CZ138793A3 - Quinoxaline derivatives, process of their preparation and their use in medicaments - Google Patents
Quinoxaline derivatives, process of their preparation and their use in medicaments Download PDFInfo
- Publication number
- CZ138793A3 CZ138793A3 CZ931387A CZ138793A CZ138793A3 CZ 138793 A3 CZ138793 A3 CZ 138793A3 CZ 931387 A CZ931387 A CZ 931387A CZ 138793 A CZ138793 A CZ 138793A CZ 138793 A3 CZ138793 A3 CZ 138793A3
- Authority
- CZ
- Czechia
- Prior art keywords
- group
- acid
- dioxo
- tetrahydroquinoxalin
- nitro
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims description 15
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 34
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- -1 substituted with R Chemical group 0.000 claims description 68
- 125000004432 carbon atom Chemical group C* 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 38
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- QOMQWUVIIVYNHO-UHFFFAOYSA-N (6-amino-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound OP(=O)(O)CN1C(=O)C(=O)NC2=CC(N)=CC=C21 QOMQWUVIIVYNHO-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- LLPWERCBDBEKLS-UHFFFAOYSA-N 1-[2,3-dioxo-6-(trifluoromethyl)-4h-quinoxalin-1-yl]ethylphosphonic acid Chemical compound C1=C(C(F)(F)F)C=C2NC(=O)C(=O)N(C(C)P(O)(O)=O)C2=C1 LLPWERCBDBEKLS-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000002912 oxalic acid derivatives Chemical class 0.000 claims description 4
- 150000003252 quinoxalines Chemical class 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- TUVFMMNANXKTRP-UHFFFAOYSA-N Ethenamine, N-methylene- Chemical compound C=CN=C TUVFMMNANXKTRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- FIZJZOZMVQFGPM-UHFFFAOYSA-N [2,3-dioxo-6-(trifluoromethyl)-4h-quinoxalin-1-yl]methylphosphonic acid Chemical compound C1=C(C(F)(F)F)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 FIZJZOZMVQFGPM-UHFFFAOYSA-N 0.000 claims description 2
- HDJUELSXFKOAMB-UHFFFAOYSA-N [3-(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)phenyl]phosphonic acid Chemical compound OP(O)(=O)C1=CC=CC(N2C(C(=O)NC3=CC(=CC=C32)[N+]([O-])=O)=O)=C1 HDJUELSXFKOAMB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 2
- 229960000911 benserazide Drugs 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- BLMRCWDANZSHDG-UHFFFAOYSA-N ethyl 4-(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1N1C(=O)C(=O)NC2=CC([N+]([O-])=O)=CC=C21 BLMRCWDANZSHDG-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- SZNFRIYTANUCHN-UHFFFAOYSA-N methyl 3-[(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]benzoate Chemical compound COC(=O)C1=CC=CC(CN2C(C(=O)NC3=CC(=CC=C32)[N+]([O-])=O)=O)=C1 SZNFRIYTANUCHN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims 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 claims description 2
- VTYNPKUTIPZLEI-UHFFFAOYSA-N 4-(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)butylphosphonic acid Chemical compound C1=C([N+]([O-])=O)C=C2NC(=O)C(=O)N(CCCCP(O)(=O)O)C2=C1 VTYNPKUTIPZLEI-UHFFFAOYSA-N 0.000 claims 1
- 108010039224 Amidophosphoribosyltransferase Proteins 0.000 claims 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 2
- 150000002431 hydrogen Chemical group 0.000 abstract 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000005711 Benzoic acid Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 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
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 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
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- SAUYTDLSSGZDMZ-UHFFFAOYSA-N (6-iodo-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound C1=C(I)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 SAUYTDLSSGZDMZ-UHFFFAOYSA-N 0.000 description 4
- BWJLAJURYPUBJI-UHFFFAOYSA-N (6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound C1=C([N+]([O-])=O)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 BWJLAJURYPUBJI-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
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- 206010015037 epilepsy Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HWYLITPIHMKCKW-UHFFFAOYSA-N ethoxy-[(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]phosphinic acid Chemical compound C1=C([N+]([O-])=O)C=C2NC(=O)C(=O)N(CP(O)(=O)OCC)C2=C1 HWYLITPIHMKCKW-UHFFFAOYSA-N 0.000 description 1
- CVBXBASSOWKOPD-UHFFFAOYSA-N ethoxy-[4-[(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]phenyl]phosphinic acid Chemical compound C1=CC(P(O)(=O)OCC)=CC=C1CN1C(=O)C(=O)NC2=CC([N+]([O-])=O)=CC=C21 CVBXBASSOWKOPD-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- KINVHGBFZKMEAW-UHFFFAOYSA-N ethyl 3-(2-amino-4-nitroanilino)benzoate Chemical compound CCOC(=O)C1=CC=CC(NC=2C(=CC(=CC=2)[N+]([O-])=O)N)=C1 KINVHGBFZKMEAW-UHFFFAOYSA-N 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- PPYZIQMKGHBTDA-UHFFFAOYSA-N methyl 4-[(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C(=O)C(=O)NC2=CC([N+]([O-])=O)=CC=C21 PPYZIQMKGHBTDA-UHFFFAOYSA-N 0.000 description 1
- ANYBOESNEDWHKF-UHFFFAOYSA-N methyl 4-[[4-[(4-methoxycarbonylphenyl)methyl]-6-nitro-2,3-dioxoquinoxalin-1-yl]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C(=O)C(=O)N(CC=2C=CC(=CC=2)C(=O)OC)C2=CC([N+]([O-])=O)=CC=C21 ANYBOESNEDWHKF-UHFFFAOYSA-N 0.000 description 1
- XRPITCBWOUOJTH-UHFFFAOYSA-N n,n-diethylpyridin-2-amine Chemical compound CCN(CC)C1=CC=CC=N1 XRPITCBWOUOJTH-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- SEPKUNXLGWMPHL-UHFFFAOYSA-N quinoxaline-2,3-dione Chemical compound C1=CC=CC2=NC(=O)C(=O)N=C21 SEPKUNXLGWMPHL-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000012546 transfer Methods 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
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
- C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems
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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
Description
Deriváty chinoxalinu, způsob jejich výroby a jejich použití v léčivechQuinoxaline derivatives, their production and their use in pharmaceuticals
Oblast technikyTechnical field
Vynález se týká derivátů kyseliny chinoxalindíon-karboxylové a chinoxalindion-fosfonové, způsobu jejich výrovy a jejich použití v léčivech.The invention relates to quinoxalinedione carboxylic acid and quinoxalinedione phosphonic acid derivatives, processes for their preparation and their use in pharmaceuticals.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
Je známé, že deriváty chinoxalinu mají afinitu ke quasiqualátovým receptorům a na základě této afinity jsou vhodné jako léčiva pro ošetření onemocnění centrálního nervového systému.Quinoxaline derivatives are known to have an affinity for quasiqualate receptors and based on this affinity are useful as medicaments for the treatment of central nervous system diseases.
Podstata vynálezuSUMMARY OF THE INVENTION
Bylo zjištěno, že se sloučeniny podle předloženého vynálezu vyznačuj i ve srovnání s chinoxaliny, známými z EP-A-315 959 a VO 91/138 78 svojí dobrou schopností vazby na quasiqualátové receptory.It has been found that the compounds of the present invention are distinguished by their good ability to bind to quasiqualate receptors as compared to the quinoxalines known from EP-A-315 959 and WO 91/138 78.
Předmětem předloženého vynálezu jsou sloučeniny obecného vzorce IThe present invention provides compounds of formula I
(I) ve kterém(I) in which
R1 značí alkylovou skupinu s 1 až 12 uhlíkovými atomy, substituovanou R , alkenylovou skupinu se 2 až 12 uhlíkovými atomy, substituovanou R2 , alkinylovou skupinu se 2 až 12 uhlíkovými atomy, substituovanou R2, cykloalkylovou skupinu se 3 až 7 uhlíkovými atomy, substituovanou R , - (CH2)n-arylovou skupinu se 6 až 12 uhlíkovými atomy v arylu, která je v arylovém nebo alkylovém zbytku substituovaná R2 , nebo -(CH2)n-hetarylovou skupinu, která je v hetarylovém nebo alkylovém zbytku substituovaná R2 , r4 značí vodíkový atom, alkylovou skupinu s 1 až 12 uhlíkovými atomy, substituovanou R2 , alkenylovou skupinu se 2 až 12 uhlíkovými atomy, substituovanou 2R 1 represents alkyl having 1 to 12 carbon atoms substituted by R, alkenyl having 2 to 12 carbon atoms substituted by R 2, alkinyl having 2 to 12 carbon atoms substituted by R 2, cycloalkyl having 3 to 7 carbon atoms, substituted R, - (CH 2) n -aryl having 6 to 12 carbon atoms in the aryl which is substituted with R 2 in the aryl or alkyl radical, or - (CH 2) n -hetaryl group which is substituted in the hetaryl or alkyl radical R 2 , r 4 is hydrogen, C 1 -C 12 alkyl substituted with R 2 , C 2 -C 12 alkenyl substituted with 2
R , alkinylovou skupinu se 2 až 12 uhlíkovými atomy, substituovanou R , cykloalkylovou skupinu se 3 až 7 uhlíkovými atomy, substituovanou R2 , -(CH2)n-arylovou skupinu se 6 až 12 uhlíkovými atomy v arylu, která je v arylovém nebo alkylovém zbytku substituovaná R , nebo -(CH2)n-hetarylovou skupinu, která je v hetarylovém nebo alkylovém zbytku substituovaná R2 aR, (C 2 -C 12) alkynyl, substituted with R, (C 3 -C 7) cycloalkyl, substituted with R 2 - (CH 2 ) n -aryl (C 6 -C 12) aryl, which is in aryl or an alkyl radical substituted with R, or a - (CH 2) n -hetaryl group substituted with R 2 in the hetaryl or alkyl radical; and
R , R , R a R° jsou stejné nebo různé a značí vodíkový atom, atom halogenu, nitroskupinu, skupinu NR^R^®, skupinu NHCOrU , skupinu SC^R^2, cykloalkoxylovou skupinu se 3 až 7 uhlíkovými atomy, skupinu COR1·^, kyanoskupinu, trifluormethylovou skupinu, alkylovou skupinu s 1 až 6 uhlíkovými atomy, alkoxyskupinu s 1 až 4 uhlíkovými atomy nebo imidazolovou skupinu, popřípadě substituovanou kyanoskupinou, alkylovou skupinou s 1 až 4 uhlíkovými atomy nebo -COO-alkylovou skupinou s 1 až 6 uhlíkovými atomy v alkylu, neboR, R, R, and R ° are the same or different and are hydrogen, halogen, nitro, NR 4 R 6, NHCO 2 R, SC 4 R 2 , C 3 -C 7 cycloalkoxy, COR 1 · ^, cyano, trifluoromethyl, alkyl having from 1 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms or an imidazole group optionally substituted by cyano, alkyl having 1 to 4 carbon atoms or -COO-alkyl having 1 to Or (C 6 -C 6) alkyl;
S 7 RS 7 R
R a R nebo R a R značí nakondensovaný benzenový kruh, přičemžR and R or R and R denote a fused benzene ring, wherein
R2 značí skupinu -CO-R2 nebo -PO-XY a R2 je jednou až dvakrát stejný nebo různý, n značí číslo 0,1,2,3,4 nebo 5 , σR 2 represents a group -CO-R 2 or -PO-XY and R 2 is one to two same or different, n is 0,1,2,3,4 or 5, σ
R značí hydroxyskupinu, alkoxyskupinu s 1 až 6 uhlíkovými atomy nebo skupinu -NR^R^-Q,R represents a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or an -NR 6 R 6 -Q,
X a Y jsou stejné nebo různé a značí hydroxyskupinu, alkoxyskupinu s 1 až 6 uhlíkovými atomy, alkylovou skupinu s 1 až 4 uhlíkovými atomy nebo skupinu -NR^rIQ , a jsou stejné nebo různé a značí vodíkový atom, alkylovou skupinu s 1 až 4 uhlíkovými atomy nebo společně s dusíkovým atomem nasycený pětičlenný nebo šestičlenný heterocyklus, který může obsahovat další atom kyslíku nebo síry,X and Y are the same or different and are hydroxy, C 1 -C 6 -alkoxy, C 1 -C 4 -alkyl, or -NR 4 R 10, and are the same or different and are hydrogen, C 1 -C 4 -alkyl. carbon atoms or, together with a nitrogen atom, a saturated 5- or 6-membered heterocycle which may contain an additional oxygen or sulfur atom,
R11 značí alkylovou skupinu s 1 až 6 uhlíkovými atomy nebo fenylovou skupinu, v R 11 represents alkyl having 1 to 6 carbon atoms or phenyl, in
R značí vodíkový atom, alkylovou skupinu s 1 až 4 uhlíkovými atomy, aminoskupinu nebo dialkylaminoskupinu se vždy 1 až 4 uhlíkovými atomy v alkylu aR represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an amino group or a dialkylamino group having from 1 to 4 carbon atoms in each alkyl, and
R značí hydroxyskupinu, alkoxyskupinu s 1 až 6 uhlíkovými atomy, alkylovou skupinu s 1 až 6 uhlíkovými atomy nebo skupinu -NR^R^-θ , jakož i jejich isomery nebo soli, přičemž pokud R4, , R*\ R^ a značí vodíkový atom, nemůže být substituent R1 karbamoylmethylová skupina, 1-karboxy-l-fenylmethylová skupina nebo přímá alkylová skupina s 1 až 6 uhlíkovými atomy, která je v poloze 1- substituovaná kar boxy lovou skupinou nebo COO-alkylovou skupinou s 1 až 6 uhlůíkovými atomy v alkylu a pokud Rl značí přímou alkylovou skupinu s 1 až 6 uhlíkovými atomy, která je v poloze 1- substituovaná kar boxy lovou skupinou nebo COO-alkylovou skupinou s 1 až uhlůíkovými atomy v alkylu, nemohou substituenty 7 6 7 a/nebo R , popřípadě R a R' značit fluor, chlor nebo brom a R4 - R® je vždy vodíkový atom a pokud R1 značí skupinu -CH2-COOH , potom 6 7R is hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or -NR 4 R 6 -θ as well as isomers or salts thereof, provided that when R 4 , R 6 , R 6 and R 6 are R @ 1 cannot be a carbamoylmethyl group, a 1-carboxy-1-phenylmethyl group or a straight-chain alkyl group having 1 to 6 carbon atoms which is in the 1- position substituted by a carboxyl group or a C1-6 alkyl group substituents 7 6 7 and / or C 1 -C 6 -alkyl C 1 -C 6 alkyl and when R1 represents a straight C 1 -C 6 alkyl group which is in the 1-position substituted by a carboxyl group or a COO alkyl group; R, or R and R 'denote fluorine, chlorine or bromine and R 4 - R® is always a hydrogen atom and if R 1 denotes a group -CH 2 COOH, and 6 7
a) R a R' neznačí současně methylovou skupinu nebo(a) R and R 'do not simultaneously represent a methyl group; or
b) R^ nebo R^ neznačí nitroskupinu a R4 - R® značí vždy vodíkový atom.b) R 4 or R 4 does not represent a nitro group and R 4 -R 4 is in each case a hydrogen atom.
Sloučeniny obecného vzorce I zahrnuj i také možné tautomerní formy a E- a Z-isomery, nebo pokud je přítomné opticky aktivní centrum, také racemáty nebo enantiomery.The compounds of formula I also include possible tautomeric forms and E- and Z-isomers or, if an optically active center is present, also racemates or enantiomers.
Substituenty se vyskytují výhodně v poloze 6- a/nebo 7- .The substituents are preferably in the 6- and / or 7-position.
oO
Substituent R stojí jednou až dvakrát stejně nebo různě v libovolné posici na alkylovém, alkenylovém, alkinylovém, cykloalkylovém, hetarylovém nebo arylovém zbytku.The substituent R is one to two times the same or different at any position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl or aryl radical.
Pod pojmem alkylová skupina se rozumí příslušný přímý nebo rozvětvený alkylový zbytek, jako je například methylová skupina, exhylová skupina, propylová skupina, isopropylová skupina, buxylová skupina, isobuxylová skupina, sek.-buxylová skupina, Xerc.-buxylová skupina, penXylová skupina, isopenxylová skupina, hexylová skupina, hepxylová skupina, okxylová skupina, nonylová skupina nebo decylová skupina, přičemž výhodné jsou alkylové skupiny s 1 až 6 uhlíkovými axomy.The term alkyl refers to an appropriate straight or branched alkyl radical such as methyl, exyl, propyl, isopropyl, buxyl, isobuxyl, sec-buxyl, X-t-buxyl, penyl, isopenyl a group, a hexyl group, a hepxyl group, an okxyl group, a nonyl group or a decyl group, alkyl groups having 1 to 6 carbon axomes being preferred.
Alkenylová skupina obsahuje obzvlášxě alkenylové zbyxky se 2 až 6 uhlíkovými axomy, kxeré mohou býx přímé nebo rozvěxvené, jakio je například 2-propenylová skupina, 2-buXenylová skupina, 3-mexhyl-2-propenylová skupina, l-buxenylová skupina, 1-propenylová skupina a vinylová skupina.The alkenyl group contains especially alkenyl residues with 2 to 6 carbon axoms, which may be straight or branched, such as 2-propenyl, 2-butenyl, 3-methyl-2-propenyl, 1-buxenyl, 1-propenyl and vinyl.
Jako alkinylové zbyxky jsou vhodné obzvlášxě exhinylová skupina, 1-propinylová skupina, 2-propinylová skupina, l-buxinylová skupina, xedy obzvlášxě zbyxky se 2 až 4 uhlíkovými axomy.Suitable alkynyl radicals are especially exhinyl, 1-propynyl, 2-propynyl, 1-buxinyl, especially those having from 2 to 4 carbon axoms.
Pod pojmem cykloalkylová skupina se 3 až 7 uhlíkovými axomy se míní cyklopropylová skupina, cyklobuxylová skupina, cyklopenxylová skupina, cyklohexylová skupina a cyklohepxylová skupina, obzvlášxě jsou vhodné cykloalkylové skupiny se 3 až 5 uhlíkovými axomy.C 3-7 cycloalkyl refers to cyclopropyl, cyclobuxyl, cyclopenxyl, cyclohexyl and cyclohepxyl, with cycloalkyl groups having from 3 to 5 carbon axoms being particularly suitable.
Jako arylové zbyxky je možno uvésx například fenylovou skupinu, nafxylovou skupinu, bifenylylovou skupinu a indenylovou skupinu, obzvlášxě (CH2)n-fenylovou skupinu s n = =0,1 nebo 2 .Aryl zbyxky uvésx may be for example phenyl, nafxylovou, biphenylyl and indenyl,, are particularly (CH 2) n -phenyl with n = 0,1 or 2 respectively.
Jako heXarylové zbyxky jsou vhodné pěxičlenné nebo šesxičlenné hexeroaromáxy s 1 až 3 dusíkovými axomy, jako je například pyrazol, imidazol, pyrazin, pyridin, pyrimidin, pyridazin a triazin.Suitable hexaryl moieties are 5- or 6-membered hexeroaromatics having 1 to 3 nitrogen axoms, such as pyrazole, imidazole, pyrazine, pyridine, pyrimidine, pyridazine and triazine.
Pod pojmem atom halogenu se rozumí atom fluoru, chloru, bromu a josu.The term halogen atom refers to a fluorine, chlorine, bromine and ios atom.
Když substituenty R9 a R10 tvoří společně s dusíkovým atomem nasycený heterocyklus, potom se míní například piperidin, pyrrolidin, morfolin, thiomorfolin nebo piperazin.When R 9 and R 10 together with the nitrogen atom form a saturated heterocycle, for example piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine are meant.
Když značí substituent R^ alkylovou skupinu s 1 až 12 uhlíkovými atomy, potom jsou R3 až R® obzvláště substituenty jako N02 , NR9R10 , NHCOR11 , SO2R12 , cykloalkoxylová skupina se 3 až 7 uhlíkovými atomy, COR13 , kyanoskupina, trifluormethylová skupina, alkoxyskupina s 1 až 4 uhlíkovými atomy, popřípadě substituovaný imidazol nebo nakondensovaný benzenový kruh. Sloučeniny obecného vzorce I , ve kterém R = -PO-XY se vyznačují velmi dobrou rozpustností ve vodě.When R ^ represents an alkyl group having 1 to 12 carbon atoms, and R 3 are particular substituents R® to as N02, NR 9 R 10, NHCOR 11, SO 2 R 12, cycloalkoxy having 3 to 7 carbon atoms, COR 13, cyano, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, an optionally substituted imidazole or a fused benzene ring. Compounds of formula I wherein R = -PO-XY are characterized by very good water solubility.
Pod pojmem fyziologicky přijatelné soli se rozumí soli s organickými a anorganickými basemi, jako jsou například dobře rozpustné soli s alkalickými kovy a kovy alkalických zemin, jakož i s N-methyl-glukaminem, dimethyl-glukaminem, ethyl-glukaminem, lysinem, 1,6-hexandiaminem, ethanolaminem, glukosaminem, sarkosinem, serinolem, tris-hydroxy-methyl-amino-methanem, aminopropandiolem, sovak-basí a 1-amino-2,3,4-butantriolem.Physiologically acceptable salts are salts with organic and inorganic bases, such as the well-soluble salts with alkali metals and alkaline earth metals, as well as with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6- hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, sovacase and 1-amino-2,3,4-butanetriol.
Sloučeniny obecného vzorce I , jakož i jejich fyziologicky přijatelné soli jsou na základě své afinity ke quasiqualátovým receptorům použitelné jako léčiva. Na základě svého spektra účinku jsou sloučeniny podle předložeΊ ného vynálezu vhodné pro ošetření nemocí, které j sou vyvolané hyperaktivitou excitatorických aminokyselin, jako je glutamát nebo aspartát. Vzhledem k tomu, že nové sloučeniny působí jako antagonisty excitatorických aminokyselin a mají vysokou afinitu k AMPA-receptorům, tím, že potlačuj radioaktivně značený specifický antagonist (RS)a-amino-3-hydroxy-5-methyl-4-isoxazolpropionát (AMPA) , jsou vhodné obzvláště pro ošetření takových nemocí, které mohou být ovlivněny přes receptory excitatorických aminokyselin, obzvláště AMPA-receptory, jako je například Parkinsonova nemoc, Alzheimerova nemoc. Huntingtonova nemoc, epilepsie, hypoglykémie, psychosy, strnutí svalů, emesis, bolestivé stavy, anoxie a deficity po ischeraii.The compounds of formula I as well as their physiologically acceptable salts are useful as medicaments because of their affinity for the quasiqualate receptors. Based on their spectrum of activity, the compounds of the present invention are suitable for the treatment of diseases caused by hyperactivity of excitatory amino acids such as glutamate or aspartate. Since the novel compounds act as antagonists of excitatory amino acids and have a high affinity for AMPA receptors, they suppress the radiolabeled specific antagonist (RS) α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) are particularly suitable for the treatment of diseases which can be influenced via excitatory amino acid receptors, in particular AMPA receptors, such as Parkinson's disease, Alzheimer's disease. Huntington's disease, epilepsy, hypoglycaemia, psychosis, muscle stiffness, emesis, pain conditions, anoxia and deficits after ischeraia.
Předložený vynález zahrnuje také kombinace sloučenin podle předloženého vynálezu s antagonisty dopaminu, jako je například lisurid, tergurid, bromokriptin, deriváty amantadinu, hemantin a jeho deriváty a sloučeniny popsané v EP-A-351 352 , jakož i kombinace s L-DOPA , popřípadě L-DOPA a benserazidem. V kombinaci se podávaná dávka dosavadního léčiva snižuje a její účinek se synergicky zvyšuj e.The present invention also encompasses combinations of the compounds of the present invention with dopamine antagonists such as lisuride, terguride, bromocriptine, amantadine derivatives, hemanthine and derivatives thereof and the compounds described in EP-A-351 352, as well as combinations with L-DOPA and L-DOPA. -DOPA and benserazide. In combination, the administered dose of the prior art drug decreases and its effect synergistically increases.
Afinita sloučenin podle předloženého vynálezu k centrálním AMPA-receptorům se zkouší in vitro v klasických vazebných pokusech. Váží se s vysokou afinitou na vazebná místa, značená 2H-AMPA .The affinity of the compounds of the present invention for central AMPA receptors was tested in vitro in classical binding assays. It binds with high affinity to the binding sites, labeled with 2 H-AMPA.
Pro zkoušku kvality účinku a účinnosti in vivo se sloučeniny zkouší po intravenosní aplikaci na myších. Po předchozím zpracování sloučeninami podle předloženého vynálezu se v závislosti na dávce antagonisují křeče, vyvolané intracerebroventrikulární injekcí AMPA .To test the quality of activity and efficacy in vivo, the compounds are tested after intravenous administration in mice. Following pretreatment with the compounds of the present invention, dose-dependent seizures induced by intracerebroventricular injection of AMPA are antagonized.
A = kyselina 1-(trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-octováA = 1- (trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -acetic acid
B · kyselina 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-prppan-l-fosfonová .B. 3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -proppan-1-phosphonic acid.
Taxo zjištěni ukazují, že se u těchto sloučenin jedná o výkonné centrálně účinné AMPA-antagonisty. Jsou tedy vhodné pro ošetření stavů nemocností, které jsou spojené s poruchami látkové výměny glutamátu. Obzvláště jsou vhodné pro ošetření mozkové ischemie různého původu, Parkinsonovy nemoci a také jiných onemocnění, uváděných v předcházejících odstavcích.Taxo findings indicate that these compounds are potent centrally active AMPA antagonists. They are therefore suitable for the treatment of morbidity conditions associated with glutamate metabolism disorders. They are particularly suitable for the treatment of cerebral ischemia of various origins, Parkinson's disease as well as other diseases mentioned in the preceding paragraphs.
Pro použití sloučenin podle předloženého vynálezu jako léčiva se tyto převádějí do formy farmaceutických preparátů, které vedle účinné látky pro enterální nebo parenterální aplikaci obsahuj i vhodné farmaceutické, organické nebo anorganické nosné materiály, jako je například voda, želatina, arabská guma, mléčný cukr, škrob, stearát horečnatý, mastek, rostlinné oleje, polyalkylenglykoly a podobně. Far9 maceutické preparáty se mohou vyskytovat v pevné formě, například jako tablety, dražé, čípky nebo kapsle, nebo v kapalné formě, například jako roztoky, suspense nebo emulse. Popřípadě obsahují kromě toho pomocné látky, jako jsou například konservační činidla, stabilisační činidla, smáčedla nebo emulgátory, soli pro změnění osmotického tlaku nebo pufry.For the use of the compounds of the present invention as medicaments, these are converted into pharmaceutical preparations which contain, in addition to the active ingredient for enteral or parenteral administration, suitable pharmaceutical, organic or inorganic carrier materials such as water, gelatin, acacia, milk sugar, starch. , magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories or capsules, or in liquid form, for example as solutions, suspensions or emulsions. If desired, they additionally contain auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.
Pro parenterální použití jsou vhodné obzvláště injekční roztoky nebo suspense, především vodné roztoky aktivních sloučenin v polyhydroxyethoxylovaném ricinovém olej i.Injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
Jako nosné systémy se mohou použít také povrchově aktivní pomocné látky, jako jsou například soli kyseliny gallové nebo živočišné nebo rostlinné fosfolipidy, ale také jejich směsi, jakož i liposomy nebo jejich součásti.Surfactant adjuvants, such as salts of gallic acid or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or components thereof, can also be used as carrier systems.
Pro orální aplikaci jsou vhodné obzvláště tablety, dražé nebo kapsle s mastkovými a/nebo uhlovodíkovými nosiči nebo pojivý, jako je například laktosa, nebo kukuřičný nebo bramborový škrob. Aplikace může probíhat také v kapalné formě, například jako šťáva, do které se popřípadě přidá sladidlo.Especially suitable for oral administration are tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, or corn or potato starch. The application can also take place in liquid form, for example as juice, to which optionally a sweetener is added.
Dávkování účinné látky se může měnit vždy podle způsobu poskytování, stáří a hmotnosti pacienta, typu a tíži ošetřovaného onemocnění a podle podobných faktorů. Denní dávka činí 0,5 až 1000 mg , výhodně 50 až 200 mg , přičemž dávka se může podávat jako jednorázová dávka nebo se může rozdělit na dvě nebo více dávek za den.The dosage of the active ingredient may vary depending on the mode of administration, the age and weight of the patient, the type and severity of the disease being treated, and similar factors. The daily dose is 0.5 to 1000 mg, preferably 50 to 200 mg, wherein the dose can be administered as a single dose or divided into two or more doses per day.
Předmětem předloženého vynálezu je dále způsob výroby sloučenin obecného vzorce I , jehož podstata spočívá v tom, že seThe present invention further provides a process for the preparation of the compounds of formula (I), the process comprising:
a) sloučenina obecného vzorce IIa) a compound of formula II
ve kterém mají R1, R2, R^, R7 a R8 výše uvedený význam, cyklisuje reaktivními deriváty kyseliny oxalové a popřípadě se nechá reagovat se sloučeninou vzorce ,4’ ve kterémwherein R 1 , R 2 , R 6, R 7 and R 8 are as defined above, cyclizes with reactive oxalic acid derivatives and optionally reacts with a compound of formula 4 'wherein:
X značí atom halogenu, tosylát, mesylát nebo triftalát aX is halogen, tosylate, mesylate or triftalate; and
Λ * ΛΛ * Λ
R má význam uvedený pro substituent R^ s vyj ímkou vodíkového atomu, nebo seR is as defined for the substituent R @ 1 except for the hydrogen atom;
ve kterém mají R4, R5, R6, R7 a R8 výše uvedený význam, nechá reagovat se sloučeninou vzorcewherein R 4 , R 5 , R 6 , R 7 and R 8 are as defined above, is reacted with a compound of formula
R1 - X na sloučeninu vzorce I a pokud je třeba, tak se esterová skupina zmýdelni nebo se kyselinová skupina esterifikuje nebo amiduje, nebo se nitroskupina redukuje na aminoskupinu nebo se arainoskupina alkyluje nebo acyluje nebo se aminoskupina vymění za halogen nebo kyanoskupinu, nebo se aminoskupina nechá reagovat s 2-azabutadienem vzorce IVR @ 1 - X to a compound of formula I and, if necessary, the ester group is saponified or the acid group is esterified or amidated, or the nitro group is reduced to an amino group, or the araino group is alkylated or acylated; is reacted with 2-azabutadiene of formula IV
U V ve kterémU V in which
U a V značí odštěpitelné skupiny , rH značí vodíkový atom, kyanoskupinu nebo COO-alkylovou skupinu s 1 až 6 uhlíkovými atomy v alkylu aU and V are leaving groups, rH is a hydrogen atom, a cyano group or a COO-alkyl group having 1 to 6 carbon atoms in the alkyl and
22
R značí vodíkový atom nebo COO-alkylovou skupinu s 1 uhlíkovými atomy v alkylu na imidazolový derivát, nebo se oddělí isomery, nebo se tvoří soli.R represents a hydrogen atom or a COO-alkyl group having 1 carbon atoms in the alkyl to the imidazole derivative, or isomers separated, or salts formed.
Cyklisace sloučenin obecného vzorce II reaktivním derivátem kyseliny oxalové se provádí jednostupňově nebo také dvoustupňové. Jako výhodný je možno uvažovat dvoustupňový postup, při kterém se nechá reagovat diamin s derivátem kyseliny oxalové, jako je například polochlorid esteru kyseliny oxalové, v polárních rozpouštědlech, jako je například dimethylformamid nebo cyklické nebo acyklické ethery nebo halogenované uhlovodíky, jako tetrahydrofuran, diethylether nebo methylenchlorid, za přítomnosti base, jako jsou organické aminy, například triethylamin, pyridin, Hunigovy base nebo diethylaminopyridin. Následující cyklisace se může provádět basicky nebo také kysele, výhodně ale v kyselém prostředí, přičemž k rozpouštědlu se může přidat alkohol.The cyclization of the compounds of formula II with a reactive oxalic acid derivative is carried out in one or two steps. Preferred is a two-step process in which the diamine is reacted with an oxalic acid derivative such as oxalic acid ester polochloride in polar solvents such as dimethylformamide or cyclic or acyclic ethers or halogenated hydrocarbons such as tetrahydrofuran, diethyl ether or methylene chloride , in the presence of a base such as an organic amine, for example triethylamine, pyridine, Hunig's base or diethylaminopyridine. Subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, with the alcohol being added to the solvent.
Zavádění substituentů R^ a R4 se provádí pomocí běžných alkylačních metod tak, že se chinoxalindion nechá reagovat se sloučeninou vzorce R - X nebo R - X , ve kterých značí X halogen, tosylát, mesylát nebo obzvláště triftalát, za přítomnosti base, při teplotě místnosti nebo za zvýšené teploty, v aprotických rozpouštědlech. Anion se může také vyrobit před tím, než se přidá sloučenina vzorce R1 - X nebo R4 - X . Jako base jsou vhodné například sloučeniny alkalických kovů, jako je uhličitan draselný, hydroxid sodný, alkoholáty alkalických kovů a obzvláště kovové hydridy, jako je hydrid sodný. Eventuelně se mohou alkalické sloučeniny nechat reagovat za podmínek přenosu fází. Když se získaj i směsi sloučenin se substituentem R^, popřípadě R4 , tak se tyto obvyklými postupy rozdělí.The introduction of substituents R and R 4 is carried out using conventional alkylation methods that quinoxalinedione reacted with a compound of formula R - X, or R - X, wherein X represents halogen, tosylate, mesylate or especially triflate, in the presence of a base, at a temperature room temperature or at elevated temperature, in aprotic solvents. The anion can also be produced before it was added the compound of formula R 1 - or R 4 X - X. Suitable bases are, for example, alkali metal compounds such as potassium carbonate, sodium hydroxide, alkali metal alcoholates and especially metal hydrides such as sodium hydride. Alternatively, the alkaline compounds can be reacted under phase transfer conditions. When mixtures are obtained by a compound having substituents R or R 4, then these separated by conventional procedures.
Jako rozpouštědla vhodná pro reakci je možno uvést aprotická polární rozpouštědla, jako je například dimethylformamid nebo N-methylpyrrolidon, ale také cyklické ethery, jako je například dioxan nebo tetrahydrofuran. Když se při variantě b) způsobu nechá proběhnout reakce se 2 mol sloučeniny R^- X za jinak analogických reakčních podmínek, zavedou se současně substituenty r! a R4 .Suitable solvents for the reaction include aprotic polar solvents such as dimethylformamide or N-methylpyrrolidone, but also cyclic ethers such as dioxane or tetrahydrofuran. When process variant b) is allowed to proceed with 2 moles of the compound R1-X under otherwise analogous reaction conditions, substituents R1 are simultaneously introduced. and R 4 .
Popřípadě následuj ící zmýdelnění esterové skupiny může probíhat basicky nebo výhodně kysele tak, že se hydrolysuje při zvýšené teplotě až k teplotě varu reakční směsi za přítomnosti kyselin, jako je výše koncentrovaná kyselina chlorovodíková, v rozpouštědlech, jako je například kyselina trifluoroctová nebo alkoholy. Estery kyseliny fosfonové se výhodně hydrolysuji zahřátím s výše koncentrovanými vodnými kyselinami, jako je například koncentrovaná kyselina chlorovodíková nebo zpracováním s trimethylsilylbromidem a následujícím zpracováním s vodou.Optionally, the subsequent saponification of the ester group may be basic or preferably acidic such that it is hydrolyzed at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as concentrated hydrochloric acid in solvents such as trifluoroacetic acid or alcohols. The phosphonic acid esters are preferably hydrolyzed by heating with higher concentrated aqueous acids, such as concentrated hydrochloric acid, or treatment with trimethylsilyl bromide followed by treatment with water.
Esterifikace karboxylové kyseliny nebo fosfonové kyseliny se provádí o sobě známým způsobem pomocí odpovídaj ících alkoholů v kyselině nebo za přítomnosti aktivovaného derivátu kyseliny. Jako aktivované deriváty kyselin přicházejí například v úvahu chloridy, imidazolidy nebo anhydridy kyselin. U fosfonových kyselin je možná reakce s ortoestery odpovídajících alkoholů. K esteru vede také reakce s adičním produktem dicyklohexylkarbodiimidu a odpovídajícím alkoholem. Methylester se může získat reakcí s diazomethanem.The esterification of the carboxylic acid or phosphonic acid is carried out in a manner known per se by means of the corresponding alcohols in the acid or in the presence of an activated acid derivative. Suitable acid derivatives are, for example, acid chlorides, imidazolides or acid anhydrides. For phosphonic acids, reaction with orthoesters of the corresponding alcohols is possible. Reaction with the addition product of dicyclohexylcarbodiimide and the corresponding alcohol also leads to the ester. The methyl ester can be obtained by reaction with diazomethane.
Amidace se provádí na volných kyselinách nebo na jejich reaktivních derivátech, jako jsou například chloridy kyselin, směsné anhydridy, imidazolidy nebo azidy, reakcí s odpovídajícími aminy při teplotě místnosti.The amidation is carried out on the free acids or on their reactive derivatives, such as acid chlorides, mixed anhydrides, imidazolides or azides, by reaction with the corresponding amines at room temperature.
Redukce nitroskupiny na aminoskupinu se provádí katalyticky v polárních rozpouštědlech při teplotě místnosti nebo při teplotě zvýšené za tlaku pod vodíkovou atmosférou. Jako katalysátory jsou vhodné kovy, jako je například Raneyův nikl nebo katalysátory na basi vzácných kovů, jako je palladium nebo platina, popřípadě na nosičích. Namísto vodíku se může známým způsobem použít amoniumformiát. Rovněž tak se mohou použít redukční činidla jako je chlorid cínatý nebo chlorid titanitý, jakož i komplexní kovové hydridy, eventuelně za přítomnosti solí těžkých kovů. Může být výhodné zavést před redukcí esterovou skupinu.The reduction of the nitro group to the amino group is carried out catalytically in polar solvents at room temperature or at elevated temperature under a hydrogen atmosphere. Suitable catalysts are metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally on supports. Ammonium formate can be used in place of hydrogen in a known manner. Reducing agents such as stannous chloride or titanium tetrachloride as well as complex metal hydrides, optionally in the presence of heavy metal salts, may also be used. It may be advantageous to introduce an ester group before the reduction.
Když se požaduje alkyláce aminoskupiny, může se alkylovat pomocí o sobě známých metod, například za použití alkylhalogenidů. Možná je také reduktivní aminace pomocí aldehydu a redukčního činidla, jako je například natriumborhydrid. Acylace se provádí pomocí známých metod. Například se reakce provádí ve vodném prostředí za přítomnosti base s odpovídajícími anhydridy kyselin nebo halogenidy kyselin.When amino alkylation is desired, it can be alkylated by methods known per se, for example using alkyl halides. Reductive amination with an aldehyde and a reducing agent such as sodium borohydride is also possible. The acylation is carried out by known methods. For example, the reaction is carried out in an aqueous medium in the presence of a base with the corresponding acid anhydrides or acid halides.
Zavádění kyanoskupiny se může provádět pomocí Sandmeyerovy reakce ; například se mohou nechat reagovat diazoniové soli, intermediárně vytvořené z aminosloučenin s nitrily, s kyanidy za přítomnosti kyanidu měďného nebo s kyanidem nikelnatodraselným.The introduction of the cyano group can be carried out by means of a Sandmeyer reaction; for example, diazonium salts, formed intermediately from amino compounds, with nitriles, with cyanides in the presence of copper (I) cyanide or with nickel potassium cyanide, can be reacted.
Zavádění halogenu, jako je chlor, brom nebo jod, přes aminoskupinu, může províhat v nevodném nebo vodném prostředí . Například podle Sandmeyera se provádí ve vodném prostředí tak, že se diazoniové soli, intermediárně vytvořené s dusitany, nechají reagovat s chloridem měďným nebo bromidem měďným za přítomnosti odpovídající kyseliny, výhodně kyseliny chlorovodíkové nebo kyseliny bromovodíkové, nebo s jodidem draselným. V nevodném prostředí se provádí známým způsobem reakce hydrochloridu s i-amylnitritem a například methylenjodidem nebo bromoformem v aprotickém rozpouštědle, jako je například dimethylformamid. Zavádění fluoru se provádí například Balz-Schiemanovou reakcí diazoniumtetrafluorborátu.The introduction of halogen, such as chlorine, bromine or iodine, via the amino group can take place in a non-aqueous or aqueous medium. For example, according to Sandmeyer, it is carried out in an aqueous medium by reacting the diazonium salts formed intermediate with nitrites with copper (I) chloride or copper (I) bromide in the presence of the corresponding acid, preferably hydrochloric or hydrobromic acid, or potassium iodide. In a non-aqueous medium, the hydrochloride is reacted in a known manner with i-amyl nitrite and, for example, methylene iodide or bromoform in an aprotic solvent such as dimethylformamide. The introduction of fluorine is carried out, for example, by the Balz-Schieman reaction of diazonium tetrafluoroborate.
Reakce aminoskupiny s 2-azabutadienem obecného VZorce IV na imidazolové deriváty se provádí za přítomnosti kyselin při teplotě v rozmezí 0 °C až 150 °C . Odštěpitelné skupiny U a V mohou být stejné nebo různé ; obzvláště vhodné jsou dialkylaminy s 1 až 3 uhlíkovými atomy, jako je například dimethylamin, diethylamin a dipropylamin, a cyklické aminy, jako je například pyrrolidin. Reakce se například provádí tak, že se nejdříve míchá aminoderivát a azadien v organické kyselině, jako je například kyselina mravenčí, kyselina octová, kyselina propionová nebo kyselina trifluoroctová a potom se reakční směs zahřeje až k varu (až asi 120 °C ) .The reaction of the amino group with the 2-azabutadiene of Formula IV to imidazole derivatives is carried out in the presence of acids at a temperature in the range of 0 ° C to 150 ° C. The leaving groups U and V may be the same or different; particularly suitable are dialkylamines having 1 to 3 carbon atoms, such as dimethylamine, diethylamine and dipropylamine, and cyclic amines, such as pyrrolidine. For example, the reaction is carried out by first mixing the amino derivative and azadiene in an organic acid, such as formic acid, acetic acid, propionic acid, or trifluoroacetic acid, and then heating the reaction mixture to boiling (up to about 120 ° C).
Kyseliny mohou sloužit současně jako reakční prostředek a rovněž jako rozpouštědlo. Mohou se ale také přidávat rozpouštědla, jako jsou například alkoholy, ethery, ketony, estery, jako je ethylester kyseliny octové, uhlovodíky, jako je toluen, nebo halogenované uhlovodíky, jako je tetrachlormethan.The acids can serve both as a reaction medium and as a solvent. However, solvents such as alcohols, ethers, ketones, esters such as ethyl acetate, hydrocarbons such as toluene, or halogenated hydrocarbons such as carbon tetrachloride may also be added.
Množství kyseliny se může pohybovat v širokém rozmezí, používá se však v přebytku. Výhodně se volí trojnásobný až desetinásobný přebytek kyseliny, vztaženo na amin a azadien.The amount of acid may vary within wide limits, but is used in excess. Preferably, a 3 to 10-fold excess of acid, based on the amine and azadiene, is selected.
Směsi isomerů se mohou rozdělit pomocí obvyklých metod, jako je napřklad krystalisace, chromatografie nebo převedení na diastereomery, například tvorbou solí, nebo na enantiomery, popřípadě E/Z isomery.Mixtures of isomers may be separated by conventional methods such as crystallization, chromatography or conversion to diastereomers, for example by salt formation, or into enantiomers or E / Z isomers.
Výroba solí se provádí obvyklými způsoby tak, že se roztok sloučeniny obecného vzorce I smísí s ekvivalentním množstvím nebo s přebytkem sloučeniny alkalického kovu nebo kovu alkalické zeminy, která je popřípadě v roztoku a vy16 tvořená sraženina se oddělí nebo se roztok zpracuje obvyklými způsoby.Salts are prepared by conventional methods by mixing a solution of a compound of formula I with an equivalent amount or an excess of an alkali metal or alkaline earth metal compound, optionally in solution, and precipitating the precipitate formed, or treating the solution by conventional methods.
Pokud není popsána výroba výchozích sloučenin, jsou tyto známé nebo jsou vyrobitelné analogicky jako známé sloučeniny nebo zde popsanými způsoby.If the preparation of the starting compounds is not described, they are known or can be produced analogously to known compounds or by the methods described herein.
Sloučeniny obecného vzorce II se mohou například připravit tak, že se vyrobí 2,4-dinitroarylaminy podle metody Sangera tím, že se o-halogen-nitroaromáty, výhodně o-fluor-nitroarornáty, jako je například dinitrofluorbenzen, nechaj i reagovat ve vodném roztoku s deriváty aminokyselin za přítomnosti base, jako je například uhličitan sodný nebo hydrogenuhličitan sodný, při teplotě v rozmezí 0 °C až teplota varu pod zpětným chladičem a potom se redukují. Tato reakce se dá přenést také na jiné substituované 2-nitrohalogensloučeniny. Diarylaminosloučeniny se dají získat také Ullmannovou reakcí z dinitrochlorbenzenu s aromatickým aminem. Pro tuto reakci se používají vysokovroucí rozpouštědla, jako je například dimethylformamid nebo collidin a pevný uhličitan draselný a práškovítá měď jako base. Je také možné vyrobit odpovídající o-nitroaniliny alkylací nebo za pomoci substituovaných aldehydů reduktivní alkylací. Následující redukce o-nitroskupiny se provádí při přítomnosti více nitroskupin selektivně sirníkem sodným za přítomnosti amoniaku, jakož i chloridu amonného, v polárních rozpouštědlech při teplotě místnosti nebo za zvýšené teploty. V některých případech je výhodné provádět reakci s estery a v posledním kroku tyto hydrolysovat.For example, the compounds of formula (II) can be prepared by producing 2,4-dinitroarylamines according to the method of Sanger by reacting o-halo nitroaromatics, preferably o-fluoro nitroarnates, such as dinitrofluorobenzene, in aqueous solution with amino acid derivatives in the presence of a base, such as sodium carbonate or sodium bicarbonate, at a temperature ranging from 0 ° C to reflux and then reduced. This reaction can also be transferred to other substituted 2-nitrohalogen compounds. Diarylamino compounds can also be obtained by Ullmann reaction from dinitrochlorobenzene with an aromatic amine. High boiling solvents such as dimethylformamide or collidine and solid potassium carbonate are used for this reaction, and powdered copper as a base. It is also possible to prepare the corresponding o-nitroanilines by alkylation or by means of substituted aldehydes by reductive alkylation. The subsequent reduction of the o-nitro group is carried out selectively with sodium sulfide in the presence of multiple nitro groups in the presence of ammonia as well as ammonium chloride, in polar solvents at room temperature or at elevated temperature. In some cases, it is preferred to carry out the reaction with esters and to hydrolyze them in the final step.
Dělení enantiomerů je možno provádět v konečném stupni nebo v mezistupních pomocí opticky aktivních pomocných basí, jako je například brucin nebo 1-fenethylamin, nebo ale také pomocí chromatografie přes opticky aktivní nosné materiály. Enantiomery se mohou ale také vyrobit synteticky reakcí odpovídajících opticky aktivních aminokyselin s odpovídajícími fluornitroaromáty metodou podle Sangera a dalším zpracováním aminonitroaromátů jak je uvedeno výše.The separation of enantiomers may be carried out in the final step or in intermediate steps using optically active auxiliary bases, such as brucine or 1-phenethylamine, or also by chromatography over optically active carrier materials. However, enantiomers can also be prepared synthetically by reacting the corresponding optically active amino acids with the corresponding fluoronitroaromatics by the Sanger method and further treating the aminonitroaromatics as described above.
Dále uvedené příklady provedení způsob podle předloženého vynálezu blíže objasňují.The following examples illustrate the process of the present invention.
Příklady provedení vynálezuDETAILED DESCRIPTION OF THE INVENTION
Příklad 1Example 1
Methylester kyseliny 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-benzoové a methylester kyseliny 3-(7-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl) - benzoové3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester and 3- (7-nitro-2,3-dioxo-1,2-methyl ester) (3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid
1,03 g (5 mM) 6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalinu se předloží pod dusíkovou atmosférou a za zamezení přístupu vlhkosti v 50 ml dimethylformamidu při teplotě místnosti. Ve třech porcích se ke vsázce přidá 330 mg (11 mM) hydridu sodného (80%) a reakční směs se míchá po dobu jedné hodiny při teplotě místnosti. Potom se ke vsázce přikape 1,26 g (5,5 mM) methylesteru kyseliny 3-brommethylbenzoové v 5 ml dimethylformamidu a míchá se po dobu 3,5 hodiny. Po zahuštění se získaný zbytek rozdělí do směsi vody a ethylesteru kyseliny octové, okyselené kyselinou octovou. Organická fáze se oddělí, vysuší se, přefiltruje a zahustí. Získaný zbytek se chromatograuje na silikagelu za použití směsi dichlormethan/ethylalkohol = =95 : 5 . Získá se takto vedle 211 mg methylesteru kyše18 líny 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahy- drochinoxalin-1-ylmethyl)-benzoové, který se dále nečistí, 222 mg methylesteru kyseliny 3-(7-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-benzoové o teplotě tání 265 až 267 °C .1.03 g (5 mM) of 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was introduced under nitrogen atmosphere and 50 ml of dimethylformamide at room temperature while avoiding moisture. In three portions, 330 mg (11 mM) of sodium hydride (80%) was added to the batch, and the reaction mixture was stirred for one hour at room temperature. 1.26 g (5.5 mM) of 3-bromomethylbenzoic acid methyl ester in 5 ml of dimethylformamide was then added dropwise to the batch and stirred for 3.5 hours. After concentration, the residue is partitioned between a mixture of water and ethyl acetate acidified with acetic acid. The organic phase was separated, dried, filtered and concentrated. The residue is chromatographed on silica gel with dichloromethane / ethanol = 95: 5. In addition to 211 mg of methyl 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester, which is not further purified, 222 mg of methyl acid ester is obtained. 3- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. 265-267 ° C.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Methylester kyseliny 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-benzoové o teplotě tání 308 až 314 °C , methylester kyseliny 4-(7-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-benzoové o teplotě tání vyšší než 300 °C , ethylester kyseliny 2-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-benzoové o teplotě tání 279 °C / 283 až 284 °C , ethylester kyseliny 2-(7-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-benzoové (bez dalšího čištění se dále zpracovává) ,4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid methyl ester, m.p. 308 DEG-314 DEG C., 4- (7-nitro-2) methyl ester 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p. > 300 ° C, 2- (6-nitro-2,3-dioxo-1,2,3-ethyl ester) 279-C / 283-284 ° C, 2- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1-yl) ethyl ester, 4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid. -ylmethyl) -benzoic acid (further processing without further purification),
1-(3-methoxykarbonyl-2-propenyl)-6-nitrochinoxalin-2,3-(1H, 4H)-dion o teplotě tání 258 až 265 °C (rozklad) ,1- (3-methoxycarbonyl-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 258 DEG-265 DEG C. (decomposition),
1-(3-ethoxykarbonylpropyl)-6-nitrochinoxalin-2,3-(1H, 4H)-dion o teplotě tání 215 až 217 °C ,1- (3-ethoxycarbonylpropyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 215-217 ° C,
1-(3-ethoxykarbonylpropyl)-7-nitrochinoxalin-2,3-(1H, 4H)-dion o teplotě tání 215 až 217 °C , diethylester kyseliny 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahy19 drochinoxalin-l-ylmethyl)-fenylf osf onové o teplotě tání 114 °C / 129 až 131 °C , diethylester kyseliny 4-(7-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl)-fenylfosfonové (bez čištění se dále zpracovává) , diethylester kyseliny 3-(6-trifluormethyl-2,3-dioxo-l,2,3,4- tetrahydrochinoxalin-1-y1)-1-propen-1-fosfonové diethylester kyseliny 3-(6-trifluormethyl-2,3-dioxo-l,2,3,4- tetrahydrochinoxalin-1-yl)-1-propin-l-fosfonové diethylester kyseliny 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-propan-1-fosfonové terč.-butylester kyseliny 1-(6-trifluormethyl-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl)-methankarboxylové .1- (3-ethoxycarbonylpropyl) -7-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 215 DEG-217 DEG C., diethyl 4- (6-nitro-2,3-dioxo-1,2,2) -ethyl ester 114,4 C / 129-131 ° C, 4- (7-nitro-2,3-dioxo-1,2,3-diethyl ester), 3,4-tetrahydro-quinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid (further processed without purification), 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1- 3- (6-nitro-prop-1-phosphonic acid diethyl ester) 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1-propyne-1-phosphonic acid diethyl ester 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic tert-butyl ester (4-tetrahydroquinoxalin-1-yl) -methanecarboxylic acid.
Příklad 2Example 2
Při dvojité dávce methyl-3-brommethylbenzoátu a jinak úplném provedení reakce jako je popsáno v příkladě 1 se dá kromě toho isolovat 503 mg kyseliny 3-[4-(3-methoxykarbonylbenzyl)-6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl-methyl]-benzoové o teplotě tání 238 až 240 °C .In addition, 503 mg of 3- [4- (3-methoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1] can be isolated at a double dose of methyl 3-bromomethylbenzoate and otherwise complete reaction as described in Example 1. 2,3,4-tetrahydroquinoxalin-1-yl-methyl] -benzoic, m.p. 238-240 ° C.
Analogicky se vyrobí :The following are produced analogously:
Methylester kyseliny 4-[4-(4-methoxykarbonylbenzyl)-6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmethyl]-benzoové o teplotě tání 225 až 227 °C , ethylester kyseliny 2-[4-(2-ethoxykarbonylbenzyl)-6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-ylmexhyl]-benzoové o teplotě tání 230 až 234 °C ,4- [4- (4-Methoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] -benzoic acid methyl ester, m.p. 225-227 ° C, ethyl ester 2- [4- (2-ethoxycarbonylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl] -benzoic acid, m.p. 230-234 ° C,
1,4-bis-(3-methoxykarbonyl-2-propenyl)-6-nitrochinoxalin-2,3-(1H, 4H)-dion o teplotě tání 181 až 183 °C .1,4-bis- (3-methoxycarbonyl-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 181-183 ° C.
Příklad 3Example 3
A) Ethylester kyseliny 4-(2,4-dinitrofenyl)-aminobenzoovéA) 4- (2,4-Dinitrophenyl) aminobenzoic acid ethyl ester
1,01 g (5 mM) l-chlor-2,4-dinitrobenzenu, 1,01 g (6 mři) ethylesteru kyseliny 4-aminobenzoové, 13 mg (0,2 mM) práškové mědi a 961 mg (7 mM) uhličitanu draselného (práškového) se míchá po dobu 25 minut při teplotě lázně 180 °C pod argonovou atmosférou a za zamezení přístupu vlhkosti.1.01 g (5 mM) of 1-chloro-2,4-dinitrobenzene, 1.01 g (6 ml) of 4-aminobenzoic acid ethyl ester, 13 mg (0.2 mM) of copper powder and 961 mg (7 mM) of carbonate Potassium (powdered) was stirred for 25 minutes at a bath temperature of 180 ° C under an argon atmosphere, avoiding the ingress of moisture.
Po zahuštění se získaný zbytek vyjme do vody, zalkalisuje se amoniakem a vytřepe se ethylesterem kyseliny octové. Organická fáze se vysuší, přefiltruje a zahustí. Získaný zbytek se chromatografuje na silikagelu za použití směsi cyklohexan/ethylacetát =8:2 a získá se takto 768 mg ethylesteru kyseliny 4-(2,4-dinitrofenyl)-aminobenzoové o teplotě tání 99 až 102 °C .After concentration, the residue is taken up in water, made alkaline with ammonia and shaken with ethyl acetate. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with cyclohexane / ethyl acetate = 8: 2 to give 768 mg of 4- (2,4-dinitrophenyl) aminobenzoic acid ethyl ester, m.p. 99-102 ° C.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
ethylester kyseliny 3-(2,4-dinitrofenyl)-aminobenzoové o teplotě tání 108 až 110 °C , ethylester kyseliny 3-(2,4-dinitrofenyl)-aminofenylfosfo21 nové (dále se zpracovává bez dalšího čištění) , ethylester kyseliny 2-(2,4-dinitrofenyl)-aminobenzoové (dále se zpracovává bez dalšího čištění) .3- (2,4-dinitrophenyl) aminobenzoic acid ethyl ester, m.p. 108-110 ° C, 3- (2,4-dinitrophenyl) aminophenylphosphonic acid ethyl ester (further processed without further purification), 2- (ethyl ester) 2,4-dinitrophenyl) aminobenzoic acid (further processed without further purification).
B) Ethylester kyseliny 4-(2-amino-4-nitrofenylamino)-benzoovéB) 4- (2-Amino-4-nitrophenylamino) -benzoic acid ethyl ester
566 mg (1,7 mM) ethylesteru kyseliny 4-(2,4-dinitrof enyl) -aminobenzoové , 761 mg (12,2 mM) chloridu amonného, 0,68 ml koncentrovaného amoniaku, 15 ml ethylalkoholu a 6 ml destilované vody se společně předloží při vnitřní teplotě 78 °C (teplota lázně 90 °C ) . Ve třech porcích se přidá 1,27 g (5,68 mM) sirníku sodného (35%) a reakční směs se míchá po dobu jedné hodiny. Vsázka se při teplotě místnosti odsaje a nejprve se promyje vodou a potom diethyletherem. Získá se takto 535 mg ethylesteru kyseliny 4-(2-amino-4-nitrofenylamino)-benzoové (dále se zpracovává bez dalšího čištění).566 mg (1.7 mM) of 4- (2,4-dinitrophenyl) -aminobenzoic acid ethyl ester, 761 mg (12.2 mM) of ammonium chloride, 0.68 ml of concentrated ammonia, 15 ml of ethanol and 6 ml of distilled water are added. jointly submitted at an internal temperature of 78 ° C (bath temperature 90 ° C). 1.27 g (5.68 mM) of sodium sulfide (35%) was added in three portions and the reaction mixture was stirred for one hour. The batch is aspirated at room temperature and washed first with water and then with diethyl ether. 535 mg of 4- (2-amino-4-nitrophenylamino) -benzoic acid ethyl ester are obtained (further processed without further purification).
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
ethylester kyseliny 3-(2-amino-4-nitrofenylamino)-benzoové o teplotě tání 145 - 150 °C , ethylester kyseliny 3-(2-amino-4-nitrofenylamino)-fenylfosfonové o teplotě tání 160- 163 °C .145-150 ° C, 3- (2-amino-4-nitrophenylamino) -benzoic acid ethyl ester, m.p. 160-163 ° C;
C) Ethylester kyseliny 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-y1)-benzoovéC) 4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid ethyl ester
582 mg (2,3 mM) ethylesteru kyseliny 4-(2-amino-4-nitrofenylamino)-benzoové se předloží se 488 mg (4,8 mM) xriexhylaminu do 27 ml vysušeného xexrahydrofuranu při Xeploxě lázně 4 °C pod argonovou aXmosférou a za zamezeni přísxupu vlhkosxi. Ke vsázce se přikape rozxok 659 mg (4,8 mM) exhylesxerchloridu kyseliny oxalové a 8 ml vysušeného xexrahydrofuranu a reakční směs se míchá po dobu 2 hodin při xeploxě mísxnosxi. PoXom se přidá 0,2 ml xriexhylaminu a 0,1 ml exhylesxerchloridu kyseliny oxalové a míchá se po dobu jedné hodiny při Xeploxě mísxnosxi. Vsázka se poXom přefilxruje a filxráx se zahusxí. Získaný zbyxek se se rozdělí mezi vodu a exhylesxer kyseliny ocxové a organická fáze se zahusxí. Takxo získaný zbyxek se ve 25 ml 1 N kyseliny chlorovodíkové a 25 ml exhylalkoholu vaří po dobu 2 hodin pod zpěxným chladičem. Vysrážený produkx se odsaje, promyje se vodou a vysuší se. Získá se XakXo 220 mg exhylesxeru kyseliny 4-(6-nixro-2,3-dioxo-1,2,3,4-xexrahydrochinoxalin-l-yl)-benzoové (dále se zpracovává bez čišxění) .582 mg (2.3 mM) of 4- (2-amino-4-nitrophenylamino) -benzoic acid ethyl ester are introduced with 488 mg (4.8 mM) of xriexhylamine in 27 ml of dried xexrahydrofuran at Xeplox bath 4 ° C under argon and Xmosphere and while avoiding moisture. A solution of 659 mg (4.8 mM) of oxylic acid exyl ester oxyl chloride and 8 ml of dried xexrahydrofuran was added dropwise to the batch, and the reaction mixture was stirred for 2 hours at room temperature. 0.2 ml of xriexhylamine and 0.1 ml of exyl oxyl oxalic chloride were added thereto, and the mixture was stirred for 1 hour at Xeplox mix. The batch is filtered and the filtrate is concentrated. The residue obtained is partitioned between water and an exoxylic acid ester and the organic phase is concentrated. The residue thus obtained is boiled under reflux for 2 hours in 25 ml of 1 N hydrochloric acid and 25 ml of exyl alcohol. The precipitated product is filtered off with suction, washed with water and dried. XakXo 220 mg of 4- (6-nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl) -benzoic acid exyl ester (further processing without purification) is obtained.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Exhylesxer kyseliny 3-(6-nixro-2,3-dioxo-l,2,3,4-xeXrahydrochinoxalin-l-yl)-benzoové o xeploxě xání 258 až 263 °C , exhylesxer kyseliny 3-(6-niXro-2,3-dioxo-l,2,3,4-xexrahydrochinoxalin-l-yl) - fenylf osf onové .3- (6-Nixro-2,3-dioxo-1,2,3,4-oxo-hydroquinoxalin-1-yl) -benzoic acid exyl ester of xeplox at 258-263 ° C; 3- (6-nitro-2-exyl ester) 3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl) -phenylphosphonic acid.
Příklad 4Example 4
A) Kyselina 2-(2,4-dinixrofenyl)-aminobenzoováA) 2- (2,4-Dinixrophenyl) aminobenzoic acid
1,37 g (10 mM) kyseliny 2-aminobenzoové a 2 g (18,7 mM) uhličitanu sodného ve 40 ml vody se při teplotě lázně 40 °C za silného míchání smísí s 1,86 g (10 mM) 2,4-dinitrobenzenu a míchá se po dobu 2 hodin. Vsázka se potom zředí asi 400 ml vody a vysráží se 4 N kyselinou chlorovodíkovou. Produkt se odsaje, promyje se vodou a vysuší se. Získá se takto 2,8 g kyseliny 2-(2,4-dinitrofenyl)-aminobenzoové s teplotou tání 266 až 270 °C .1.37 g (10 mM) of 2-aminobenzoic acid and 2 g (18.7 mM) of sodium carbonate in 40 ml of water are mixed with 1.86 g (10 mM) of 2.4 at a bath temperature of 40 ° C with vigorous stirring. -dinitrobenzene and stirred for 2 hours. The batch is then diluted with about 400 ml of water and precipitated with 4 N hydrochloric acid. The product is filtered off with suction, washed with water and dried. 2.8 g of 2- (2,4-dinitrophenyl) aminobenzoic acid of melting point 266 DEG-270 DEG C. are obtained.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Kyselina 3-(2,4-dinitrofenylamino)-propionová s teplotou tání 134 až 137 °C , kyselina 4-(2,4-dinitrofenylamino)-fenylfosfonová s teplotou tání 271 až 272 °C (rozklad) , kyselina 2-(2,4-dinitrofenylamino)-fenylfosfonová (dále se zpracovává bez čištění) , kyselina (2,4-dinitrofenylamino)-methanfosfonová s teplotou tání 225 až 227 °C , kyselina 2-(2,4-dinitrofenylamino)-ethanfosfonová (dále se zpracovává bez čištění , kyselina 3-(2,4-dinitrofenylamino)-fenylfosfonová , kyselina (2-nitro-l-naftylamino)-methanfosfonová , kyselina (l-nitro-2-naftylamino)-methanfosfonová , kyselina 1-(2-nitro-l-naftylamino)-ethan-l-fosfonová , kyselina 1-(l-nitro-2-naftylamino)-ethan-l-fosfonová , kyselina (2-nitro-4-trif luormethyl-fenylamino) -methanfosf Cínová , kyselina 1-(2-nitro-4-trifluormethyl-fenylamino)-ethan-1-fosfonová ,134-137 ° C, 3- (2,4-dinitrophenylamino) -propionic acid, m.p. 271-272 ° C (decomposition), 2- (2) (4-dinitrophenylamino) -phenylphosphonic acid (further processed without purification), (2,4-dinitrophenylamino) -methanephosphonic acid, m.p. 225-227 ° C, 2- (2,4-dinitrophenylamino) -ethanephosphonic acid (further processed without purification, 3- (2,4-dinitrophenylamino) -phenylphosphonic acid, (2-nitro-1-naphthylamino) -methanephosphonic acid, (1-nitro-2-naphthylamino) -methanephosphonic acid, 1- (2-nitro- 1-naphthylamino) -ethan-1-phosphonic acid, 1- (1-nitro-2-naphthylamino) -ethan-1-phosphonic acid, (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphinic acid, 1- (2-Nitro-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid,
kyselina (2-nitro-4-fluorfenylamino)-methanfosfonová , kyselina (2-nitro-4-chlorfenylamino)-methanfosfonová , kyselina (2-nitro-4-bromfenylamino)-methanfosfonová , kyselina (2-nitro-4-methylf enylamino)-methanf osf onová ,(2-Nitro-4-fluorophenylamino) -methanephosphonic acid, (2-nitro-4-chlorophenylamino) -methanephosphonic acid, (2-nitro-4-bromophenylamino) -methanephosphonic acid, (2-nitro-4-methylphenylamino) -methanf osfon,
kyselina 1-(2-nitro-4-methylfehylamino)-ethan-l-fosfonová , kyselina 1-fenyl-l-(2-nitro-4-trifluormethyl-fenylamino)-me thanfosfonová , kyselina l-methyl-l-(2-nitro-4-trifluormethyl-fenylamino)ethan-l-fosfonová , kyselina 1- (2-nitro-4-trifluormexhyl-fenylamino) -hexan-1-fosfonová , kyselina l-methyl-2- (2-nitro-4-trif luormexhyl-fenylamino) ethan-l-fosfonová , kyselina 2- (2-nitro-4-trifluormexhyl-fenylamino) -propan-1-fosfonová , kyselina l-mexhyl-2- (2-nitro-4-trif luormethyl-f enylamino) propan-l-fosfonová , kyselina 1- (2-nitro-4-trifluormethyl-fenylamino) -cyklopropan-l-fosfonová , kyselina (+) -1- (2-nitro-4-trifluormexhyl-fenylamino) -ethan—1—fosfonová , kyselina (-) -1- (2-nitro-4-trifluormexhyl-fenylamino) -ethan-1-fosfonová ,1- (2-nitro-4-methylphenylamino) -ethan-1-phosphonic acid, 1-phenyl-1- (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphonic acid, 1-methyl-1- (2 -nitro-4-trifluoromethyl-phenylamino) ethane-1-phosphonic acid 1- (2-nitro-4-trifluoromethyl-phenylamino) -hexane-1-phosphonic acid 1-methyl-2- (2-nitro-4- trifluoromethyl-phenylamino) ethane-1-phosphonic acid, 2- (2-nitro-4-trifluoromethyl-phenylamino) -propane-1-phosphonic acid, 1-mexhyl-2- (2-nitro-4-trifluoromethyl-f) enylamino) propane-1-phosphonic acid, 1- (2-nitro-4-trifluoromethyl-phenylamino) -cyclopropane-1-phosphonic acid, (+) -1- (2-nitro-4-trifluoromethyl-phenylamino) -ethane- 1-phosphonic acid, (-) -1- (2-nitro-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid,
P , P-dimethyl- (2,4-dinitrofenylamino) -methan-f osf inoxid , kyselina P-methyl-(2,4-dinitrofenylamino)-methanfosfinová , kyselina 1- [5- (imidazol-l-yl) -2,4-dinitrofenylamino] -methyl fosfonová , kyselina 1-[5-(imidazol-l-yl)-2-nitro-4-trifluormethyl-fenylamino]-methylfosfonová .P, P-dimethyl- (2,4-dinitrophenylamino) -methanephosphine oxide, P-methyl- (2,4-dinitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2] 1- [5- (imidazol-1-yl) -2-nitro-4-trifluoromethyl-phenylamino] methylphosphonic acid, 4-dinitrophenylamino] methylphosphonic acid.
B) Kyselina 1-[5-(imidazol-l-yl)-2,4-dinitrofenylamino] -ethan-1-fosfonováB) 1- [5- (Imidazol-1-yl) -2,4-dinitrophenylamino] -ethan-1-phosphonic acid
600 mg 5-fluor-2,2-dinitrofluorbenzenu se při teplotě 40 °C předloží do 30 ml vody a 10 ml ethylalkoholu a smísí se po kapkách s roztokem 376 mg racemické kyseliny aminoethylfosfonové v 10 ml vody a 600 mg uhličitanu sodného. Reakční směs se míchá po dobu 1,5 hodin a po oddestilování ethylalkoholu se extrahuje proti kyselině octové. Vodná fáze se smísí se 200 mg imidazolu a zahřívá se po dobu 2 hodin na teplotu 11 °C . Potom se přidá dalších 200 mg imidazolu a znovu se zahřívá po dobu 2 hodin na teplotu 110 °C . Dále se směs okyselí 4 N kyselinou chlorovodíkovou, odfiltrují se nerozpustné součásti a filtrát se promyje ethylesterem kyseliny octové. Vodná fáze se zahustí a provaří se s ethylalkoholem. Ethanolový extrakt se zahustí a chromatografuje se na silikagelu za použití směsi methylalkohol/butylalkohol/voda/amoniak = 75 : 25 : 17 : 3. Získá se takto 300 mg kyseliny 1-[5-(imidazol-l-yl)-2,4-dinitrofenylamino] -ethan-l-f osf onové .600 mg of 5-fluoro-2,2-dinitrofluorobenzene is introduced into 40 ml of water and 10 ml of ethanol at 40 DEG C. and treated dropwise with a solution of 376 mg of racemic aminoethylphosphonic acid in 10 ml of water and 600 mg of sodium carbonate. The reaction mixture was stirred for 1.5 hours and after distilling off the ethanol, it was extracted against acetic acid. The aqueous phase was mixed with 200 mg of imidazole and heated at 11 ° C for 2 hours. An additional 200 mg of imidazole was then added and reheated to 110 ° C for 2 hours. The mixture was acidified with 4 N hydrochloric acid, the insoluble matter was filtered off, and the filtrate was washed with ethyl acetate. The aqueous phase is concentrated and boiled with ethanol. The ethanol extract was concentrated and chromatographed on silica gel using methanol / butyl alcohol / water / ammonia = 75: 25: 17: 3 to give 300 mg of 1- [5- (imidazol-1-yl) -2,4] acid. -dinitrophenylamino] -ethan-1-phosphonium.
C) Kyselina 2-(2-amino-4-nitrofenylamino)-benzoováC) 2- (2-Amino-4-nitrophenylamino) -benzoic acid
1,80 g (6 mM) kyseliny 2-(2,4-dinitrofenylamino)-benzoové, 2,66 g (42,6 mM) chloridu amonného, 2,4 ml koncentrovaného amoniaku, 52 ml ethylalkoholu a 21 ml destilované vody se předloží při vnitřní teplotě 78 °C (teplota lázně 90 °C). Ve třech dávkách se přidá 4,44 g (20 mM) sirníku sodného (35%) a reakční směs se míchá po dobu jedné hodiny. Vsázka se 'potom při teplotě místnosti odsaje a postupně se promyje vodou a diethyletherem. Filtrát se odpaří až do vodné fáze a vytřepe se ethylesterem kyseliny octové. Organická fáze se vysuší, přefiltruje a zahustí. Vodná fáze se okyselí 1 N kyselinou chlorovodíkovou a odsaje se. Získá se takto 1,1 g kyseliny 2-(2-amino-4-nitrofenylamino)-benzoové (zpracovává se bez čištění).1.80 g (6 mM) of 2- (2,4-dinitrophenylamino) -benzoic acid, 2.66 g (42.6 mM) of ammonium chloride, 2.4 ml of concentrated ammonia, 52 ml of ethanol and 21 ml of distilled water were added. The mixture was charged at an internal temperature of 78 ° C (bath temperature 90 ° C). 4.44 g (20 mM) of sodium sulfide (35%) was added in three portions and the reaction mixture was stirred for one hour. The batch is then filtered off with suction at room temperature and washed successively with water and diethyl ether. The filtrate was evaporated to an aqueous phase and shaken with ethyl acetate. The organic phase is dried, filtered and concentrated. The aqueous phase is acidified with 1 N hydrochloric acid and filtered off with suction. 1.1 g of 2- (2-amino-4-nitrophenylamino) benzoic acid are obtained (worked up without purification).
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Kyselina 3-(2-amino-4-nitrofenylamino)-propionová , kyselina 4-(2-amino-4-nitrofenylamino)-fenylfosfonová , kyselina 2-(2-amino-4-nitrofenylamino)-fenylfosfonová , kyselina (2-amino-4-nitrofenylamino)-methylfosfonová , kyselina (2-amino-4-nitrofenylamino)-ethylfosfonová , kyselina 1-(2-amino-4-nitrofenylamino)-ethan-l-fosfonová , kyselina 3-(2-amino-4-nitrofenylamino)-propan-l-fosfonová , kyselina 4-(2-amino-4-nitrofenylamino)-butan-l-fosfonová , kyselina 1- (2-amino-4-trif luormethyl-fenylamino) -cyklopropan-l-fosfonová ,3- (2-Amino-4-nitrophenylamino) -propionic acid, 4- (2-amino-4-nitrophenylamino) -phenylphosphonic acid, 2- (2-amino-4-nitrophenylamino) -phenylphosphonic acid, (2-amino) 4-nitrophenylamino) -methylphosphonic acid, (2-amino-4-nitrophenylamino) ethylphosphonic acid, 1- (2-amino-4-nitrophenylamino) -ethan-1-phosphonic acid, 3- (2-amino-4- nitrophenylamino) -propane-1-phosphonic acid, 4- (2-amino-4-nitrophenylamino) -butane-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -cyclopropane-1-phosphonic acid,
P , P-dimethyl- (2-amino-4-nitrofenylamino) -methanfosfinoxid , kyselina P-methyl-(2-amino-4-nitrofenylamino)-methanfosfinová , kyselina 1-[5-(imidazol-l-yl)-2-amino-4-nitrofenylamino]-me thylfosfonová .P, P-dimethyl- (2-amino-4-nitrophenylamino) -methanphosphine oxide, P-methyl- (2-amino-4-nitrophenylamino) -methanephosphinic acid, 1- [5- (imidazol-1-yl) -2] -amino-4-nitrophenylamino] -methylphosphonic acid.
D) Kyselina (2-amino-4-trifluormethyl-fenylamino)-methanfosfonováD) (2-Amino-4-trifluoromethyl-phenylamino) -methanephosphonic acid
894 mg kyseliny (2-nitro-4-trifluormethyl-fenylamino)-methanfosfonové se ve 180 ml ethylalkoholu smísí se 3 g Raneyova niklu a po dobu 3 hodin se hydrogenuje při teplotě místnosti a za normálního tlaku vodíku. Ze vsázky se potom odsaje katalysátor a filtrát se zahustí. Produkt se bez dalšího čištění použije ve stupni E) .894 mg of (2-nitro-4-trifluoromethyl-phenylamino) -methanephosphonic acid in 180 ml of ethanol are treated with 3 g of Raney nickel and hydrogenated for 3 hours at room temperature and under normal hydrogen pressure. The catalyst is then filtered off with suction and the filtrate is concentrated. The product was used in step E) without further purification.
V zásadě analogickým způsobem se vyrobí :In a substantially analogous manner, the following are produced:
Kyselina 1-(2-amino-l-naftylamino)-ethan-l-fosfonová , kyselina 1-(l-amino-2-naftylamino)-ethan-l-fosfonová , kyselina 1-(2-amino-l-naftylamino)-methanfosfonová , kyselina 1-(l-amino-2-naftylamino)-methanfosfonová ,1- (2-Amino-1-naphthylamino) -ethan-1-phosphonic acid, 1- (1-Amino-2-naphthylamino) -ethan-1-phosphonic acid, 1- (2-Amino-1-naphthylamino) -methanephosphonic acid, 1- (1-amino-2-naphthylamino) -methanephosphonic acid,
Kyselina 1-(2-amino-4-trifluormethyl-fenylamino)-ethan-1fosfonová , kyselina 1- (2-amino-4-trif luormethyl-fenylamino) -methan-1fosfonová , kyselina (2-amino-4-methylfenylamino)-methanfosfonová , kyselina 1-(2-amino-4-methylfenylamino)-ethan-l-fosfonová , kyselina 1-fenyl-l-(2-amino-4-trifluormethyl-fenylamino)-methanfosfonová , kyselina 1-methyl-l-(2-amino-4-trifluormethyl-fenylamino)-ethan-l-fosfonová , kyselina 1- (2-amino-4-trif luormethyl-fenylamino) -hexan-1-fosfonová , kyselina l-mexhyl-2-(2-amino-4-trifluormethyl-fenylamino) -ethan-l-fosfonová , kyselina 2- (2-amino-4-trif luormethyl-fenylamino) -propan-1-1-fosfonová , kyselina l-methyl-2- (2-amino-4-trif luormethyl-f enylamino) -propan-l-fosfonová , kyselina (+) -1- (2-amino-4-trif luormethyl-f enylamino) -ethan —1—fosfonová , kyselina (-) -1- (2-amino-4-trif luormethyl-f enylamino) -ethan -1-fosfonová , kyselina (4-chlor-2-aminofeny lamino) -methanf osf onová , kyselina 1-(4-chlor-2-aminof enylamino)-ethan-l-f osf onová , kyselina (4-fluor-2-aminofenylamino)-methanfosfonová ,1- (2-Amino-4-trifluoromethyl-phenylamino) -ethan-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -methane-1-phosphonic acid, (2-amino-4-methylphenylamino) - methanphosphonic acid, 1- (2-amino-4-methylphenylamino) -ethan-1-phosphonic acid, 1-phenyl-1- (2-amino-4-trifluoromethyl-phenylamino) -methanephosphonic acid, 1-methyl-1- ( 2-Amino-4-trifluoromethyl-phenylamino) -ethan-1-phosphonic acid, 1- (2-amino-4-trifluoromethyl-phenylamino) -hexane-1-phosphonic acid, 1-Mexethyl-2- (2-amino) 4-Trifluoromethyl-phenylamino) -ethan-1-phosphonic acid, 2- (2-amino-4-trifluoromethyl-phenylamino) -propane-1-1-phosphonic acid, 1-methyl-2- (2-amino- 4-Trifluoromethyl-phenylamino) -propane-1-phosphonic acid, (+) -1- (2-amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, (-) -1- ( 2-amino-4-trifluoromethyl-phenylamino) -ethane-1-phosphonic acid, (4-chloro-2-aminophenylamino) -methanephosphonic acid, 1- (4-chloro-2-aminophenylamino) -ethane acid -l- Phosphonic acid, (4-fluoro-2-aminophenylamino) -methanephosphonic acid,
Kyselina [5-(imidazol-l-yl)-4-trifluormethyl-2-amino-fenyl amino]-methylfosfonová , kyselina 1-(4-f luor-2-aminof enylamino)-ethan-l-f osf onová .[5- (Imidazol-1-yl) -4-trifluoromethyl-2-amino-phenyl amino] methylphosphonic acid, 1- (4-fluoro-2-aminophenylamino) -ethan-1-phosphonic acid.
E) Kyselina 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-propionováE) 3- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propionic acid
211 mg (0,9 mM) kyseliny 3-(2-amino-4-nitrofenyl30 amino)-propionové se předloží se 200 mg (2 mM) triethylaminu do 20 ml vysušeného tetrahydrofuranu při teplotě lázně 4 °C pod argonovou atmosférou a za zamezení přístupu vlhkosti. Ke vsázce se přikape roztok 270 mg (2 mM) ethylesterchloridu kyseliny oxalové a 5 ml vysušeného tetrahydrofuranu a reakční směs se míchá po dobu 2 hodin při teplotě místnosti. Potom se přidá ještě 0,05 ml triethylaminu a 0,05 ml ethylesterchloridu kyseliny oxalové a míchá se další hodinu při teplotě místnosti. Vsázka se potom přefiltruje a filtrát se zahustí. Získaný zbytek se rozdělí mezi vodu a ethylester kyseliny octové, načež se organická fáze zahustí. Tento zbytek se vyjme do 15 ml ethylalkoholu a 15 ml 1 N kyseliny chlorovodíkové a vaří se po dobu 2 hodin při teplotě lázně 110 °C pod zpětným chladičem. Vsázka se potom zahustí, vyjme se do malého množství vody a zahustí se. Získá se takto 120 mg kyseliny 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-propionové s teplotou tání 148 až 156 °C (rozklad) .211 mg (0.9 mM) of 3- (2-amino-4-nitrophenyl-30 amino) -propionic acid are introduced with 200 mg (2 mM) of triethylamine in 20 ml of dried tetrahydrofuran at a bath temperature of 4 ° C under argon and avoiding access to moisture. A solution of 270 mg (2 mM) of oxalic acid ethyl ester and 5 ml of dried tetrahydrofuran was added dropwise to the batch, and the reaction mixture was stirred at room temperature for 2 hours. 0.05 ml of triethylamine and 0.05 ml of ethyl oxalic acid chloride were then added and the mixture was stirred at room temperature for a further hour. The batch is then filtered and the filtrate is concentrated. The residue is partitioned between water and ethyl acetate, and the organic phase is concentrated. This residue is taken up in 15 ml of ethanol and 15 ml of 1 N hydrochloric acid and refluxed for 2 hours at a bath temperature of 110 ° C. The batch is then concentrated, taken up in a small amount of water and concentrated. 120 mg of 3- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propionic acid, m.p. 148 DEG-156 DEG C. (decomposition), are obtained.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
kyselina 2-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-benzoová s teplotou tání > 255 °C , kyselina 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-fenylfosfonová s teplotou tání > 252 °C , kyselina 2-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-fenylfosfonová s teplotou tání > 310 °C , kyselina (6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanfosfonová s teplotou tání 180 až 200 °C (rozklad) , kyselina 2-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethanfosfonová s teplotou tání 304 až 308 °C (rozklad) , kyselina (2,3-dioxo-l,2,3,4-tetrahydrobenzo(f)chinoxalin-4-yl)-methanfosfonová , kyselina (2,3-dioxo-l,2,3,4-tetrahydrobenzo(f)chinoxalin-4-yl)-ethan-l-fosfonová , kyselina (2,3-dioxo-l,2,3,4-tetrahydrobenzo(f)chinoxalin-l-yl)-methanfosfonová , kyselina (2,3-dioxo-l,2,3,4-tetrahydrobenzo(f)chinoxalin-l-yl)-ethan-l-fosfonová , kyselina (6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonová s teplotou tání 202 °C , kyselina 1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-ethanfosfonová s teplotou tání 274 °C , kyselina 1-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-ethan-l-fosfonová s teplotou tání 297 až 300 °C (rozklad) , kyselina 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-propan-l-fosfonová s teplotou tání 200 °C (za vypěnění) , kyselina 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-butan-1-fosfonová s teplotou tání 285 až 287 °C kyselina (6-fluor-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanfosfonová , kyselina (6-chlor-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanfosfonová , kyselina (6-brom-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanfosfonová , kyselina (6-methyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanfosfonová , kyselina 1-(6-fluor-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethan-l-fosfonová s teplotou tání 259 °C , kyselina 1-(6-chlor-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethan-l-fosfonová , kyselina 1-(6-brom-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethan-l-fosfonová , kyselina 1-(6-methyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-ethan-l-fosfonová , kyselina 1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-l-fenyl-methan-l-fosfonová s teplotou tání 245 °C , kyselina 1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-l-methyl-ethan-fosfonová , kyselina 1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-hexan-l-fosfonová , kyselina l-methyl-2-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -ethan-l-fosfonová , kyselina 2-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-propan-l-fosfonová , kyselina l-mexhyl-2-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -propan-l-fosfonová , kyselina 1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-cyklopropan-l-fosfonová , kyselina (+)-1-(6-trifluormethyl-2,3-dioxo-l ,2,3,4-tetrahydrochinoxalin-l-yl)-exhan-l-fosfonová = + 7,4 ° (c = 0,505 ; H20) , kyselina (-)-1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethan-l-fosfonová [α2θ246^ = - 5,9 ° (c = 0,510 ; H20) , kyselina P-mexhyl-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfinová s teplotou tání 320 až 325 °C (rozklad) , (P,P-dimethyl)-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfinoxid s teplotou tání 325 až 330 °C (rozklad) ,2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid, m.p. > 255 ° C, 4- (6-nitro-2,3- Dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid, m.p. > 252 ° C, 2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-); 1-yl) -phenylphosphonic acid, m.p. > 310 ° C, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphonic acid, m.p. 180-200 ° C (decomposition), 2- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, m.p. 304 DEG-308 DEG C. (decomposition), acid (2, 3-Dioxo-1,2,3,4-tetrahydro-benzo (f) quinoxalin-4-yl) -methanephosphonic acid (2,3-dioxo-1,2,3,4-tetrahydro-benzo (f) quinoxalin-4-yl) (1) -ethane-1-phosphonic acid, (2,3-dioxo-1,2,3,4-tetrahydrobenzo (f) quinoxalin-1-yl) -methanephosphonic acid, (2,3-dioxo-1,2,3) (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, 4-tetrahydro-benzo (f) quinoxalin-1-yl) -ethan-1-phosphonic acid m.p. 202 DEG C., 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid, m.p. 274 DEG C., 1- (6-) nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, m.p. 297-300 ° C (dec.), 3- (6-nitro-2, 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid, m.p. 200 ° C (with foaming), 4- (6-nitro-2,3-dioxo-1) 285 DEG-287 DEG C. (6-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-1, 2,3,4-tetrahydroquinoxalin-1-yl) -butane-1-phosphonic acid (6-chloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid (6-bromo-2,3-dioxo-1,2-yl) -methanephosphonic acid (3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, (6-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, 1- (6-fluoro) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, m.p. 259 DEG C., 1- (6-chloro-2,3-dioxo-1), m.p. 2.3 1,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid 1- (6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid 1- (6-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, 1- (6-trifluoromethyl-2,3-dioxo-) 1,2,3,4-tetrahydroquinoxalin-1-yl) -1-phenyl-methane-1-phosphonic acid, m.p. 245 ° C, 1- (6-trifluoromethyl-2,3-dioxo-1,2,3) 1,4-tetrahydroquinoxalin-1-yl) -1-methyl-ethane-phosphonic acid 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -hexan-1 -phosphonic acid, 1-methyl-2- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid, 2- (6-trifluoromethyl- 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid, 1-mexhyl-2- (6-trifluoromethyl-2,3-dioxo-1,2,3) 4-tetrahydroquinoxalin-1-yl) -propane-1-phosphonic acid 1- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -cyclopropane-1-phosphonic acid , (+) - 1- (6-trifluoromethyl-2,3-dioxo acid) -1,2,3,4-tetrahydroquinoxalin-1-yl) -exane-1-phosphonic acid = + 7.4 ° (c = 0.505; H 2 O), (-) - 1- (6-Trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethan-1-phosphonic acid [α 2 θ246 ^ = - 5.9 ° (c = 0.510; H 2 O), β-mexyl- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphinic acid, m.p. 320 to 325 ° C (decomposition), (β, P-dimethyl) - (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphine oxide, m.p. 325-330 ° C (decomposition),
Kyselina [6-nitro-7-(imidazol-l-yl)-2,3-dioxo-l,2,3,4-tetrahydroxhinoxalin-l-yl]-methylfosfonová ,[6-Nitro-7- (imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroxhinoxalin-1-yl] methylphosphonic acid,
Kyselina [6-trifluormethyl-7-(imidazol-l-yl) -2,3-dioxo-1,2,3,4-tetrahydroxhinoxalin-l-yl]-methylfosfonová .[6-Trifluoromethyl-7- (imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroxhinoxalin-1-yl] methylphosphonic acid.
Příklad 5Example 5
Kyselina 3-(6-nixro-2,3-dioxo-l,2,3,4-xeXrahydrochinoxalin-1-yl-mexhyl)-benzoová3- (6-Nixro-2,3-dioxo-1,2,3,4-oxo-hydroquinoxalin-1-yl-methyl) -benzoic acid
211 mg (0,6 mM) mexhylesxeru kyseliny 3-(6-nixro-2,3-dioxo-l ,2,3,4-xexrahydrochinoxalin-l-yl-mexhyl) -benzoové se předloží do 4 ml 4 N kyseliny chlorovodíkové, smísí se se 4 ml kyseliny xrifluorocxové a reakční směs se míchá po dobu 3,5 hodin při xeploxě lázně 110 °C . Vsázka se po ochlazení na xeploxu mísxnosxi zředí vodou a odsaje se. Filxrační koláč se promyje vodou a exhylalkoholem a vysuší se. Získá se xakxo kyselina 3-(6-nixro-2,3-dioxo-l,2,3,4-xexrahydrochinoxalin-l-yl-mexhyl)-benzoová s xeploxou xání > 330 °C .211 mg (0.6 mM) of 3- (6-nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid mexyl ester were added to 4 ml of 4 N hydrochloric acid 4 ml of xrifluoroacetic acid are added and the reaction mixture is stirred for 3.5 hours at a bath temperature of 110 ° C. The batch is diluted with water and sucked off after cooling on the xeplox bowl. The filter cake was washed with water and ethyl alcohol and dried. 3- (6-Nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox m.p. > 330 ° C is obtained.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Kyselina 3-(7-nixro-2,3-dioxo-l,2,3,4-xeXrahydrochinoxalin-l-yl-mexhyl)-benzoová s xeploxou xání > 330 °C , kyselina 3-[4-(3-karboxybenzyl)-6-nixro-2,3-dioxo-l,2,3,4-xexrahydrochinoxalin-l-yl-mexhyl)-benzoová s xeploxou xání 298 až 300 °C , kyselina 2-(6-nixro-2,3-dioxo-l,2,3,4-xexrahydrochinoxalin-l-yl-mexhyl)-benzoová s xeploxou xání 329 až 334 °C (rozklad) , kyselina 2-(7-nixro-2,3-dioxo-l,2,3,4-xexrahydrochinoxalin-l-yl-mexhyl)-benzoová s xeploxou xání 328 až 330 °C , kyselina 2-[4-(2-karboxybenzyl)-6-nixro-2,3-dioxo-l,2,3,4353- (7-Nixro-2,3-dioxo-1,2,3,4-oxo-hydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox at> 330 ° C, 3- [4- (3-carboxybenzyl) 6-Nixro-2,3-dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox at 298-300 ° C, 2- (6-nixro-2,3) acid -dioxo-1,2,3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox m.p. 329-334 ° C (dec.), 2- (7-nixro-2,3-dioxo-1,2,2-oxoic acid) 3,4-xexrahydroquinoxalin-1-yl-methyl) -benzoic acid with xeplox melting at 328 DEG-330 DEG C., 2- [4- (2-carboxybenzyl) -6-nixro-2,3-dioxo-1,2, 3,435
-tetrahydrochinoxalin-l-yl-methyl)-benzoová s teplotou tání > 300 °C , kyselina 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl-methyl)-benzoová s teplotou tání > 310 °C , kyselina 4-(7-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl-methyl)-benzoová s teplotou tání 320 až 324 °C , kyselina 4-[4-(4-karboxymethylbenzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl-methyl)-benzoová s teplotou tání > 310 °C , kyselina 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-benzoová s teplotou tání > 345 °C , kyselina 3- (6-nitro-2,3-dioxo-l, 2,3,4-tetrahydroch.inoxalin-l-yl)-benzoová s teplotou tání > 250 °C ,-tetrahydroquinoxalin-1-yl-methyl) -benzoic acid, m.p. > 300 ° C, 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl) - benzoic acid, m.p. > 310 DEG C., 4- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) benzoic acid, m.p. 320 DEG-324 DEG C., 4- [4- (4-carboxymethylbenzyl) -6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -benzoic acid, m.p.> 310 ° C, acid 4 - (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid, m.p. > 345 DEG C., 3- (6-nitro-2,3-dioxo-) 1,2,3,4-tetrahydroquinoxalin-1-yl) -benzoic acid, m.p.> 250 ° C,
1-(3-karboxy-2-propenyl)-6-nitrochinoxalin-2,3-(1H,4H)-dion s teplotou tání 242 až 243 °C ,1- (3-carboxy-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 242-243 ° C;
1,4-bis-(3-karboxy-2-propenyl)-6-nitrochinoxalin-2,3-(1H,4H) -dion s teplotou tání 241 až 247 °C ,1,4-bis- (3-carboxy-2-propenyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 241-247 ° C,
1-(3-karboxypropyl)-6-nitrochinoxalin-2,3-(1H,4H)-dion s teplotou tání 230 až 232 °C- ,1- (3-carboxypropyl) -6-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 230-232 ° C,
1-(3-karboxypropyl)-7-nitrochinoxalin-2,3-(1H,4H)-dion s teplotou tání 325 až 327 °C (rozklad) , kyselina 1-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-octová s teplotou tání 320 °C .1- (3-carboxypropyl) -7-nitroquinoxaline-2,3- (1H, 4H) -dione, m.p. 325-327 ° C (dec.), 1- (6-trifluoromethyl-2,3-dioxo-1) acid (2,3,4-tetrahydroquinoxalin-1-yl) -acetic acid, m.p. 320 ° C.
Příklad 6Example 6
Kyselina 4-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl-methyl)-fenylfosfonová4- (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid
582 mg (1,4 mM) ethylesteru kyseliny 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl-methyl) -fenylf osfonové se vaří pod zpětným chladičem po dobu 2 hodin se 6 ml koncentrované kyseliny chlorovodíkové. Po ochlazení se vsázka snísí s vodou a odsaje se. Filtrační koláč se potom vysuší a získá se 53 mg kyseliny 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-1-yl-methyl) -fenylf osf onové s teplotou tání 253 až 265 °C (rozklad) .582 mg (1.4 mM) of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid ethyl ester was heated at reflux for 2 hours. 6 hours with concentrated hydrochloric acid. After cooling, the batch is reduced with water and aspirated. The filter cake was then dried to give 53 mg of 4- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. 253-265. ° C (dec.).
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
kyselina 4- (7-nitro-2,3-dioxo-l, 2,3,4-tetrahydrochinoxalin-1-yl-methyl)-fenylfosfonová s teplotou tání > 250 °C , kyselina 3-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-fenylf osf onová s teplotou tání 304 až 307 °C (rozklad) , kyselina 3-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -1-propin-l-f osfonová , kyselina 3-(6-trifluormethyl-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-1-propen-l-fosfonová .4- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) -phenylphosphonic acid, m.p. > 250 DEG C., 3- (6-nitro-2, 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -phenylphosphonic acid, m.p. 304-307 ° C (dec.), 3- (6-trifluoromethyl-2,3-dioxo-1), 2,3,4-tetrahydroquinoxalin-1-yl) -1-propyne-1-phosphonic acid, 3- (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -1 -propene-1-phosphonic acid.
Příklad 7Example 7
Monoethylester a diethylester kyseliny (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonové(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid monoethyl ester and diethyl ester
Ke 300 mg kyseliny (6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -methanfosfonové v 5 ml absolutního dimethylformamidu se při teplotě -15 °C přikape 0,29 ml thionylchloridu. Po ukončení přídavku se reakční směs máchá po dobu 20 minut při teplotě lázně 4 °C , načež se přidá 0,35 ml (276 mg) ethylalkoholu a míchá se 1,5 hodiny při teplotě místnosti. Po zahuštění ve vakuu se získaný zbytek chromatografuje na silikagelu za použití směsi toluen/ledová kyselina octová/voda = 10 : 10 : 1 . Získá se nejprve diethylester kyseliny (6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -methanf osf onové s teplotou tání 220 až 260 °C a potom monoethylester kyseliny (6-nitro-2,3-dioxo-l , 2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonové s teplotou tání 197 °C , přičemž diethylester se získá v množství 100 mg a monoethylester v množství 36 mg .To 300 mg of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid in 5 ml of absolute dimethylformamide was added dropwise 0.29 ml of thionyl chloride at -15 ° C. After the addition was complete, the reaction mixture was stirred for 20 minutes at a bath temperature of 4 ° C, after which 0.35 ml (276 mg) of ethanol was added and stirred at room temperature for 1.5 hours. After concentration in vacuo, the residue is chromatographed on silica gel using toluene / glacial acetic acid / water = 10: 10: 1. First, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid diethyl ester of melting point 220 DEG-260 DEG C. is obtained, followed by (6-nitro) monoethyl ester. -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid, m.p. 197 [deg.] C, 100 mg of diethyl ester and 36 mg of monoethyl ester.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Μοηο-Ν,Ν-dimethylamid kyseliny (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonové , bis-N,N-dimethylamid kyseliny (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonové .(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid Μοηο-Ν, Ν-dimethylamide, (6-nitro-2-acid, bis-N, N-dimethylamide) 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid.
PříkladeExample
Kyselina 1-(6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -methanfosfonová1- (6-Amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid
300 mg kyseliny 1-(6-nitro-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -methanf osf onové se rozpustí v 60 ml methylalkoholu a pod dusíkovou atmosférou se postupně přidá 50 mg Pd/C (10%) , 300 mg amoniumformiátu a 18 ml vody a reakční směs se zahřívá po dobu jedné hodiny na teplotu 80 °C . Po ochlazení se katalysátor odfiltruje, filtrát se odpaří a získaný zbytek se mrazově vysuší. Získá se takto 200 mg kyseliny 1-(6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanfosfonové ve formě bílé pevné látky.300 mg of 1- (6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid were dissolved in 60 ml of methanol and 50 mg of Pd were gradually added under a nitrogen atmosphere. / C (10%), 300 mg of ammonium formate and 18 ml of water, and the reaction mixture was heated at 80 ° C for one hour. After cooling, the catalyst is filtered off, the filtrate is evaporated and the residue is freeze-dried. 200 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphonic acid are obtained in the form of a white solid.
Analogickým způsobem se vyrobí ;It is produced in an analogous manner;
Kyselina 1-(6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-ethanfosfonová .1- (6-Amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid.
Příklad 9Example 9
Kyselina 1-[6-(4-karbethoxy-imidazol-l-yl)-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl]-methanfosfonová1- [6- (4-Carbethoxy-imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid
200 mg 1,4-bis-dimethylamino-3-karbethoxy-2-azabutadienu-1,4 se za stálého chlazení smísí se 3 ml ledové kyseliny octové a reakční směs se míchá po dobu 10 minut při teplotě místnosti. Potom se ke vsázce přidá 180 mg kyseliny 1-(6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonové, rozpuštěných ve 3 ml ledové kyseliny octové a směs se míchá přes noc při teplotě místnosti. Potom se zahřívá po dobu 4 hodin při teplotě lázně 100 °C . Po zahuštění se získá 50 mg kyseliny 1-[6-(4-karbethoxy-iraidazol-l-yl)-2,3-dioxo- -1,2,3,4-tetrahydrochinoxalin-l-yl]-methanfosfonové ve formě olejovité kapaliny.200 mg of 1,4-bis-dimethylamino-3-carbethoxy-2-azabutadiene-1,4 are mixed with 3 ml of glacial acetic acid while cooling and the reaction mixture is stirred for 10 minutes at room temperature. 180 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid dissolved in 3 ml of glacial acetic acid are added to the batch and the mixture is stirred over night at room temperature. It is then heated for 4 hours at a bath temperature of 100 ° C. After concentration, 50 mg of 1- [6- (4-carbethoxy-iraidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid is obtained in the form of an oily substance. liquid.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Kyselina 1-[6-(4-kyano-5-methyl-imidazol-l-yl)-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-l-yl]-methanfosfonová .1- [6- (4-Cyano-5-methyl-imidazol-1-yl) -2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid.
Příklad 10Example 10
Kyselina 1-[6-j od-2, 3-dioxo-1,2,3,4-tetrahydrochinoxalin-1-yl]-methanfosfonová1- [6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid
180 mg kyseliny 1-(6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl) -methanf osf onové se nakape do 10 ml 25% kyseliny sírové. Po pětiminutovém míchání se vytvoří suspense soli, která se chladí na teplotu 0 °C a přikape se k ní roztok 60 mg dusitanu sodného ve 2 ml vody. Po patnáctiminutovém míchání při teplotě 0 °C je reakční směs prakticky rozpuštěná a přikape se k ní roztok 180 mg jodidu draselného ve 2 ml vody. Ledová lázeň se odstraní a vsázka se zahřívá po dobu 2 hodin na teplotu 100 °C . Ochlazená reakční směs se potom zneutralisuje koncentrovaným roztokem amoniaku a odpaří se do sucha. Získaný zbytek se provaří s ethylalkoholem a malým množstvím vody, přefiltruje se a filtrát se zahustí. Po chromatografií na silanisovaném silikagelu za použití směsi voda/methylalkohol =4:1 se získá 40 mg kyseliny 1-[6-jod-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl] -methanf osf onové s teplotou tání 295 až 297 °C .180 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid were added dropwise to 10 ml of 25% sulfuric acid. After stirring for 5 minutes, a salt suspension is formed which is cooled to 0 DEG C. and a solution of 60 mg of sodium nitrite in 2 ml of water is added dropwise. After stirring at 0 ° C for 15 minutes, the reaction mixture is practically dissolved and a solution of 180 mg of potassium iodide in 2 ml of water is added dropwise. Remove the ice bath and heat the batch to 100 ° C for 2 hours. The cooled reaction mixture was then neutralized with concentrated ammonia solution and evaporated to dryness. The residue is boiled with ethanol and a small amount of water, filtered and the filtrate is concentrated. Chromatography on silanised silica gel with water / methanol = 4: 1 gives 40 mg of 1- [6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid. m.p. 295 DEG-297 DEG.
Analogickým, popřípadě z literatury známým způsobem se vyrobí :The following are produced in an analogous or literature-known manner:
Kyselina 1- [6-j od-2,3-dioxo-l ,'2,3,4-tetrahydrochinoxalin-1-yl]-ethan-1-fosfonová , kyselina 1-[6-brom-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl]-ethan-l-fosfonová , kyselina 1-[6-brom-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin401- [6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -ethan-1-phosphonic acid, 1- [6-bromo-2,3-dioxoic acid -1,2,3,4-tetrahydroquinoxalin-1-yl] -ethan-1-phosphonic acid 1- [6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-40
-l-yl]-methanfosfonová , kyselina 1- [6-kyano-2,3-dioxo-l, 2,3,4-tetrahydrochinoxalin-1-yl]-methanfosfonová .1- [1-yl] -methanephosphonic acid, 1- [6-cyano-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl] -methanephosphonic acid.
Příklad 11Example 11
Kyselina 6-jod-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl-methanfos fonová6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methanephosphonic acid
100 mg kyseliny 6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl-methanfosfonové se rozpustí v koncentrované kyselině chlorovodíkové, načež se odpaří do sucha.100 mg of 6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethanephosphonic acid was dissolved in concentrated hydrochloric acid and evaporated to dryness.
Získaný hydrochlorid se dobře usuší, předloží se do 10 ml d imethy 1 formám i du a postupně se smísí se 4 ml methy len jodidu a 0,6 ml isoamylonitrilu. Po dvou hodinách na lázni o teplotě 80 °C se vše převede do roztoku. Směs se ve vakuu na kuličkové koloně odpaří a získaný zbytek se chromatografuje na silanisovaném silikagelu 60 (reversní fáze) za použití směsi voda/methylalkohol =4:1 jako pohyblivé fáze. Získá se takto 20 mg kyseliny 6-jod-2,3-dioxo-l ,2,3,4-tetrahydrochinoxalin-l-yl-methanfosfonové s teplotou tání 295 až 297 °C .The hydrochloride obtained is dried well, taken up in 10 ml of dimethylformamide and treated successively with 4 ml of methylene iodide and 0.6 ml of isoamylonitrile. After two hours in a bath at 80 ° C, everything is dissolved. The mixture was evaporated in a bead column vacuum and the residue was chromatographed on silanised silica gel 60 (reverse phase) using water / methanol = 4: 1 as the mobile phase. 20 mg of 6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methanephosphonic acid of melting point 295 DEG-297 DEG C. is obtained.
Analogickým způsobem se vyrobí :The following are produced in an analogous manner:
Kyselina 6-brom-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl-methanfosfonová , kyselina l-(6-jod-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethanfosfonová , kyselina 1-(6-brom-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-ethanfosfonová .6-Bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methanephosphonic acid 1- (6-iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline) 1-yl) -ethanephosphonic acid, 1- (6-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -ethanephosphonic acid.
Příklad 12Example 12
100 mg kyseliny 1-(6-amino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-l-yl)-methanfosfonové se rozpustí ve 20 ml vody a hodnota pH se pomocí nasyceného roztoku uhličitanu sodného nastaví na 9,5 . K této směsi se přidá 0,2 ml anhydridu kyseliny octové, míchá se po dobu jedné hodiny a zahustí se. Získaný zbytek se rozpustí v pokud možno malém množství vody, nanese se na iontoměnič (IR 120, silně kyselý) a eluuje se vodou. Odpovídající frakce se shromáždí, zahustí a vysuší. Získá se takto 110 mg kyseliny 1-(6-acetylamino-2,3-dioxo-l,2,3,4-tetrahydrochinoxalin-1-yl)-methanf osf onové o teplotě tání 120 °C .100 mg of 1- (6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) -methanephosphonic acid are dissolved in 20 ml of water and the pH is adjusted to 9 with saturated sodium carbonate solution. , 5. To this mixture was added 0.2 mL of acetic anhydride, stirred for one hour, and concentrated. The residue obtained is dissolved in as little water as possible, applied to an ion exchanger (IR 120, strongly acidic) and eluted with water. The appropriate fractions were collected, concentrated and dried. 110 mg of 1- (6-acetylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanesulfonic acid, m.p. 120 DEG C., are obtained.
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SK72793A3 (en) | 1993-10-06 |
NZ244896A (en) | 1995-07-26 |
AU2889492A (en) | 1993-05-21 |
JP3258008B2 (en) | 2002-02-18 |
KR100262371B1 (en) | 2000-08-01 |
FI932959A (en) | 1993-06-24 |
RU2117663C1 (en) | 1998-08-20 |
IL103538A (en) | 2001-07-24 |
NO932344D0 (en) | 1993-06-25 |
CN1038840C (en) | 1998-06-24 |
EP0565683A1 (en) | 1993-10-20 |
JPH06503583A (en) | 1994-04-21 |
CA2099270A1 (en) | 1993-04-27 |
PT101004B (en) | 1999-10-29 |
AU664212B2 (en) | 1995-11-09 |
CZ286351B6 (en) | 2000-03-15 |
SK281518B6 (en) | 2001-04-09 |
HUT64756A (en) | 1994-02-28 |
IL103538A0 (en) | 1993-03-15 |
FI932959A0 (en) | 1993-06-24 |
NO932344L (en) | 1993-06-25 |
HU9301877D0 (en) | 1993-09-28 |
CN1072929A (en) | 1993-06-09 |
WO1993008173A1 (en) | 1993-04-29 |
KR930703271A (en) | 1993-11-29 |
PL171125B1 (en) | 1997-03-28 |
PT101004A (en) | 1994-01-31 |
PL299929A1 (en) | 1994-04-05 |
NO304693B1 (en) | 1999-02-01 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
IF00 | In force as of 2000-06-30 in czech republic | ||
MM4A | Patent lapsed due to non-payment of fee |
Effective date: 20021025 |