丝氨醇、三-羟基-甲基-氨基甲烷、氨基丙二醇、Sovak碱、1-氨基-2，3，4-丁三醇。
式1化合物及其生理可容盐由于其对quisqualat受体的亲合性而可用作药物。根据其作用范围，本发明化合物适用于治疗由于激发性氨基酸如谷氨酸盐或天冬氨酸盐机能亢进所引起的疾病。由于这些新化合物起激发性氨基酸拮抗药作用，并对AMPA受体有高的特定亲合性，它们取代AMPA受体放射扫描的特定兴奋剂(RS)-α-氨基-3-羟基-5-甲基-4-异噁唑丙酸盐(AMPA)，因而特别适用于治疗受激发性氨基酸受体尤其是AMPA受体影响的疾病，例如帕金森病、阿耳茨海默病、亨廷顿病、癫痈、低血糖、精神病、肌肉僵硬、呕吐、疼痛、缺氧症和局部缺血后的损伤。
在试管中用经典的结合试验检验本发明化合物对中心AMPA受体的亲合性。它们以高亲和力结合在用3H-AMPA标定的结合位置上。
为了检验在体内的作用性质及效率，检验这些化合物对老鼠静脉施用后的情况。用本发明化合物预处理后，由于脑内注射AMPA引起的痉挛依剂量不同而得到不同程度的抑制。
这些检查结果表明，这些化合物是有力的中心作用的AMPA拮抗药。因此，它们适用于治疗由于谷氨酸盐代谢紊乱引起的疾病。它们特别适用于治疗各种情况发生的大脑局部缺血、帕金森病和其它在上节提到的疾病。
为了用本发明化合物作药品，将其制成一种形式的药物制剂，该药剂除活性成分外，还含有适于肠内或胃肠外施用的药物、有机或无机惰性的载体，例如水、明胶、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、滑石粉、植物油、聚二醇等等。药物制剂可为固体形式，例如作为片剂、糖衣丸、栓剂、胶囊，也可为液体形式，例如作为溶液、悬浮液或乳液。必要时，它们还含有助剂如防腐剂、稳定剂、润滑剂或乳化剂、用于改变渗透压的盐类或缓冲物质。
对于胃肠外施用，特别合适的是注射溶液或悬浮液，尤其是活性化合物在多羟基乙氧化蓖麻油中形成的水溶液。
作为载体体系，也可利用界面活性助洗如胆酸的盐类或动物或植物磷脂，但也可用其混合物以及脂质体或其组分。
对于肠内应用，特别合适的是片剂、糖衣丸或者含滑石和/或烃载体或粘合剂的胶囊，例如乳糖、玉米或土豆淀粉可作上述载体或粘合剂。也可以液体形式应用，例如作为液汁，必要时还可加进甜料。
有效物质的剂量可以根据服用方式、病人的年龄和体重、待治疗疾病的种类及严重程度和其它类似的因素而改变。日服量为0.5～1000mg，优选50-200mg，其中该剂量可以作为一次性服用的单独剂量或者一天分成2或多次服用的剂量。
本发明的化合物可以本身已知的方法制备。例如用下述方法得到式I的化合物：
a)使式II的化合物式中R1、R5、R6、R7和R8含义同上，由活性草酸衍生物环化，并在需要时与R4′-X反应，其中X为卤素、甲苯磺酸盐、甲磺酸盐或三氟甲磺酸盐，R4′含义除氢之外与R4相同，或者
b)使式III的化合物
式中R4、R5、R6、R7和R8含义同上，与R1-X反应生成式I化合物，并在必要时使其酯基皂化或使酸基酯化或酰胺化或使硝基还原成氨基或使氨基烷化或酰化或使氨基与卤素或氰基交换，或者使氨基与式IV的2-氮杂丁二烯反应生成咪唑衍生物。式中U和V是离去基团，R11为氢、氢基或COOC1-5-烷基，R12为氢C1-5-烷基，或者分离异构体或形成盐。
用活性草酸衍生物使式II化合物环化可一步或也可两步完成。优选采用两步法，其中使二胺与一种草酸衍生物如草酸酯半氯化物在极性溶液如二甲基甲酰胺或环或无环醚或卤代烃例如四氢呋喃、二乙醚或二氯甲烷中于一种碱如有机胺例如三乙胺、吡啶、Honig碱或二乙氨基吡啶存在下反应。随后的环化可在碱性或者也可在酸性但优选酸性介质中进行，其中向溶剂中加入醇。
取代基R1和R4的导入按常见的烷基化方法进行，其中使对二氮萘二酮与R1-或R4-X在碱存在下于室温或高温下在非质子溶剂中反应，式中X为甲苯磺酸盐、甲磺酸盐或特别是Triflat或卤素。在加入P1-或R4-X之前，也可产生阴离子。作为碱合适的是例如像碳酸钾氢氧化钠，碱醇化物这样的碱性化合物和特别是像氢化钠这样的金属氢化物。偶尔也可使碱性化合物在相转移条件下反应。如果得到带取代基R1及R4，的化合物的混合物，可用常用方法分离。
适用于该反应的溶剂是非质子极性溶剂如二甲基甲酰胺、N-甲基吡咯烷酮，但也可用环醚如二噁烷或四氢呋喃。
如果在工艺方案b)中用2Mol R1-X在其它相似反应条件下反应，则同时引入取代基R1和R4。
必要时随后进行的酯基的皂化可在碱性或优选在酸性条件下进行，其中在直至反应混合物沸点的高温下在酸如高浓含水盐存在下于溶剂例如三氟醋酸或醇中水解。膦酸酯优选通过在高浓含水酸例如浓盐酸中加热或通过用三甲基甲硅烷基溴处理并随后处理用水处理来水解。
羧酸或膦酸的酯化在酸中或在活性酸衍生物存在下用相应的醇以本身已知的方式完成。作为活性酸衍生物例如可以考虑酰基氯、酰基咪唑化物或酸酐。膦酸可以和相应醇的原酸酯反应。与二环己基碳化二亚胺的加成产物和相应醇反应也可先成酯。与重氮甲烷反应可产生甲酯。
酰胺化通过使游离酸或其活性衍生物例如酰基氯、混合酐、咪唑化物或叠氮化物与相应的胺在室温下反应进行。
硝基变成氨基的反应在极性溶剂中于室温或高温下在氢气压下催化进行。催化剂可用金属如阮内镍或贵金属催化剂如钯或铂，必要时在载体上。也可用甲酸铵以公知方式代替氢。还原剂如氯化锌-II或氯化钛-III同样可以像络合的金属氢化物那样使用，必要时在重金属盐存在下。在还原前引入酯基可能是有利的。
若需要使氨基烷基化，可按常规方式例如用烷基卤化物烷基化。用醛和还原剂如氰基硼氢钠也可进行还原胺化。酰基化用已知方法进行。例如在含水介质中在碱存在下与相应的酸酐或酰基卤反应。
氰基的引入可借助于Sandmeyer反应完成；例如可使由氨基化合物与亚硝酸盐中间形成的重氮盐与氰化物在氰化铜-I存在下或与K2Ni(CN)4反应。
经氨基引入卤素氯、溴或碘可在无水或有水存在下进行；例如用含水的Sandmeyer法，使与亚硝酸盐中间生成的重氮盐与氯化铜(I)或溴化铜在相应的酸盐或溴氢酸存在下反应或与碘化钾反应。非水法使氯化氢以已知方式与i-亚硝酸戊醋和例如二碘甲烷或溴仿在非质子溶剂如二甲基甲酰胺存在下反应。氟的引入例如通过四氟硼酸重氮盐的巴兹谢曼反应完成。
氨基与式IV的2-氮杂丁二烯生成咪唑衍生物的反应在酸存在下在0至150℃温度下进行。挥发性基团U和V可相同或不同；特别合适的是C1-3-二烷基胺如二甲基-、二乙基-和二丙基胺的环胺如吡咯烷。
该反应例如这样进行：使胺衍生物和氮杂二烯在有机酸如蚁酸、醋酸、丙酸或三氟醋酸中先在室温下搅拌，然后加热到反应混合物的沸点(直至约120℃)。
酸可同时作为反应试剂和溶剂。但是也可加入溶剂例如醇、醚、酮、酯如醋酸乙酯、烃如甲苯或卤化烃如四氯化碳。
酸的量可在大范围内政变，但应过量应用。优选酸过量3-10倍，以胺和氮杂二烯为基准。
异构体混合物可用常见方法例如结晶、色谱分离或转化成非对映体例如形成盐分离成对映体或E/Z异构体。
以常见方式制备盐类，其中使式I化合物的溶液与等当量或过量的碱金属或碱土金属化合物(必要时在溶液中)混合，分离出现沉淀物或以常见方式处理该溶液。
因为没有描述原料化合物的制备，它们是已知的或类似于已知化合物或者可用这里所述的方法制备。
例如，式II的化合物可以这样制备：用Sanger的方法制备2，4-二硝基芳基胺，使邻-卤素-硝基芳香物优选邻-氟-硝基芳香物例如二硝基氟苯在水溶液中与氨基酸衍生物在碱如碳酸钠或碳酸氢钠存在下于0℃至回流温度下反应，随后还原。该反应也可转用到其它取代的2-硝基卤化物上。通过二硝基氯苯与芳香胺的Ullman反应也可得到二芳香基氨基化合物。对该反应，可以采用高沸点溶剂如二甲基甲酰胺或可力丁和固体碳酸钾和钢粉作为碱。也可以通过烷基化或用取代的醛进行还原性烷基化制备相应的邻硝基苯胺。随后邻硝基的还原在多个硝基存在下选择性地通过亚硫酸钠在氨及氯化铵存在下在极性溶剂中在室温或高温下完成。在几种情况下，先与酯反应，在最后一步使其水解是有利的。
对映体分离可在最后步骤或在中间阶段通过光活化辅助碱例如番木鳖碱或1-苯乙胺完成，或者也可经光活化载体物质进行色谱分离。但对映体也可通过使相应的光活化氨基酸与相应的氟硝基芳香物质按Sanger法合成并进而如上所述处理氨基硝基芳香物质而制备。
应当注意到，无需作更进一步的解释，本专业人员就可参照上述说明而充分有效地实施本发明。因此，优选的具体实施方案仅仅是说明性的，并不以任何方式限制本发明的公开或实施。
上述所有专利申请，专利和出版物以及相应的德国专利申请P4d135871.6和P4224200.2的全部公开内容均作为本文参考。
下面用实施例详述本发明的方法：
例1
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸甲酯和
3-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸甲酯
将1.03g(nM)6-硝基-2，3-二氧代-l，2，3，4-四氢对二氮萘在N2流下和排除湿气条件下在室温下放入50ml二甲基甲酰胺中。将330mg(11mM)氢化钠(80％的)分为三份加入。然后在室温下搅拌1小时。滴入1.26g(5.5mM)溶在5ml二甲基甲酰胺中的3-溴甲基苯甲酸甲酯搅拌
小时。浓缩后在醋酸水/醋酯乙酯中分配残渣。分离有机相干燥、过滤并浓缩。用二氯甲烷∶乙醇＝95∶5的硅胶对残渣进行色谱分离。除了211mg未进一步净化的3-(6-硝基-2，3-二氧代-l，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸甲酯外，还得到222mg溶点为265～267℃的3-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸甲酯。
以类似方式制备了：
4-(6-硝基-2，3-二氧代-1，2，3，-四氢对二氮萘-1-基甲基)-苯甲酸甲酯，溶点：308-314℃；
4-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸甲酯，溶点：＞300℃；
2-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸乙酯，溶点：279°/283-284℃；
2-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸乙酯(未净化即进而处理)；
1-(3-甲氧基羰基-2-丙烯基)-6-硝基对二氮萘-2，3-(1H，4H)-二酮，溶点：258-265℃并分解。
1-(3-乙氧基羰丙基)-6-硝基对二氮萘-2，3-(1H，4H)-二酮，溶点：215-217℃ ；
1-(3-乙氧基羰丙基)-7-硝基对二氮萘-2，3-(1H，4H)-二酮，溶点：215-217℃；
4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯基膦酸二乙酯，溶点：114℃/129-131℃ ；
4-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯基膦酸二乙酯(未净化即处理)；
3-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-丙-1-烯-1-膦酸二乙酯；
3-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-丙-1-炔-1-膦酸二乙酯；
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-丙烷-1-膦酸二乙酯；
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲烷羧酸叔丁酯。
例2
加入两倍甲基-3-溴甲基苯甲酸酯，其它反应过程与例1相同，此外还可分离出503mg 3-[4-(3-甲氧基羰基苄基)-6-硝基-2，3-二氧-1，2，3，4-四氢对二氮萘-1-基]-苯甲酸，熔点：238-240℃。
类似制得：
4-[4-(4-甲氧基羰基苄基)-6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基]-苯甲酸甲酯，熔点：225-227℃；
2-[4-(2-乙氧基羰基苄基)-6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基]-苯甲酸乙酯，熔点：230-234℃；
1，4-双-(3-甲氧基羰基-2-丙烯基)-6-硝基对二氮萘-2，3-(1H，4H)-二酮，熔点：181-183℃。
例3
A)4-(2，4-二硝基苯基)-氨基苯甲酸甲酯
将1.01g(5mM)1-氯-2，4-二硝基苯、1.01g(6mM)4-氨基苯甲酸乙酯、13mg(0.2mM)铜粉和961mg(7mM)碳酸钾在5ml绝对二甲基甲酰胺中于180℃浴热温度下在氩气和排除湿气条件下搅拌25分钟。
浓缩后放入水中，用氨调成碱性，用醋酸乙酯摇动萃取，将有机相干燥、过滤并浓缩。用环己烷∶醋酸乙酯＝8∶2的硅胶进行色谱分离。得到768mg 4-(2，4-二硝基苯基)-氨基苯甲酸乙酯，熔点为99-102℃。
以类似方式制得：
3-(2，4-二硝基苯基)-氨基苯甲酸乙酯，熔点：108-110C；
3-(2，4-二硝基苯基)-氨基苯基膦酸乙酯，未净化即进而处理；
2-(2，4-二硝基苯基)-氨基苯甲酸乙酯，未净化即进而处理。
B)4-(2-氨基-4-硝基苯基氨基)-苯甲酸乙酯
将566mg(1.7mM)4-(2，4-二硝基苯基氨基)-苯甲酸乙酯、761mg(12.2mM)氯化铵、0.68ml浓氨水、15ml乙醇和6ml蒸馏水在78℃的内温下(浴温90℃)放在一起。分三份加入1.27g(5.68mM)亚硫酸钠(35％的)，再搅拌1小时。在室温下抽出沉淀物，接着用水再用乙醚洗涤。得到535mg 4-(2-氨基-4-硝基苯基氨基)-苯甲酸乙酯粗产物(未净化即进而处理)。
以类似方式制得：
3-(2-氨基-4-硝基苯基氨基)-苯甲酸乙酯，熔点：145-150℃；
3-(2-氨基-4-硝基苯基氨基)-苯基膦酸乙酯，熔点：160-163℃。
C)4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯甲酸乙酯
将582mg(2.3mM)4-(2-氨基-4-硝基苯基氨基)-苯甲酸乙酯和488mg(4.8mM)三乙胺在氩气和排除湿气条件下放入+4℃浴温下的27ml无水四氢呋喃中。滴加一种由659mg(4.8mM)草酸乙酯氯化物和8ml无水四氢呋喃配成的溶液，并在室温下搅拌2小时。然后加入0.2ml三乙胺和0.1ml草酸乙酯氯化物，再在室温下搅拌1小时。滤出沉淀物，浓缩滤液。在水/醋酸乙酯中分配。浓缩有机相。在浴温及回流条件下将残余物在25ml 1-N盐酸和25ml乙醇中蒸煮2小时。抽出沉淀的产物，用水洗涤并干燥。得到：220mg 4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯甲酸乙酯(未提纯即继续使用)。
以类似方式制得：
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯甲酸乙酯，熔点：258-263℃；
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯基膦酸乙酯。
例4
A)2-(2，4-二硝基苯基)-氨基苯甲酸
使1.37g(10mM)2-氨基苯甲酸与2g(18.7mM)碳酸钠在40ml水中于40℃浴温下在剧烈搅拌下与1.86g(10mM)2，4-二硝基氟苯混合，并搅拌2小时。用大约400ml水稀释沉淀物，并用4-N HCl使之沉淀。抽出产物，水洗并干燥。得到2.8g 2-(2，4-二硝基苯基氨基)苯甲酸，熔点：266-270℃。
以类似方式制得：
3-(2，4-二硝基苯基氨基)-丙酸，熔点：134-137℃；
4-(2，4-二硝基苯基氨基)-苯基膦酸，熔点：271-272℃，同时分解；
2-(2，4-二硝基苯基氨基)-苯基膦酸，未提纯即继续加工；
(2，4-二硝基苯基氨基)-甲膦酸，熔点：225-227℃ ；
2-(2，4-二硝基苯基氨基)-乙膦酸，未提纯即继续加工；
3-(2，4-二硝基苯基氨基)-苯基膦酸；
(2-硝基-1-萘基氨基)-甲膦酸；
(1-硝基-2-萘基氨基)-甲膦酸；
1-(2-硝基-1-萘基氨基)-乙烷-1-膦酸；
1-(1-硝基-2-萘基氨基)-乙烷-1-膦酸；
(2-硝基-4-三氟甲基-苯基氨基)-甲膦酸；
1-(2-硝基-4-三氟甲基-苯基氨基)-乙烷-1-膦酸；
1-(2，4-二硝基苯基氨基)-乙烷-1-膦酸；
3-(2，4-二硝基苯基氨基)-丙烷-1-膦酸；
4-(2，4-二硝基苯基氨基)-丁烷-1-膦酸；
(2-硝基-4-氟苯基氨基)-甲膦酸；
(2-硝基-4-氯苯基氨基)-甲膦酸；
(2-硝基-4-溴苯基氨基)-甲膦酸；
(2-硝基-4-甲基苯基氨基)-甲膦酸；
1-(2-硝基-4-氟苯基氨基)-乙烷-1-膦酸；
1-(2-硝基-4-氯苯基氨基)-乙烷-1-膦酸；
1-(2-硝基-4-溴苯基氨基)-乙烷-1-膦酸；
1-(2-硝基4-甲基苯基氨基)-乙烷-1-膦酸；
1-苯基-1-(2-硝基-4-三氟甲基-苯基氨基)-甲膦酸；
1-甲基1-(2-硝基-4-三氟甲基-苯基氨基)-乙烷-1-膦酸；
1-(2-硝基-4-三氟甲基-苯基氨基)-己烷-1-膦酸；
1-甲基-2-(2-硝基-4-三氟甲基-苯基氨基)-乙烷-1-膦酸；
2-(2-硝基-4-三氟甲基-苯基氨基)-丙烷-1-膦酸；
1-甲基-2-(2-硝基-4-三氟甲基-苯基氨基)-丙烷-1-膦酸；
1-(2-硝基-4-三氟甲基-苯基氨基)-环丙烷-1-膦酸；
(+)-1-(2-硝基-4-三氟甲基-苯基氨基)-乙烷-1-膦酸；
(-)-1-(2-硝基-4-三氟甲基-苯基氨基)-乙烷-1-膦酸；
P，P-二甲基-(2，4-二硝基苯基氨基)-甲烷膦化氧；
P-甲基-(2，4-二硝基苯基氨基)-甲膦酸；
1-[5-(咪唑-1-基)-2，4-二硝基苯基氨基]-甲基膦酸；
1-[5-(咪唑-1-基)-2-硝基-4-三氟甲基苯基氨基]-甲基膦酸；
B)1-[5-(咪唑-1-基)-2，4-二硝基苯基氨基]-乙烷-1-膦酸
将600mg 5-氟-2，2-二硝基氟苯在40℃下放入30ml水和10ml乙醇中，并滴入一种由376mg外消旋氨基乙基膦酸在10ml水中和600mg碳酸钠形成的溶液。在温度下搅拌1.5小时。蒸出乙醇后用醋酸萃取。向水相掺加200mg咪唑，加热至110℃2小时，此后再加入200mg咪唑，并加热至110℃2小时。用4N盐酸酸化，吸滤出不溶物，用醋酸乙酯洗滤液。浓缩含水相，用乙醇煮透。浓缩乙醇萃取物，并用甲醇∶丁醇∶水∶氨＝75∶25∶17∶3的硅胶进行色谱分离。得到300mg 5-(咪唑-1-基)-2，4-二硝基苯基-(1-氨乙基膦酸)。
C)2-(2-氨基-4-硝基苯基氨基)-苯甲酸
将1.80g(6mM)2-(2，4-二硝基苯基氨基)-苯甲酸、2.66g(42.6mM)氯化铵、2.4ml浓氨水、52ml乙醇和21ml蒸馏水在78℃内温下(90℃浴温)放在一起。分3份加入4.44g(20mM)亚硫酸钠(35％的)并搅拌1小时。在室温下抽出沉淀物，先后用水和乙醚洗涤。将滤液浓缩成含水相，用醋酯乙酯摇振萃取。对有机相脱水、过滤并浓缩。用1N盐酸酸化含水相并将其抽出。得到1.1g 2-(2-氨基-4-硝基苯基氨基)-苯甲酸(未提纯即进一步使用)。
以类似方式制备且未提纯即继续加工：
3-(2-氨基-4-硝基苯基氨基)-丙酸；
4-(2-氨基-4-硝基苯基氨基)-苯基膦酸；
2-(2-氨基-4-硝基苯基氨基)-苯基膦酸；
(2-氨基-4-硝基苯基氨基)-甲基膦酸；
(2-氨基-4-硝基苯基氨基)-乙基膦酸；
1-(2-氨基-4-硝基苯基氨基)-乙烷-1-膦酸；
3-(2-氨基-4-硝基苯基氨基)-丙烷-1-膦酸；
4-(2-氨基-4-硝基苯基氨基)-丁烷-1-膦酸；
1-(2-氨基-4-三氟甲基苯基氨基)-环丙烷-1-膦酸；
P，P-二甲基-(2-氨基-4-硝基苯基氨基)-甲膦化氧；
P-甲基-(2-氨基-4-硝基苯基氨基)-甲膦酸；
1-[5-(咪唑-1-基)-2-氨基-4-硝基苯基氨基]-甲基膦酸。
D)(2-氨基-4-三氟甲基苯基氨基)-甲膦酸
将894mg(2-NO2-4-三氟甲基苯基氨基)-甲膦酸与3g阮内镍在180ml乙醇中相混合，并在室温及氢气常压下氢化3小时。由催化剂中吸滤沉淀物，并浓缩滤液。未提纯即将其加入步骤D。
以基本上类似的方式制得：
1-(2-氨基-1-萘基氨基)-乙烷-1-膦酸；
1-(1-氨基-2-萘基氨基)-乙烷-1-膦酸；
1-(2-氨基-1-萘基氨基)-甲膦酸；
1-(1-氨基-2-萘基氨基)-甲膦酸；
1-(2-氨基4-三氟甲基苯基氨基)-乙烷-1-膦酸；
1-(2-氨基-4-三氟甲基苯基氨基)-甲烷-1-膦酸；
(2-氨基-4-甲基苯基氨基)-甲膦酸；
1-(2-氨基-4-甲基苯基氨基)-乙烷-1-膦酸；
1-苯基-1-(2-氨基-4-三氟甲基苯基氨基)-甲膦酸；
1-甲基-1-(2-氨基-4-三氟甲基苯基氨基)-乙烷-1-膦酸；
1-(2-氨基-4-三氟甲基苯基氨基)-己烷-1-膦酸；
1-甲基-2-(2-氨基-4-三氟甲基苯基氨基)-乙烷-1-膦酸；
2-(2-氨基-4-三氟甲基苯基氨基)-丙烷-1-膦酸；
1-甲基-2-(2-氨基-4-三氟甲基苯基氨基)-丙烷-1-膦酸；
(+)-1-(2-氨基-4-三氟甲基苯基氨基)-乙烷-1-膦酸；
(-)-1-(2-氨基-4-三氟甲基苯基氨基)-乙烷-1-膦酸；
(4-氯-2-氨基苯基氨基)-甲膦酸；
1-(4-氯-2-氨基苯基氨基)-乙烷-1-膦酸；
(4-氟-2-氨基苯基氨基)-甲膦酸；
[5-(咪唑-1-基)-4-三氟甲基-2-氨基苯基氨基]-甲基膦酸；
1-(4-氟-2-氨基苯基氨基)-乙烷-1-膦酸；
D)3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-丙酸
将211mg(0.9mM)3-(2-氨基-4-硝基苯基氨基)-丙酸与200mg(2mM)三乙胺一起在+4℃浴温及氩气和排除湿气条件下放入20ml无水的四氢呋喃中。滴加一种由270mg(2mM)草酸乙酯氯化物和5ml无水四氢呋喃配成的溶液，并在室温下搅拌2小时。再加入0.05ml三乙胺和0.05草酸乙酯氯化物并在室温下搅拌1小时。滤出沉淀物，浓缩滤液。在水和醋酯乙酯中分配。浓缩有机相。将残渣放入15ml乙醇和15ml 1N盐酸中，在110℃浴温下回流蒸煮2小时。浓缩沉淀物，加些水并吸滤。得到120mg 3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-丙酸，熔点：148-156℃并分解。
以类似方式制得：
2-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯甲酸，熔点：＞255℃ ；
4-(6-硝基-2，3 二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯基膦酸，熔点：＞252℃；
2-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯基膦酸，熔点：＞310℃；
(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸，熔点：180-200℃，同时分解
2-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-乙膦酸，熔点：304-308℃，同时分解
2，3-二氧代-1，2，3，4-四氢苯并(f)-对二氮萘-4-基甲膦酸；
2，3-二氧代-1，2，3，4-四氢苯并(f)-对二氮萘-4-基乙烷-1-膦酸；
2，3-二氧代-1，2，3，4-四氢苯并(f)-对二氮萘-1-基甲膦酸；
2，3-二氧代-1，2，3，4-四氢苯并(f)-对二氮萘-1-基乙烷-1-膦酸；
(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸，熔点：202℃
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙膦酸，熔点：274℃
1-(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸，熔点：297-300℃，并分解；
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-丙烷-1-膦酸，熔点：200℃，并起泡
4-(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-丁烷-1-膦酸，熔点：285-287℃
(6-氟-2，3-二氧代1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸；
(6-氯-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸；
(6-溴-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸；
(6-甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸；
1-(6-氟-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸；熔点：259℃
1-(6-氯-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸
1-(6-溴-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸
1-(6-甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-1-苯基-甲烷-1-膦酸，熔点：245℃
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-1-甲基-乙烷-1-膦酸，
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-己烷-1-膦酸，
1-甲基-2-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸；
2-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-丙烷-1-膦酸，
1-甲基-2-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-丙烷-1-膦酸；
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-环丙烷-1-膦酸，
(+)-1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸，[α546 20]＝+7.4°(C＝0.505；H2O)；
(-)-1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸，[α546 20]＝-5.9°(C＝0.510；H2O)；
P-(甲基-(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸，熔点：320-325℃，并分解；
P，P-二甲基-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)甲膦化氧，熔点：325-330℃，并分解；
6-(硝基-7-(咪唑-1-基)-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲基膦酸，
6-(三氟甲基-7-(咪唑-1-基)-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲基膦酸；
例5
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸
将211mg(0.6mM)3-(6-硝基-2，3-二氧代-1，2，3，4一四氢对二氮萘-1-基甲基)-苯甲酸甲酯放入4ml4N盐酸中，掺入4ml三氟醋酸并在110℃浴温下搅拌
小时。沉淀物冷却到室温后用水稀释并吸滤。用水和乙醇洗滤并干燥。得到179mg 3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯甲酸，熔点：＞330℃。
以类似方式制得：
3-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：＞330℃；
3-[4-(3-羧基苄基)-6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基]-苯甲酸，熔点：298-300℃；
2-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：329-334℃，同时分解
2-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：328-330℃，
2-[4-(2-羧基苄基)-6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基]-苯甲酸，熔点：＞300℃ ；
4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：＞310℃；
4-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：320-324℃，并分解
4-[4-(4-羧甲基苄基)-6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基]-苯甲酸，熔点：＞310℃；
4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：＞345℃；
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯甲酸，熔点：＞250℃；
1-(3-羧基-2-丙烯基)-6-硝基对二氮萘-2，3-(1H，4H)-二酮，熔点：242-243℃
1，4-双-(3-羧基-2-丙烯基)-6-硝基对二氮萘-2，3-(1H，4H)-二酮，熔点：241-247℃，并分解
1-(3-羧丙基)-6-硝基对二氮萘-2，3-(1H，4H)-二酮，熔点：230-232℃
1-(3-羧丙基)-7-硝基对二氮萘-2，3-(1H，4H)-二酮，熔点：325-327℃，并分解
1-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-醋酸，熔点：320℃
例6
4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯基膦酸
将582mg(1.4mM)4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-甲基)-苯基膦酸乙酯在6ml浓盐酸中回流蒸煮2小时。冷却后用水稀释沉淀物并吸滤。干燥滤饼。得到253mg 4-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯基膦酸，熔点为253-265℃，并分解。
以类似方式制得：
4-(7-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基甲基)-苯基膦酸，熔点：＞250℃
3-(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-苯基膦酸，熔点：304-307℃，并分解
3-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-丙-1-炔-1-膦酸
3-(6-三氟甲基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-丙-1-烯-1-膦酸
例7
(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸-乙及二乙酯
在-15℃下向溶入5ml绝对二甲基甲酰胺中的300mg(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸滴入0.29ml(476mg)亚硫酰氢。加入结束后，在+4℃浴温下搅拌沉淀物20分钟。接着向沉淀物加入0.35ml(276mg)乙醇，并在室温下搅拌1.5小时。
真空浓缩后，用甲苯∶醋酸乙酯∶水＝10∶10∶1的硅胶进行色谱分离。先得到100mg(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸二乙酯，熔点为220-260℃，随后得到36mg(6-硝基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸-乙酯，熔点为197℃。
以类似方式制得：
(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸-单-N，N-二甲基酰胺及双-N，N-二甲基酰胺。
例8
1-(6-氨基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸
使300mg 1-(6-硝基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸溶于60mg甲醇中，在氮气氛下先后掺入50mg Pd/c(10％)、300mg甲酸胺和18ml水加热1小时到80℃。冷却后由催化剂中滤出，蒸发滤液并冷冻干燥残渣。得到200mg1-(6-氨基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸，其形状为白色固体。
以类似方式制备：
1-(6-氨基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-乙膦酸。
例9
1-[6-(4-乙酯基-咪唑-1-基)-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基]-甲膦酸
使200mg 1，4-双-二甲基氨基-3-乙酰基-2-氮杂丁二烯-1，4与3ml冰醋酸在轻微冷却下混合，并在室温下搅拌10分钟。接着加入180mg溶于3ml冰醋酸的1-(6-氨基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸，在室温下搅拌一夜。然后加热4小时到100℃浴温。浓缩后得到50mg油状的1-[6-(4-乙酯基-咪唑-1-基)-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基]-甲膦酸。
以类似方式制得：
1-[6-(4-氰基-5-甲基-咪唑-1-基)-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸。
例10
1-(6-碘-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸
将180mg 1-(6-氨基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸滴入10ml 25％的硫酸中。搅拌5分钟后形成一种盐的悬浮液，将其冷却到0℃。向其滴入一种由60mg亚硝酸钠在2ml水中形成的溶液。在0℃搅拌15分钟后反应混合物差不多已溶解。向其滴入一种由180mg碘化钾在2ml水中形成的溶液。去掉冰浴并加热到100℃。用浓氨水溶液中和冷却的反应混合物并蒸发至干。用乙醇和少量水煮透残渣，过滤并浓缩滤液。用水∶甲醇＝4∶1的硅烷化硅胶进行色谱分离后，得到40mg 6-碘-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基-甲膦酸，熔点：295-297℃。
以类似及文献已知的类似方式得到：
1-(6-碘-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸；
1-(6-溴-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸；
1-(6-溴-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-乙烷-1-膦酸；
1-(6-氰基-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基)-甲膦酸；
例11
6-碘-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基-甲膦酸
使100mg6-氨基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基-甲膦酸溶于浓盐酸中并浓缩至干。
将良好脱水的氯化氢放入10ml的二甲基甲酰胺中，先后掺入4ml二碘甲烷和0.6ml亚硝酸异戊酯。在80℃浴温下2小时后全部溶解。在球管中真空浓缩，用水∶甲醇＝4∶1作洗脱剂在硅烷化的硅胶60(反相)对残渣进行色谱分离。得到20mg 6-碘-2，3-二氧代-1，2，3，4-四氢-对二氮萘-1-基-甲膦酸，熔点：295-297℃。
以类似方式制得：
6-溴-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基-甲膦酸；
1-(6-碘-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-乙膦酸；
1-(6-溴-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-乙膦酸；
例12
将100mg 1-(δ-氨基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸溶于20ml水中，用饱和碳酸钠溶液将pH值调节到9.5，加入0.2ml乙酐。搅拌1小时后浓缩，在尽可能少的水中溶解，送入离子交换器中(IR120，强酸性)，用水洗脱：收集相应的馏份，浓缩并干燥。得到110mg 1-(6-乙酰胺基-2，3-二氧代-1，2，3，4-四氢对二氮萘-1-基)-甲膦酸，熔点：120℃。
用一般性或具体说明的本发明反应物和/或操作条件代替上述实施例中所用反应物和条件重复上述实施例而获得了成功。
根据上述说明，本专业人员可很容易确定本发明的基本特征，并且在其构思和范围内，还可对本发明作出各种变化和改进以适应不同的用途和条件。
Claims (1)
1.式I化合物及其盐或异构体的制备方法
式中：
R1为由R2取代的C1-12-烷基、由R2取代的C2-12-链烯基、由R2取代的C2-12-炔基、由R2取代的C3-7环烷基、在苯基或烷基上由R2取代的-(CH2)n-苯基，
R4为氢、由R2取代的C1-12-烷基、由R2取代的C2-12-链烯基、由R2取代的C2-12-炔基、在苯基或烷基上由R2取代的(CH2)n-苯基，
R5、R6、R7和R8相同或不同，代表氢、卤素、硝基、NR9R10、NHCOR11、氰基、CF3、C1-6-烷基、或必要时由氰基、C1-4烷基或-COOC1-6-烷基取代的咪唑或R5和R6或R7和R8形成一个稠合的苯环，其中
R2为-CO-R3或-POXY且R2可一或两次相同或不同，
n为0、1、2、3、4或5，
R3为羟基、C1-6-烷氧基，
X和Y相同或不同，为羟基、C1-6-烷氧基、C1-4-烷基或NR9R10，
R9和R10相同或不同，为氢、C1-4-烷基或与氮原子一起形成一个咪唑环，
R11为C1-6-烷基，
并且其中，如果R4为氢且R1为R2＝-COR3取代的C1-12烷基或由R2＝-COR3取代的-(CH2)n-苯基，则R5、R6、R7和R8不为氢、NO2、卤素、或烷基，
其特征在于，a)使式II化合物
式中R1、R5、R6、R7和R8含义同上，与活性草酸衍生物环化，并在必要时与R4，-X反应，其中X为卤素、甲苯磺酸盐、甲磺酸盐或三氟甲磺酸盐，R4′含义与R4相同，但氢除外，或者
b)使式III的化合物式中R4、R5、R6、R7和R8含义同上，与R1-X反应生成式I的化合物，并在必要时皂化酯基或酯化或酰胺化酸基或使硝基还原成氨基或使氨基烷基化或酰化或使氨基与卤素或氰基交换或使氨基与式IV的2-氮杂丁二烯
式中U和V表示离去基团，R11为氢、氰基或COOC1-6-烷基，R12为氢或C1-6-烷基，反应生成咪唑衍生物或分离异构体或形成盐类。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4135871A DE4135871A1 (de) | 1991-10-26 | 1991-10-26 | Chinoxalinderivate, deren herstellung und verwendung in arzneimitteln |
| DEP4135871.6 | 1991-10-26 | ||
| DEP4224200.2 | 1992-07-17 | ||
| DE4224200 | 1992-07-17 |
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| CN1072929A CN1072929A (zh) | 1993-06-09 |
| CN1038840C true CN1038840C (zh) | 1998-06-24 |
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| CN92113338A Expired - Fee Related CN1038840C (zh) | 1991-10-26 | 1992-10-26 | 对二氮荼衍生物、其制法及其医药用途 |
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| EP (1) | EP0565683A1 (zh) |
| JP (1) | JP3258008B2 (zh) |
| KR (1) | KR100262371B1 (zh) |
| CN (1) | CN1038840C (zh) |
| AU (1) | AU664212B2 (zh) |
| CA (1) | CA2099270A1 (zh) |
| CZ (1) | CZ286351B6 (zh) |
| FI (1) | FI932959A0 (zh) |
| HU (1) | HUT64756A (zh) |
| IL (1) | IL103538A (zh) |
| NO (1) | NO304693B1 (zh) |
| NZ (1) | NZ244896A (zh) |
| PL (1) | PL171125B1 (zh) |
| PT (1) | PT101004B (zh) |
| RU (1) | RU2117663C1 (zh) |
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| DK162491D0 (da) * | 1991-09-20 | 1991-09-20 | Novo Nordisk As | Heterocycliske forbindelser, deres fremstilling og farmaceutiske praeparater indeholdende forbindelserne |
| DK0647137T3 (da) * | 1992-06-22 | 2008-12-08 | State Of Oregon Through Oregon | Glycinreceptorantagonister og anvendelse deraf |
| DE4314592A1 (de) * | 1993-04-28 | 1994-11-03 | Schering Ag | Benzo(f)chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| IL109397A0 (en) * | 1993-04-28 | 1994-07-31 | Schering Ag | Quinoxalinedione derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
| DE4428152A1 (de) * | 1994-06-22 | 1996-01-04 | Basf Ag | Neue Amido-chinoxalindione, ihrer Herstellung und Verwendung |
| GB9419318D0 (en) * | 1994-09-24 | 1994-11-09 | Pfizer Ltd | Therapeutic agents |
| CN1067387C (zh) * | 1994-09-27 | 2001-06-20 | 山之内制药株式会社 | 1,2,3,4－四氢喹喔啉二酮衍生物 |
| DE4439493A1 (de) * | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| DE4439492A1 (de) * | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| US6110911A (en) * | 1995-06-07 | 2000-08-29 | Warner-Lambert Company | Cyclic amine derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists |
| DE19521058A1 (de) * | 1995-06-09 | 1996-12-12 | Basf Ag | Verfahren zur Herstellung von Aromaten enthaltenden Polyetherpolyolen |
| DE19545251A1 (de) * | 1995-11-24 | 1997-05-28 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| TW448171B (en) * | 1996-06-06 | 2001-08-01 | Yamanouchi Pharma Co Ltd | Imidazole-substituted quinoxalinedione derivatives |
| DE19624808A1 (de) | 1996-06-21 | 1998-01-02 | Basf Ag | Pyrrolylchinoxalindione, ihre Herstellung und Verwendung |
| DE19728326A1 (de) * | 1997-06-27 | 1999-01-07 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| US6015800A (en) * | 1997-09-03 | 2000-01-18 | Warner-Lambert Company | Substituted quinoxaline-2-ones as glutamate receptor antagonists |
| IL125950A0 (en) * | 1997-09-05 | 1999-04-11 | Pfizer Prod Inc | Methods of administering ampa receptor antagonists to treat dyskinesias associated with dopamine agonist therapy |
| EP0900567A3 (en) * | 1997-09-05 | 2001-05-02 | Pfizer Products Inc. | Quinazoline-4-one AMPA antagonists for the treatment of dyskinesias associated with dopamine agonist therapy |
| FR2769309B1 (fr) | 1997-10-08 | 2001-06-15 | Oreal | Composition de teinture d'oxydation des fibres keratiniques comprenant un derive d'aminoacide en tant que base d'oxydation et nouveaux derives d'aminoacides |
| GB0311406D0 (en) * | 2003-05-17 | 2003-06-25 | Queen Mary & Westfield College | Substituted phosphonate fluorescent sensors,and use thereof |
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| EP0118982A1 (en) * | 1983-02-01 | 1984-09-19 | Sumitomo Chemical Company, Limited | Organic phosphorous quinoxalinone and their production and use |
| NO179551C (no) * | 1987-11-10 | 1996-10-30 | Novo Nordisk As | Analogifremgangsmåte for fremstilling av terapeutisk virksomme kinoxalinforbindelser |
| DK69790D0 (da) * | 1990-03-16 | 1990-03-16 | Novo Nordisk As | Heterocykliske forbindelser, deres fremstilling af anvendelse |
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- 1992-10-25 CA CA002099270A patent/CA2099270A1/en not_active Abandoned
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| Publication number | Publication date |
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| AU664212B2 (en) | 1995-11-09 |
| CZ286351B6 (cs) | 2000-03-15 |
| NO304693B1 (no) | 1999-02-01 |
| KR100262371B1 (ko) | 2000-08-01 |
| HUT64756A (en) | 1994-02-28 |
| WO1993008173A1 (de) | 1993-04-29 |
| RU2117663C1 (ru) | 1998-08-20 |
| NO932344D0 (no) | 1993-06-25 |
| PL299929A1 (en) | 1994-04-05 |
| PL171125B1 (pl) | 1997-03-28 |
| NZ244896A (en) | 1995-07-26 |
| FI932959A (fi) | 1993-06-24 |
| CN1072929A (zh) | 1993-06-09 |
| FI932959A0 (fi) | 1993-06-24 |
| JP3258008B2 (ja) | 2002-02-18 |
| SK72793A3 (en) | 1993-10-06 |
| SK281518B6 (sk) | 2001-04-09 |
| IL103538A (en) | 2001-07-24 |
| AU2889492A (en) | 1993-05-21 |
| IL103538A0 (en) | 1993-03-15 |
| HU9301877D0 (en) | 1993-09-28 |
| CA2099270A1 (en) | 1993-04-27 |
| CZ138793A3 (en) | 1994-01-19 |
| JPH06503583A (ja) | 1994-04-21 |
| KR930703271A (ko) | 1993-11-29 |
| NO932344L (no) | 1993-06-25 |
| PT101004A (pt) | 1994-01-31 |
| EP0565683A1 (de) | 1993-10-20 |
| PT101004B (pt) | 1999-10-29 |
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